8-Prenylkaempferol Suppresses Influenza A Virus-Induced RANTES Production in A549 Cells via Blocking PI3K-Mediated Transcriptional Activation of NF-κB and IRF3

PubMed Central

Chiou, Wen-Fei; Chen, Chen-Chih; Wei, Bai-Luh

2011-01-01

8-Prenylkaempferol (8-PK) is a prenylflavonoid isolated from Sophora flavescens, a Chinese herb with antiviral and anti-inflammatory properties. In this study, we investigated its effect on regulated activation, normal T cell expressed and secreted (RANTES) secretion by influenza A virus (H1N1)-infected A549 alveolar epithelial cells. Cell inoculation with H1N1 evoked a significant induction in RANTES accumulation accompanied with time-related increase in nuclear translocation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF-3), but showed no effect on c-Jun phosphorylation. 8-PK could significantly inhibit not only RANTES production but also NF-κB and IRF-3 nuclear translocation. We had proved that both NF-κB and IRF-3 participated in H1N1-induced RANTES production since NF-κB inhibitor pyrrolidinedithio carbamate (PDTC) and IRF-3 siRNA attenuated significantly RANTES accumulation. H1N1 inoculation also increased PI3K activity as well as Akt phosphorylation and such responsiveness were attenuated by 8-PK. In the presence of wortmannin, nuclear translocation of NF-κB and IRF3 as well as RANTES production by H1N1 infection were all reversed, demonstrating that PI3K-Akt pathway is essential for NF-κB- and IRF-3-mediated RANTES production in A549 cells. Furthermore, 8-PK but not wortmannin, prevented effectively H1N1-evoked IκB degradation. In conclusion, 8-PK might be an anti-inflammatory agent for suppressing influenza A virus-induced RANTES production acts by blocking PI3K-mediated transcriptional activation of NF-κB and IRF-3 and in part by interfering with IκB degradation which subsequently decreases NF-κB translocation. PMID:19592477

NF-κB and androgen receptor variant expression correlate with human BPH progression.

PubMed

Austin, David C; Strand, Douglas W; Love, Harold L; Franco, Omar E; Jang, Alex; Grabowska, Magdalena M; Miller, Nicole L; Hameed, Omar; Clark, Peter E; Fowke, Jay H; Matusik, Robert J; Jin, Ren J; Hayward, Simon W

2016-04-01

Benign prostatic hyperplasia (BPH) is a common, chronic progressive disease. Inflammation is associated with prostatic enlargement and resistance to 5α-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-κB) pathway is linked to both inflammation and ligand-independent prostate cancer progression. NF-κB activation and androgen receptor variant (AR-V) expression were quantified in transition zone tissue samples from patients with a wide range of AUASS from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. To further investigate these pathways, human prostatic stromal and epithelial cell lines were transduced with constitutively active or kinase dead forms of IKK2 to regulate canonical NF-κB activity. The effects on AR full length (AR-FL) and androgen-independent AR-V expression as well as cellular growth and differentiation were assessed. Canonical NF-κB signaling was found to be upregulated in late versus early stage BPH, and to be strongly associated with non-insulin dependent diabetes mellitus. Elevated expression of AR-variant 7 (AR-V7), but not other AR variants, was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS and TRUS volume. Forced activation of canonical NF-κB in human prostatic epithelial and stromal cells resulted in elevated expression of both AR-FL and AR-V7, with concomitant ligand-independent activation of AR reporters. Activation of NF-κB and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment. Activation of NF-κB and AR-V7 in the prostate is associated with increased disease severity. AR-V7 expression is inducible in human prostate cells by forced activation of NF-κB resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy. © 2015 Wiley Periodicals, Inc.

A bi-stable nanoelectromechanical non-volatile memory based on van der Waals force

NASA Astrophysics Data System (ADS)

Soon, Bo Woon; Jiaqiang Ng, Eldwin; Qian, You; Singh, Navab; Julius Tsai, Minglin; Lee, Chengkuo

2013-07-01

By using complementary-metal-oxide-semiconductor processes, a silicon based bi-stable nanoelectromechanical non-volatile memory is fabricated and characterized. The main feature of this device is an 80 nm wide and 3 μm high silicon nanofin (SiNF) of a high aspect ratio (1:35). The switching mechanism is realized by electrostatic actuation between two lateral electrodes, i.e., terminals. Bi-stable hysteresis behavior is demonstrated when the SiNF maintains its contact to one of the two terminals by leveraging on van der Waals force even after voltage bias is turned off. The compelling results indicate that this design is promising for realization of high density non-volatile memory application due to its nano-scale footprint and zero on-hold power consumption.

Development, Integration, and Testing of a Nano-Satellite Coupling Mechanism Using Shape Memory Alloy for an Interference Joint

DTIC Science & Technology

2012-12-01

a case hardened steel bushing with interference of 0.127 mm (0.005 in), 2,600 N (590 lbs) of static holding force in the axial direction is...radial force, along with the materials’ coefficient of friction, produces the axial and torsional holding strength. The pressure between the two parts...2 4 dT pL  (1.7) nF = Normal force (relative to the press-fit surface) nF p dL (1.8) F= Frictional axial “holding” force of the

STAT3/NF-κB-Regulated Lentiviral TK/GCV Suicide Gene Therapy for Cisplatin-Resistant Triple-Negative Breast Cancer

PubMed Central

Kuo, Wei-Ying; Hwu, Luen; Wu, Chun-Yi; Lee, Jhih-Shian; Chang, Chi-Wei; Liu, Ren-Shyan

2017-01-01

Triple-negative breast cancer (TNBC) represents approximately 20% of all breast cancers and appears resistance to conventional cytotoxic chemotherapy, demonstrating a particularly poor prognosis and a significantly worse clinical outcome than other types of cancer. Suicide gene therapy has been used for the in vivo treatment of various solid tumors in recent clinical trials. In tumor microenvironment, STAT3/NF-κB pathways are constitutively activated in stromal cells as well as in cancer stem cells (CSCs). In this study, we have cloned a novel STAT3/NF-κB-based reporter system to drive the expression of herpes simplex virus thymidine kinase (HSV-TK) against breast cancer. Lentiviral vector expressing HSV-TK under the regulation of STAT3/NF-κB fused response element was developed. In this setting, we exploited the constitutive STAT3/NF-κB activation in tumors to achieve higher transgene expression than that driven by a constitutively active CMV promotor in vivo. An orthotropic MDA-MB-231 triple negative breast cancer mouse model was used for evaluating the feasibility of STAT3-NF-κB-TK/GCV suicide gene therapy system. The basal promoter activity of Lenti-CMV-TK and Lenti-STAT3-NF-κB-TK in MDA-MB-231 cells was compared by 3H-FEAU uptake assay. The Lenti-CMV-TK showed ~5 fold higher 3H-FEAU uptake then Lenti -STAT3-NF-κB-TK. In clonogenic assay, cells expressing Lenti-CMV-TK were 2-fold more sensitive to GCV than Lenti-STAT3-NF-κB-TK transduced cells. In vitro effect of STAT3-NF-κB-induced transgene expression was determined by 10ng/mL TNF-α induction and confirmed by western blot analysis and DsRedm fluorescent microscopy. In vivo evaluation of therapeutic effect by bioluminescence and [18F]FHBG microPET imaging indicated that Lenti-STAT3-NF-κB-TK showed more tumor growth retardation than Lenti-CMV-TK when GCV (20 mg/kg) was administered. The invasiveness and expression of cancer stem cell markers were both decreased after STAT3/NF-κB-regulated HSV-TK/GCV therapy. Moreover, STAT3/NF-κB signaling targeting could further sensitize tumor cells to cisplatin. This study successfully established a theranositic approach to treat triple-negative breast cancer via STAT3-NF-κB responsive element-driven suicide gene therapy. This platform may also be an alternative strategy to handle with drug-resistant cancer cells. PMID:28255357

NF-κB-Induced IL-6 Ensures STAT3 Activation and Tumor Aggressiveness in Glioblastoma

PubMed Central

McFarland, Braden C.; Hong, Suk W.; Rajbhandari, Rajani; Twitty, George B.; Gray, G. Kenneth; Yu, Hao; Benveniste, Etty N.; Nozell, Susan E.

2013-01-01

Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance. In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo. We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness. PMID:24244348

NF-κB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma.

PubMed

McFarland, Braden C; Hong, Suk W; Rajbhandari, Rajani; Twitty, George B; Gray, G Kenneth; Yu, Hao; Benveniste, Etty N; Nozell, Susan E

2013-01-01

Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance. In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo. We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness.

Cyanidin-3-O-Glucoside Modulates the In Vitro Inflammatory Crosstalk between Intestinal Epithelial and Endothelial Cells.

PubMed

Ferrari, Daniela; Cimino, Francesco; Fratantonio, Deborah; Molonia, Maria Sofia; Bashllari, Romina; Busà, Rossana; Saija, Antonella; Speciale, Antonio

2017-01-01

Intestinal epithelium represents a protective physical barrier and actively contributes to the mucosal immune system. Polarized basolateral intestinal secretion of inflammatory mediators, followed by activation of NF- κ B signaling and inflammatory pathways in endothelial cells, efficiently triggers extravasation of neutrophils from the vasculature, therefore contributing to the development and maintenance of intestinal inflammation. Proper regulation of NF- κ B activation at the epithelial interface is crucial for the maintenance of physiological tissue homeostasis. Many papers reported that anthocyanins, a group of compounds belonging to flavonoids, possess anti-inflammatory effects and modulate NF- κ B activity. In this study, by using a coculture in vitro system, we aimed to evaluate the effects of TNF- α -stimulated intestinal cells on endothelial cells activation, as well as the protective effects of cyanidin-3-glucoside (C3G). In this model, TNF- α induced nuclear translocation of NF- κ B and TNF- α and IL-8 gene expression in Caco-2 cells, whereas C3G pretreatment dose-dependently reduced these effects. Furthermore, TNF- α -stimulated Caco-2 cells induced endothelial cells activation with increased E-selectin and VCAM-1 mRNA, leukocyte adhesion, and NF- κ B levels in HUVECs, which were inhibited by C3G. We demonstrated that selective inhibition of the NF- κ B pathway in epithelial cells represents the main mechanism by which C3G exerts these protective effects. Thus, anthocyanins could contribute to the management of chronic gut inflammatory diseases.

[Effect of NF-κB on the expression of interleukin-6 induced by lipopolysaccharides of Porphyromonas endodontalis in MC3T3-E1 cells].

PubMed

Yu, Ya-qiong; Guo, Jia-jie; Qiu, Li-hong; Lv, You; Jia, Ge; Guo, Yan

2013-08-01

To investigate the effect of NF-κB signaling on the expression of interleukin-6(IL-6) induced by lipopolysaccharides(LPS) extracted from Porphyromonas endodontalis(P.e) in MC3T3-El cells. MC3T3-E1 cells were pretreated with BAY-117082 for 1 h, and then were treated with 10 mg/L P.e-LPS for different times. The translocation of NF-κB was observed by immunofluorescence. The expression of IL-6 was detected by reverse transcription polymerse chain reaction (RT-PCR) and enzyme-linked immuno sorbent assay (ELISA). Statistical analysis was performed using multi-way ANOVA and Dunnett's t test with SPSS 13.0 software package. The staining of NF-κB was mostly in cytoplasm in untreated cells. Rapid translocation of NF-κB into nucleus was observed in the cells stimulated for 30 min and mostly relocalization of NF-κB from nucleus to cytoplasm was observed after 60 min. Pretreatment with 10 μmol/L BAY-117082 for 1h significantly inhibited P.e-LPS-induced translocation of NF-κB .The mRNA and proteins of IL-6 decreased significantly after pretreatment with 10 μmol/L BAY-117082 and the expression of IL-6 proteins was reduced from (774.983±6.585) ng/L to (377.384±14.620) ng/L (P<0.01). The group of treatment with BAY-117082 alone had no significant difference from the blank control group. P.e-LPS can induce translocation of NF-κB in mouse osteoblast MC3T3-El, and P.e-LPS may induce the expression of IL-6 in mouse osteoblast through the signaling of NF-κB.

Glycogen Synthase Kinase-3β, NF-κB Signaling, and Tumorigenesis of Human Osteosarcoma

PubMed Central

Tang, Qing-Lian; Xie, Xian-Biao; Wang, Jin; Chen, Qiong; Han, An-Jia; Zou, Chang-Ye; Yin, Jun-Qiang; Liu, Da-Wei; Liang, Yi; Zhao, Zhi-Qiang; Yong, Bi-Cheng; Zhang, Ru-Hua; Feng, Qi-Sheng; Deng, Wu-Guo; Zhu, Xiao-Feng; Zhou, Binhua P.; Zeng, Yi-Xin

2012-01-01

Background Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, may function as a tumor suppressor or an oncogene, depending on the tumor type. We sought to determine the biological function of GSK-3β in osteosarcoma, a rare pediatric cancer for which the identification of new therapeutic targets is urgent. Methods We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK-3β expression in U2OS, MG63, SAOS2, U2OS/MTX300, and ZOS osteosarcoma cell lines. Nude mice (n = 5–8 mice per group) were injected with U2OS/MTX300, and ZOS cells to assess the role of GSK-3β in osteosarcoma growth in vivo and to evaluate the effects of inhibitors and/or anticancer drugs on tumor growth. We used an antibody array, polymerase chain reaction, western blotting, and a luciferase reporter assay to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Immunochemistry was performed on primary tumor specimens from osteosarcoma patients (n = 74) to determine the relationship of GSK-3β activity with overall survival. Results Osteosarcoma cells with low levels of inactive p-Ser9-GSK-3β formed colonies in vitro and tumors in vivo more readily than cells with higher levels and cells in which GSK-3β had been silenced formed fewer colonies and smaller tumors than parental cells. Silencing or pharmacological inhibition of GSK-3β resulted in apoptosis of osteosarcoma cells. Inhibition of GSK-3β resulted in inhibition of the NF-κB pathway and reduction of NF-κB-mediated transcription. Combination treatments with GSK-3β inhibitors, NF-κB inhibitors, and chemotherapy drugs increased the effectiveness of chemotherapy drugs in vitro and in vivo. Patients whose osteosarcoma specimens had hyperactive GSK-3β, and nuclear NF-κB had a shorter median overall survival time (49.2 months) compared with patients whose tumors had inactive GSK-3β and NF-κB (109.2 months). Conclusion GSK-3β activity may promote osteosarcoma tumor growth, and therapeutic targeting of the GSK-3β and/or NF-κB pathways may be an effective way to enhance the therapeutic activity of anticancer drugs against osteosarcoma. PMID:22534782

Activating PXR by Imperatorin Attenuates Dextran Sulphate Sodium-Induced Colitis in Mice.

PubMed

Liu, Meijing; Zhang, Guohui; Zheng, Chunge; Song, Meng; Liu, Fangle; Huang, Xiaotao; Bai, Shasha; Huang, Xinan; Lin, Chaozhan; Zhu, Chenchen; Hu, Yingjie; Mi, Suiqing; Liu, Changhui

2018-06-26

The activation of human pregnane X receptor (PXR) has potential therapeutic uses for inflammatory bowel disease (IBD). Imperatorin (IMP), a naturally-occurring coumarin, is the main bioactive ingredient of Angelica dahurica Radix, which is regularly used to treat the common cold and intestinal disorders. However, there are no data on the protective effects of IMP against IBD. The effects of IMP on PXR-modulated cytochrome P450 3A4 (CYP3A4) expression were assessed using a PXR transactivation assay, a mammalian two-hybrid assay, a competitive ligand-binding assay, analysis of CYP3A4 mRNA and protein expression levels, and measurement of CYP3A4 activity using a cell-based reporter gene assay and in vitro model. The inhibitory effects of IMP on NF-κB activity was evaluated by a reporter assay and NF-κB p65 nuclear translocation. The anti-IBD effects of IMP were investigated in a dextran sulphate sodium (DSS)-induced colitis mouse model. Colon inflammatory cytokines were assessed by ELISA. IMP activated CYP3A4 promoter activity, recruited steroid receptor coactivator 1 (SRC-1) to the ligand-binding domain of PXR, and increased the expression and activity of CYP3A4. However, PXR knockdown substantially reduced PXR-mediated CYP3A4 expression. Furthermore, IMP-mediated PXR activation suppressed NF-κB nuclear translocation and downregulated lipopolysaccharide-induced proinflammatory gene expression. Nevertheless, PXR knockdown partially reduced the IMP-mediated inhibition of NF-κB. IMP ameliorated DSS-induced colitis by PXR/NF-κB signalling. IMP serves as a PXR agonist to attenuate DSS-induced colitis by the suppression of the NF-κB-mediated proinflammatory response in a PXR/NF-κB- dependent manner. This article is protected by copyright. All rights reserved.

Synergistic interaction between Astragali Radix and Rehmanniae Radix in a Chinese herbal formula to promote diabetic wound healing.

PubMed

Lau, Kit-Man; Lai, Kwok-Kin; Liu, Cheuk-Lun; Tam, Jacqueline Chor-Wing; To, Ming-Ho; Kwok, Hin-Fai; Lau, Ching-Po; Ko, Chun-Hay; Leung, Ping-Chung; Fung, Kwok-Pui; Poon, Simon Kar-Sing; Lau, Clara Bik-San

2012-05-07

Astragali Radix (AR) and Rehmanniae Radix (RR) are two traditional Chinese medicines widely used in China for treating diabetes mellitus and its complications, such as diabetic foot ulcer. In our previous study, a herbal formula NF3 comprising AR and RR in the ratio of 2:1 was found effective in enhancing diabetic wound healing in rats through the actions of tissue regeneration, angiogenesis promotion and inflammation inhibition. The aims of the present study were to investigate the herb-herb interaction (or the possible synergistic effect) between AR and RR in NF3 to promote diabetic wound healing and to identify the principal herb in the formula by evaluating the potencies of individual AR and RR in different mechanistic studies. A chemically induced diabetic foot ulcer rat model was used to examine the wound healing effect of NF3 and its individual herbs AR and RR. For mechanistic studies, murine macrophage cell (RAW 264.7) inflammation, human fibroblast (Hs27) proliferation and human endothelial cell (HMEC-1) migration assays were adopted to investigate the anti-inflammatory, granulation formation and angiogenesis-promoting activities of the herbal extracts, respectively. In the foot ulcer animal model, neither AR nor RR at clinical relevant dose (0.98g/kg) promoted diabetic wound healing. However, when they were used in combination as NF3, synergistic interaction was demonstrated, of which NF3 could significantly reduce the wound area of rats when compared to water group (p<0.01). For anti-inflammation and granulation formation, AR was more effective than RR in inhibiting lipopolysaccharide (LPS)-induced nitric oxide production from RAW 264.7 cells and promoting Hs27 fibroblast proliferation. In the aspect of angiogenesis promotion, only NF3 promoted cell migration of HMEC-1 cells. AR plays a preeminent role in the anti-inflammatory and fibroblast-proliferating activities of NF3. The inclusion of RR, however, is crucial for NF3 to exert its overall wound-healing as well as the underlying angiogenesis-promoting effects. The results of present study justified the combined usage of AR and RR in the ratio of 2:1 as NF3 to treat diabetic foot ulcer and illustrated that AR is the principal herb in this herbal formula. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

On the force-velocity relationship of a bundle of rigid bio-filaments

NASA Astrophysics Data System (ADS)

Perilli, Alessia; Pierleoni, Carlo; Ciccotti, Giovanni; Ryckaert, Jean-Paul

2018-03-01

In various cellular processes, bio-filaments like F-actin and F-tubulin are able to exploit chemical energy associated with polymerization to perform mechanical work against an obstacle loaded with an external force. The force-velocity relationship quantitatively summarizes the nature of this process. By a stochastic dynamical model, we give, together with the evolution of a staggered bundle of Nf rigid living filaments facing a loaded wall, the corresponding force-velocity relationship. We compute the evolution of the model in the infinite wall diffusion limit and in supercritical conditions (monomer density reduced by critical density ρ^ 1>1 ), and we show that this solution remains valid for moderate non-zero values of the ratio between the wall diffusion and the chemical time scales. We consider two classical protocols: the bundle is opposed either to a constant load or to an optical trap setup, characterized by a harmonic restoring force. The constant load case leads, for each F value, to a stationary velocity Vs t a t(F ;Nf,ρ^ 1 ) after a relaxation with characteristic time τmicro(F). When the bundle (initially taken as an assembly of filament seeds) is subjected to a harmonic restoring force (optical trap load), the bundle elongates and the load increases up to stalling over a characteristic time τOT. Extracted from this single experiment, the force-velocity VO T(F ;Nf,ρ^ 1 ) curve is found to coincide with Vs t a t(F ;Nf,ρ^ 1 ) , except at low loads. We show that this result follows from the adiabatic separation between τmicro and τOT, i.e., τmicro ≪ τOT.

Nickel(II) Complex of Polyhydroxybenzaldehyde N4-Thiosemicarbazone Exhibits Anti-Inflammatory Activity by Inhibiting NF-κB Transactivation

PubMed Central

Loh, Sheng Wei; Looi, Chung Yeng; Hassandarvish, Pouya; Phan, Alicia Yi Ling; Wong, Won Fen; Wang, Hao; Paterson, Ian C.; Ea, Chee Kwee; Mustafa, Mohd Rais; Maah, Mohd Jamil

2014-01-01

Background The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity. Methodology/Principal Findings Four ligands (1–4) and their respective nickel-containing complexes (5–8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis. Conclusions/Significance Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects. PMID:24977407

Direct Force Measurements on Neurofilaments: Gel Expanded to Gel Condensed Transition

NASA Astrophysics Data System (ADS)

Beck, R.; Deek, J.; Jones, J. B.; Safinya, C. R.

2010-03-01

Neurofilaments (NFs)--the major cytoskeletal constituent of axons in vertebrates, consist of three subunit proteins assembled to form filaments with protruding unstructured C-terminus sidearms. Liquid crystal gel networks of sidearm-mediated NF assemblies play a key role in the mechanical while disruptions of this network, due to over-accumulation or incorrect sidearm interactions, are a hallmark of motor neuron diseases. Using synchrotron SAXS [1,2] and microscopy techniques [1,3] we report a direct force measurement of reconstituted NF-gels under osmotic pressure (P), which revealed the role of subunit sidearms on structure and interaction of NFs. With increasing P, near physiological condition, the gels undergo an abrupt nonreversible gel expanded to gel condensed transition that indicates sidearm-mediated attractions between NFs. This attraction is consistent with an electrostatic model of interpenetrating chains.[4pt] [1] J.B. Jones, C.R. Safinya, Biophys. J. 95, 823 (2008);[0pt] [2] R. Beck et al., Nature Mat. (2009) in press;[0pt] [3] H. Hess et al. Langmuir 24, 8397 (2008)

Chronic Fluoxetine Treatment Upregulates the Activity of the ERK1/2-NF-κB Signaling Pathway in the Hippocampus and Prefrontal Cortex of Rats Exposed to Forced-Swimming Stress.

PubMed

Cui, Jingqiu; Yang, Kun; Yu, Xue; Wang, Jing-Lan; Li, Jie; Zhang, Yong; Li, Hengfen

2016-01-01

The aim of this study was to explore whether or not the antidepressant actions of fluoxetine (FLX) are correlated with extracellular signal-regulated kinase 1 and 2 (ERK1/2) and nuclear factor κ-light chain enhancer of activated B cells (NF-κB) in the hippocampus (HC) and prefrontal cortex (PFC) of rats. A total of 108 male Sprague-Dawley rats were randomly divided into 6 groups of 18 rats each. Group 1 was the control group, while group 2 comprised the depressed model in which rats were subjected to 28 days of forced-swimming stress (FST); groups 3-6 were also subjected to 28 days of FST and treated with FLX once a day for 1 day (group 3; F1d), 1 week (group 4; F1w), 2 weeks (group 5; F2w), or 4 weeks (group 6; F4w). The control group was not subjected to FST or treated with FLX. Behavior tests that included the Morris water maze (MWM) and saccharin preference were performed, and ERK1/2 and NF-κB proteins were assayed using Western blot. The rats in the control group and in groups 5 and 6 (F2w and F4w, respectively) had a significantly shorter average escape latency, needed more attempts in order to successfully cross the platform, and had a greater saccharin preference than those in the depressed group (p < 0.05). In the depressed group, the phosphorylated ERK1/2 (p-ERK1/2) and phosphorylated NF-κB (p-NF-κB) expression in the HC and PFC were lower than in the control group (p < 0.05). Treatment with FLX reversed the changes in the expression of p-ERK1/2 and p-NF-κB in rats in the F2w and F4w groups. In this study, FLX treatment for 2 weeks or longer reversed the impaired spatial learning, memory, and anhedonia observed in the depressed model rats and upregulated the activities of the ERK1/2-NF-κB signaling pathway. © 2016 S. Karger AG, Basel.

In vitro study on reversal of ovarian cancer cell resistance to cisplatin by naringin via the nuclear factor-κB signaling pathway.

PubMed

Zhu, Hong; Gao, Jun; Wang, Lei; Qian, Ke-Jian; Cai, Li-Ping

2018-03-01

The aim of the present study was to investigate the mechanism of action by which naringin reverses the resistance of ovarian cancer cells to cisplatin. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting assays were used to detect the effects of different concentrations of naringin on the expressions of nuclear factor (NF)-κB and P-glycoprotein (P-gp) in the SKOV3/CDDP cell line. Small interfering RNA (siRNA) targeting NF-κB was designed and synthesized to silence NF-κB, and recombinant plasmid vectors overexpressing NF-κB were constructed to transfect cells. RT-qPCR and western blotting assays were subsequently performed to detect the effects of NF-κB on the expression of P-gp at the mRNA and protein levels. Naringin was added to the NF-κB-overexpressing SKOV3/CDDP cells and cultured for 48 h, followed by the detection of the expression of P-gp. RT-PCR and western blotting results demonstrated that the gene and protein expressions of NF-κB and P-gp were significantly decreased in a dose-dependent manner by naringin treatment (P<0.05). In cells overexpressing NF-κB, P-gp expression was significantly elevated (P<0.05), and the expression of P-gp was significantly decreased when NF-κB was silenced (P<0.05). Treatment with naringin was able to significantly ameliorate the NF-κB-induced overexpression of P-gp (P<0.05). These results indicate that naringin is able to inhibit the expression of NF-κB and P-gp in SKOV3/CDDP cells. Such an inhibitory effect may increase gradually with concentration, and is associated with blockade of the NF-κB signaling pathway. This pathway may represent one of the mechanisms of action by which Naringin reverses resistance to platinum-based agents in ovarian cancer cells.

Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-κB and STAT3 pathways in head and neck cancer cells.

PubMed

Macha, Muzafar A; Matta, Ajay; Chauhan, S S; Siu, K W Michael; Ralhan, Ranju

2011-03-01

Understanding the molecular pathways perturbed in smokeless tobacco- (ST) associated head and neck squamous cell carcinoma (HNSCC) is critical for identifying novel complementary agents for effective disease management. Activation of nuclear factor-kappaB (NF-κB) and cyclooxygenase-2 (COX-2) was reported in ST-associated HNSCC by us [Sawhney,M. et al. (2007) Expression of NF-kappaB parallels COX-2 expression in oral precancer and cancer: association with smokeless tobacco. Int. J. Cancer, 120, 2545-2556]. In search of novel agents for treatment of HNSCC, we investigated the potential of guggulsterone (GS), (4,17(20)-pregnadiene-3,16-dione), a biosafe nutraceutical, in inhibiting ST- and nicotine-induced activation of NF-κB and signal transducer and activator of transcription (STAT) 3 pathways in HNSCC cells. GS inhibited the activation of NF-κB and STAT3 proteins in head and neck cancer cells. This inhibition of NF-κB by GS resulted from decreased phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha the inhibitory subunit of NF-κB. Importantly, treatment of HNSCC cells with GS abrogated both ST- and nicotine-induced nuclear activation of NF-κB and pSTAT3 proteins and their downstream targets COX-2 and vascular endothelial growth factor. Furthermore, GS treatment decreased the levels of ST- and nicotine-induced secreted interleukin-6 in culture media of HNSCC cells. In conclusion, our findings demonstrated that GS treatment abrogates the effects of ST and nicotine on activation of NF-κB and STAT3 pathways in HNSCC cells that contribute to inflammatory and angiogenic responses as well as its progression and metastasis. These findings provide a biologic rationale for further clinical investigation of GS as an effective complementary agent for inhibiting ST-induced head and neck cancer.

GATA-6 and NF-κB Activate CPI-17 Gene Transcription and Regulate Ca2+ Sensitization of Smooth Muscle Contraction

PubMed Central

Boopathi, Ettickan; Hypolite, Joseph A.; Zderic, Stephen A.; Gomes, Cristiano Mendes; Malkowicz, Bruce; Liou, Hsiou-Chi; Wein, Alan J.

2013-01-01

Protein kinase C (PKC)-potentiated inhibitory protein of 17 kDa (CPI-17) inhibits myosin light chain phosphatase, altering the levels of myosin light chain phosphorylation and Ca2+ sensitivity in smooth muscle. In this study, we characterized the CPI-17 promoter and identified binding sites for GATA-6 and nuclear factor kappa B (NF-κB). GATA-6 and NF-κB upregulated CPI-17 expression in cultured human and mouse bladder smooth muscle (BSM) cells in an additive manner. CPI-17 expression was decreased upon GATA-6 silencing in cultured BSM cells and in BSM from NF-κB knockout (KO) mice. Moreover, force maintenance by BSM strips from KO mice was decreased compared with the force maintenance of BSM strips from wild-type mice. GATA-6 and NF-κB overexpression was associated with CPI-17 overexpression in BSM from men with benign prostatic hyperplasia (BPH)-induced bladder hypertrophy and in a mouse model of bladder outlet obstruction. Thus, aberrant expression of NF-κB and GATA-6 deregulates CPI-17 expression and the contractile function of smooth muscle. Our data provide insight into how GATA-6 and NF-κB mediate CPI-17 transcription, PKC-mediated signaling, and BSM remodeling associated with lower urinary tract symptoms in patients with BPH. PMID:23275439

Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice.

PubMed

Markham, Bruce E; Kernodle, Stace; Nemzek, Jean; Wilkinson, John E; Sigler, Robert

2015-01-01

Poloxamer 188 NF (national formulary (NF) grade of P-188) improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P-188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin-/- (dko) muscular dystrophy models. In the first study 7-month old mdx mice were treated for 22 weeks with subcutaneous (s.c.) injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg) for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg) significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone's effects were similar to those seen with P-188 NF. Diaphragms from P-188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P-188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients.

Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice

PubMed Central

Markham, Bruce E.; Kernodle, Stace; Nemzek, Jean; Wilkinson, John E.; Sigler, Robert

2015-01-01

Poloxamer 188 NF (national formulary (NF) grade of P-188) improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P-188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin-/- (dko) muscular dystrophy models. In the first study 7-month old mdx mice were treated for 22 weeks with subcutaneous (s.c.) injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg) for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg) significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone’s effects were similar to those seen with P-188 NF. Diaphragms from P-188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P-188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients. PMID:26248188

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

PubMed Central

Liu, Ruozhou Tom; Wang, Aikun; To, Eleanor; Gao, Jiangyuan; Cao, Sijia; Cui, Jing Z.; Matsubara, Joanne A.

2015-01-01

Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κB. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Aβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use. PMID:25041941

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells.

PubMed

Liu, Ruozhou Tom; Wang, Aikun; To, Eleanor; Gao, Jiangyuan; Cao, Sijia; Cui, Jing Z; Matsubara, Joanne A

2014-10-01

Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κΒ. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Αβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use. Copyright © 2014 Elsevier Ltd. All rights reserved.

Resveratrol Modulates Interleukin-1β-induced Phosphatidylinositol 3-Kinase and Nuclear Factor κB Signaling Pathways in Human Tenocytes

PubMed Central

Busch, Franziska; Mobasheri, Ali; Shayan, Parviz; Lueders, Cora; Stahlmann, Ralf; Shakibaei, Mehdi

2012-01-01

Resveratrol, an activator of histone deacetylase Sirt-1, has been proposed to have beneficial health effects due to its antioxidant and anti-inflammatory properties. However, the mechanisms underlying the anti-inflammatory effects of resveratrol and the intracellular signaling pathways involved are poorly understood. An in vitro model of human tenocytes was used to examine the mechanism of resveratrol action on IL-1β-mediated inflammatory signaling. Resveratrol suppressed IL-1β-induced activation of NF-κB and PI3K in a dose- and time-dependent manner. Treatment with resveratrol enhanced the production of matrix components collagen types I and III, tenomodulin, and tenogenic transcription factor scleraxis, whereas it inhibited gene products involved in inflammation and apoptosis. IL-1β-induced NF-κB and PI3K activation was inhibited by resveratrol or the inhibitors of PI3K (wortmannin), c-Src (PP1), and Akt (SH-5) through inhibition of IκB kinase, IκBα phosphorylation, and inhibition of nuclear translocation of NF-κB, suggesting that PI3K signaling pathway may be one of the signaling pathways inhibited by resveratrol to abrogate NF-κB activation. Inhibition of PI3K by wortmannin attenuated IL-1β-induced Akt and p65 acetylation, suggesting that p65 is a downstream component of PI3K/Akt in these responses. The modulatory effects of resveratrol on IL-1β-induced activation of NF-κB and PI3K were found to be mediated at least in part by the association between Sirt-1 and scleraxis and deacetylation of NF-κB and PI3K. Overall, these results demonstrate that activated Sirt-1 plays an essential role in the anti-inflammatory effects of resveratrol and this may be mediated at least in part through inhibition/deacetylation of PI3K and NF-κB. PMID:22936809

Prolyl Hydroxylase EGLN3 Regulates Skeletal Myoblast Differentiation through an NF-κB-dependent Pathway

PubMed Central

Fu, Jian; Taubman, Mark B.

2010-01-01

The egg-laying abnormal-9 (EGLN) prolyl hydroxylases have been shown to regulate the stability and thereby the activity of the α subunits of hypoxia-inducible factor (HIF) through its ability to catalyze their hydroxylation. We have previously shown that EGLN3 promotes differentiation of C2C12 skeletal myoblasts. However, the mechanism underlying this effect remains to be fully elucidated. Here, we report that exposure of C2C12 cells to dimethyl oxalylglycine (DMOG), desferrioxamine, and hypoxia, all inhibitors of prolyl hydroxylase activity, led to repression of C2C12 myogenic differentiation. Inactivation of HIF by expression of a HIF dominant-negative mutant or deletion of HIF-1α by RNA interference did not affect the inhibitory effect of DMOG, suggesting that the effect of DMOG is HIF-independent. Pharmacologic inactivation of EGLN3 hydroxylase resulted in activation of the canonical NF-κB pathway. The inhibitory effect of DMOG on myogenic differentiation was markedly impaired in C2C12 cells expressing a dominant-negative mutant of IκBα. Exogenous expression of wild-type EGLN3, but not its catalytically inactive mutant, significantly inhibited NF-κB activation induced by overexpressed TRAF2 or IκB kinase 2. In contrast, deletion of EGLN3 by small interfering RNAs led to activation of NF-κB. These data suggest that EGLN3 is a negative regulator of NF-κB, and its prolyl hydroxylase activity is required for this effect. Furthermore, wild-type EGLN3, but not its catalytically inactive mutant, potentiated myogenic differentiation. This study demonstrates a novel role for EGLN3 in the regulation of NF-κB and suggests that it is involved in mediating myogenic differentiation, which is HIF-independent. PMID:20089853

Neuroprotection by triptolide against cerebral ischemia/reperfusion injury through the inhibition of NF-κB/PUMA signal in rats.

PubMed

Zhang, Bin; Song, Cunfeng; Feng, Bo; Fan, Weibing

2016-01-01

Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent antitumor activity. Recently, triptolide was found to have protective effects against acute cerebral ischemia/reperfusion (I/R) injury through inhibition of cell apoptosis. However, the regulatory mechanism of the effect remains unclear. We hypothesize that the regulatory mechanisms of triptolide are mediated by nuclear factor κB (NF-κB) and p53-upregulated-modulator-of-apoptosis signal inhibition. To verify this hypothesis, we occluded the middle cerebral artery in male rats to establish focal cerebral I/R model. The rats received triptolide or vehicle at the onset of reperfusion following middle cerebral artery occlusion. At 24 hours after reperfusion, neurological deficits, infarct volume, and cell apoptosis were evaluated. The expression levels of NF-κBp65, PUMA, and caspase-3 were determined by Western blot. Real-time polymerase chain reaction was used to determine the levels of NF-κBp65 mRNA, PUMA mRNA, and caspase-3 mRNA. NF-κB activity was determined by electrophoretic mobility shift assay. Apoptotic cells were detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. In I/R group, neurological deficit scores, cerebral infarct volume, expression of NF-κBp65, PUMA, caspase-3, NF-κB activity, and TUNEL-positive cells were found to be increased at 24 hours after I/R injury. The I/R/triptolide rats showed significantly better neurological deficit scores, decreased neural apoptosis, and reduced cerebral infarct volume. In addition, the expression of NF-κBp65, PUMA, caspase-3, and NF-κB activity was suppressed in the I/R/triptolide rats. These results indicate that the neuroprotective effects of triptolide during acute cerebral I/R injury are possibly related to the inhibition of apoptosis through suppression of NF-κB/PUMA signaling pathway.

Functional conservation of rice OsNF-YB/YC and Arabidopsis AtNF-YB/YC proteins in the regulation of flowering time.

PubMed

Hwang, Yoon-Hyung; Kim, Soon-Kap; Lee, Keh Chien; Chung, Young Soo; Lee, Jeong Hwan; Kim, Jeong-Kook

2016-04-01

Rice Os NF - YB and Os NF - YC complement the late flowering phenotype of Arabidopsis nf - yb double and nf - yc triple mutants, respectively. In addition, OsNF-YB and OsNF-YC interact with AtNF-YC and AtNF-YB, respectively. Plant NUCLEAR FACTOR Y (NF-Y) transcription factors play important roles in plant development and abiotic stress. In Arabidopsis thaliana, two NF-YB (AtNF-YB2 and AtNF-YB3) and five NF-YC (AtNF-YC1, AtNF-YC2, AtNF-YC3, AtNF-YC4, and AtNF-YC9) genes regulate photoperiodic flowering by interacting with other AtNF-Y subunit proteins. Three rice NF-YB (OsNF-YB8, OsNF-YB10, and OsNF-YB11) and five rice OsNF-YC (OsNF-YC1, OsNF-YC2, OsNF-YC4, OsNF-YC6, and OsNF-YC7) genes are clustered with two AtNF-YB and five AtNF-YC genes, respectively. To investigate the functional conservation of these NF-YB and NF-YC genes in rice and Arabidopsis, we analyzed the flowering phenotypes of transgenic plants overexpressing the respective OsNF-YB and OsNF-YC genes in Arabidopsis mutants. Overexpression of OsNF-YB8/10/11 and OsNF-YC2 complemented the late flowering phenotype of Arabidopsis nf-yb2 nf-yb3 and nf-yc3 nf-yc4 nf-yc9 mutants, respectively. The rescued phenotype of 35S::OsNF-YC2 nf-yc3 nf-yc4 nf-yc9 plants was attributed to the upregulation of FLOWERING LOCUS T (FT) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1). In vitro and in planta protein-protein analyses revealed that OsNF-YB8/10/11 and OsNF-YC1/2/4/6/7 interact with AtNF-YC3/4/9 and AtNF-YB2/3, respectively. Our data indicate that some OsNF-YB and OsNF-YC genes are functional equivalents of AtNF-YB2/3 and AtNF-YC3/4/9 genes, respectively, and suggest functional conservation of Arabidopsis and rice NF-Y genes in the control of flowering time.

Activation of the NF-κB pathway by the STAT3 inhibitor JSI-124 in human glioblastoma cells

PubMed Central

McFarland, Braden C.; Gray, G. Kenneth; Nozell, Susan E.; Hong, Suk W.; Benveniste, Etty N.

2013-01-01

Glioblastoma tumors are characterized by their invasiveness and resistance to therapies. The transcription factor STAT3 was recently identified as a master transcriptional regulator in the mesenchymal subtype of GBM, which has generated an increased interest in targeting STAT3. We have evaluated more closely the mechanism of action of one particular STAT3 inhibitor, JSI-124 (cucurbitacin I). In this study, we confirmed that JSI-124 inhibits both constitutive and stimulus-induced JAK2 and STAT3 phosphorylation, and decreases cell proliferation while inducing apoptosis in cultured GBM cells. However, we discovered that prior to the inhibition of STAT3, JSI-124 activates the NF-κB pathway, via NF-κB p65 phosphorylation and nuclear translocation. In addition, JSI-124 treatment induces the expression of IL-6, IL-8 and SOCS3 mRNA, which leads to a corresponding increase in IL-6, IL-8 and SOCS3 protein expression. Moreover, the NF-κB driven SOCS3 expression acts as a negative regulator of STAT3, abrogating any subsequent STAT3 activation and provides a mechanism of STAT3 inhibition following JSI-124 treatment. Chromatin immunoprecipitation analysis confirms that NF-κB p65 in addition to other activating co-factors are found at the promoters of IL-6, IL-8 and SOCS3, following JSI-124 treatment. Using pharmacological inhibition of NF-κB and inducible knockdown of NF-κB p65, we found that JSI-124-induced expression of IL-6, IL-8 and SOCS3 was significantly inhibited, demonstrating an NF-κB dependent mechanism. Our data indicate that although JSI-124 may demonstrate potential anti-tumor effects through inhibition of STAT3, other off-target pro-inflammatory pathways are activated, emphasizing that more careful and thorough pre-clinical investigations must be implemented to prevent potential harmful effects. PMID:23386688

Towards Lattice QCD Baryon Forces at the Physical Point: First Results

NASA Astrophysics Data System (ADS)

Doi, Takumi; Aoki, Sinya; Gongyo, Shinya; Hatsuda, Tetsuo; Ikeda, Yoichi; Inoue, Takashi; Iritani, Takumi; Ishii, Noriyoshi; Miyamoto, Takaya; Murano, Keiko; Nemura, Hidekatsu; Sasaki, Kenji

Lattice QCD calculations of baryon forces are performed for the first time with (almost) physical quark masses. Nf = 2 + 1 dynamical clover fermion gauge configurations are generated at the lattice spacing of a ≃ 0.085 fm on a (96a)4 ≃ (8.2 fm)4 lattice with quark masses corresponding to (mπ,mK) ≃ (146,525) MeV. Baryon forces are calculated using the time-dependent HAL QCD method. In this report, we study ΞΞ and NN systems both in 1S0 and 3S1-3D1 channels, and the results for the central and tensor forces as well as phase shifts in the ΞΞ (1S0) channel are presented.

NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)-carbonylimino))-bis(1,3-xylene-alpha,alpha'-diphosphonic acid) tetrasodium salt] is a non-nucleotide P2Y11 agonist and stimulates release of interleukin-8 from human monocyte-derived dendritic cells.

PubMed

Meis, Sabine; Hamacher, Alexandra; Hongwiset, Darunee; Marzian, Claudia; Wiese, Michael; Eckstein, Niels; Royer, Hans-Dieter; Communi, Didier; Boeynaems, Jean-Marie; Hausmann, Ralf; Schmalzing, Günther; Kassack, Matthias U

2010-01-01

The G protein-coupled P2Y(11) receptor is involved in immune system modulation. In-depth physiological evaluation is hampered, however, by a lack of selective and potent ligands. By screening a library of sulfonic and phosphonic acid derivatives at P2Y(11) receptors recombinantly expressed in human 1321N1 astrocytoma cells (calcium and cAMP assays), the selective non-nucleotide P2Y(11) agonist NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)carbonylimino))-bis(1,3-xylene-alpha,alpha'-diphosphonic acid) tetrasodium salt] was identified. NF546 had a pEC(50) of 6.27 and is relatively selective for P2Y(11) over P2Y(1), P2Y(2), P2Y(4), P2Y(6), P2Y(12), P2X(1), P2X(2), and P2X(2)-X(3). Adenosine-5'-O-(3-thio)triphosphate (ATPgammaS), a nonhydrolyzable analog of the physiological P2Y(11) agonist ATP, and NF546 use a common binding site as suggested by molecular modeling studies and their competitive behavior toward the nanomolar potency antagonist NF340 [4,4'-(carbonylbis(imino-3,1-(4-methyl-phenylene)carbonylimino))bis(naphthalene-2,6-disulfonic acid) tetrasodium salt] in Schild analysis. The pA(2) of NF340 was 8.02 against ATPgammaS and 8.04 against NF546 (calcium assays). NF546 was further tested for P2Y(11)-mediated effects in monocyte-derived dendritic cells. Similarly to ATPgammaS, NF546 led to thrombospondin-1 secretion and inhibition of lipopolysaccharide-stimulated interleukin-12 release, whereas NF340 inhibited these effects. Further, for the first time, it was shown that ATPgammaS or NF546 stimulation promotes interleukin 8 (IL-8) release from dendritic cells, which could be inhibited by NF340. In conclusion, we have described the first selective, non-nucleotide agonist NF546 for P2Y(11) receptors in both recombinant and physiological expression systems and could show a P2Y(11)-stimulated IL-8 release, further supporting the immunomodulatory role of P2Y(11) receptors.

Structure-activity relationship studies of chalcone leading to 3-hydroxy-4,3',4',5'-tetramethoxychalcone and its analogues as potent nuclear factor kappaB inhibitors and their anticancer activities.

PubMed

Srinivasan, Balasubramanian; Johnson, Thomas E; Lad, Rahul; Xing, Chengguo

2009-11-26

Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-kappaB) activation. The structures of chalcone-based NF-kappaB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-kappaB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-kappaB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-kappaB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-kappaB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-kappaB inhibitory activities, suggesting that suppressing NF-kappaB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.

RANK-c attenuates aggressive properties of ER-negative breast cancer by inhibiting NF-κB activation and EGFR signaling.

PubMed

Sirinian, Chaido; Papanastasiou, Anastasios D; Schizas, Michail; Spella, Magda; Stathopoulos, Georgios T; Repanti, Maria; Zarkadis, Ioannis K; King, Tari A; Kalofonos, Haralabos P

2018-05-29

The RANK/RANKL axis emerges as a key regulator of breast cancer initiation, progression, and metastasis. RANK-c is a RANK receptor isoform produced through alternative splicing of the TNFRSF11A (RANK) gene and a dominant-negative regulator of RANK-induced nuclear factor-κB (NF-κB) activation. Here we report that RANK-c transcript is expressed in 3.2% of cases in The Cancer Genome Atlas breast cancer cohort evenly between ER-positive and ER-negative cases. Nevertheless, the ratio of RANK to RANK-c (RANK/RANK-c) is increased in ER-negative breast cancer cell lines compared to ER-positive breast cancer cell lines. In addition, forced expression of RANK-c in ER-negative breast cancer cell lines inhibited stimuli-induced NF-κB activation and attenuated migration, invasion, colony formation, and adhesion of cancer cells. Further, RANK-c expression in MDA-MB-231 cells inhibited lung metastasis and colonization in vivo. The RANK-c-mediated inhibition of cancer cell aggressiveness and nuclear factor-κB (NF-κB) activation in breast cancer cells seems to rely on a RANK-c/TNF receptor-associated factor-2 (TRAF2) protein interaction. This was further confirmed by a mutated RANK-c that is unable to interact with TRAF2 and abolishes the ability to attenuate NF-κB activation, migration, and invasion. Additional protein interaction characterization revealed epidermal growth factor receptor (EGFR) as a novel interacting partner for RANK-c in breast cancer cells with a negative effect on EGFR phosphorylation and EGF-dependent downstream signaling pathway activation. Our findings further elucidate the complex molecular biology of the RANKL/RANK system in breast cancer and provide preliminary data for RANK-c as a possible marker for disease progression and aggressiveness.

SIRT1 counteracted the activation of STAT3 and NF-κB to repress the gastric cancer growth.

PubMed

Lu, Juanjuan; Zhang, Liping; Chen, Xiang; Lu, Qiming; Yang, Yuxia; Liu, Jingping; Ma, Xin

2014-01-01

Sirtuin-1 (SIRT1) possesses apparently dual roles in regulation of tumor. Previous reports have documented the crosstalk between SIRT1 with signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-B (NF-κB) signaling in leukemia, lymphoma and myeloma. In this study, the purpose was to survey the regulatory effects of SIRT1 on gastric cancer (GC) cells (AGS and MKN-45) and the relationships between SIRT1 and activation of STAT3 and NF-κB in GC cells. We found the SIRT1 activator (resveratrol RSV) contributed to the repression of viability and increase of senescence, which were rescued by SIRT1 inhibitor (nicotinamide NA) and SIRT1 depletion by CCK-8 assay and SA-β-gal assay respectively. Further study found SIRT1 activation (RSV supplement) not only inhibited the activation of STAT3 including STAT3 mRNA level, c-myc mRNA level phosphorylated STAT3 (pSTAT3) proteins and acetylizad STAT3 (acSTAT3) proteins, but also repression of pNF-κB p65 and acNF-κB p65. NA reversed the effects of RSV. In addition, either RSV or NA application could not change the cellular viability and senescence in MKN-45 cells with STAT3 knockdown or NF-κB knockdown. Overall, our findings suggested SIRT1 activation could induced the loss of viability and increases of senescence in GC in vitro. Moreover, our observations revealed SIRT1 displayed growth inhibitory activity in GC cells highly associated with causing repression of activation of STAT3 and NF-κB proteins via deacetylation.

Encephalomyocarditis Virus 3C Protease Relieves TRAF Family Member-associated NF-κB Activator (TANK) Inhibitory Effect on TRAF6-mediated NF-κB Signaling through Cleavage of TANK*

PubMed Central

Huang, Li; Liu, Qinfang; Zhang, Lijie; Zhang, Quan; Hu, Liang; Li, Changyao; Wang, Shengnan; Li, Jiangnan; Zhang, Yuanfeng; Yu, Huibin; Wang, Yan; Zhong, Zhaohua; Xiong, Tao; Xia, Xueshan; Wang, Xiaojun; Yu, Li; Deng, Guohua; Cai, Xuehui; Cui, Shangjin; Weng, Changjiang

2015-01-01

TRAF family member-associated NF-κB activator (TANK) is a negative regulator of canonical NF-κB signaling in the Toll-like receptor- and B-cell receptor-mediated signaling pathways. However, functions of TANK in viral infection-mediated NF-κB activation remain unclear. Here, we reported that TANK was cleaved by encephalomyocarditis virus 3C at the 197 and 291 glutamine residues, which depends on its cysteine protease activity. In addition, encephalomyocarditis virus 3C impaired the ability of TANK to inhibit TRAF6-mediated NF-κB signaling. Interestingly, we found that several viral proteases encoded by the foot and mouth disease virus, porcine reproductive and respiratory syndrome virus, and equine arteritis virus also cleaved TANK. Our results suggest that TANK is a novel target of some viral proteases, indicating that some positive RNA viruses have evolved to utilize their major proteases to regulate NF-κB activation. PMID:26363073

RANKL release from self-assembling nanofiber hydrogels for inducing osteoclastogenesis in vitro.

PubMed

Xing, James Z; Lu, Lei; Unsworth, Larry D; Major, Paul W; Doschak, Michael R; Kaipatur, Neelambar R

2017-02-01

To develop a nanofiber hydrogel (NF-hydrogel) for sustained and controlled release of the recombinant receptor activator of NF-kB ligand; (RANKL) and to characterize the release kinetics and bioactivity of the released RANKL. Various concentrations of fluorescently-labelled RANKL protein were added to NF-hydrogels, composed of Acetyl-(Arg-Ala-Asp-Ala) 4 -CONH 2 [(RADA) 4 ] of different concentrations, to investigate the resulting in vitro release rates. The nano-structures of NF-hydrogel, with and without RANKL, were determined using atomic force microscopy (AFM). Released RANKL was further analyzed for changes in secondary and tertiary structure using CD spectroscopy and fluorescent emission spectroscopy, respectively. Bioactivity of released RANKL protein was determined using NFATc1 gene expression and tartrate resistant acid phosphatase (TRAP) activity of osteoclast cells as biomarkers. NF-hydrogel concentration dependent sustained release of RANKL protein was measured at concentrations between 0.5 and 2%(w/v). NF-hydrogel at 2%(w/v) concentration exhibited a sustained and slow-release of RANKL protein up to 48h. Secondary and tertiary structure analyses confirmed no changes to the RANKL protein released from NF-hydrogel in comparison to native RANKL. The results of NFATc1 gene mRNA expression and TRAP activities of osteoclast, showed that the release process did not affect the bioactivity of released RANKL. This novel study is the first of its kind to attempt in vitro characterization of NF-hydrogel based delivery of RANKL protein to induce osteoclastogenesis. We have shown the self-assembling NF-hydrogel peptide system is amenable to the sustained and controlled release of RANKL locally; that could in turn increase local concentration of RANKL to induce osteoclastogenesis, for application to the controlled mobilization of tooth movement in orthodontic procedures. Orthodontic tooth movement (OTM) occurs through controlled application of light forces to teeth, facilitating the required changes in the surrounding alveolar bone through the process of bone remodelling. The RANKL system regulates alveolar bone remodelling and controls root resorption during OTM. The use of exogenous RANKL to accelerate OTM has not been attempted to date because large quantities of RANKL for systemic therapy may subsequently cause serious systemic loss of skeletal bone. The controlled and sustained local release of RANKL from a carrier matrix could maximize its therapeutic benefit whilst minimizing systemic side effects. In this study a NF-hydrogel was used for sustained and controlled release of RANKL and the release kinetics and biofunctionality of the released RANKL was characterized. Our results provide fundamental insight for further investigating the role of RANKL NF-hydrogel release systems for inducing osteoclastogenesis in vivo. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Effects of age and sedentary lifestyle on skeletal muscle NF-kappaB signaling in men.

PubMed

Buford, Thomas W; Cooke, Matthew B; Manini, Todd M; Leeuwenburgh, Christiaan; Willoughby, Darryn S

2010-05-01

Nuclear factor kappa B (NF-kappaB) is a critical signaling molecule of disuse-induced skeletal muscle atrophy. However, few studies have carefully investigated whether similar pathways are modulated with physical activity and age. The present study examined lean mass, maximal force production, and skeletal muscle NF-kappaB signaling in 41 men categorized as sedentary (OS, N = 13, 63.85 +/- 6.59 year), physically active (OA, N = 14, 60.71 +/- 5.54 year), or young and sedentary (YS, N = 14, 21.35 +/- 3.84 year). Muscle tissue from the vastus lateralis was assayed for messenger RNA (mRNA) expression of the beta subunit of IkB kinase (IKKbeta), cytosolic protein content of phosphorylated inhibitor of kappa B alpha (pIKBalpha), and nuclear content of NF-kappaB subunits p50 and p65. When compared with YS, OS demonstrated age-related muscle atrophy and reduced isokinetic knee extension torque. Physical activity in older individuals preserved maximal isokinetic knee extension torque. OS muscle contained 50% more pIKBalpha than OA and 61% more pIKBalpha than YS. Furthermore, nuclear p65 was significantly elevated in OS compared with YS. OS muscle did not differ from either of the other two groups for nuclear p50 or for mRNA expression of IKKbeta. These results indicate that skeletal muscle content of nuclear-bound p65 is elevated by age in humans. The elevation in nuclear-bound p65 appears to be at least partially due to significant increases in pIKBalpha. A sedentary lifestyle appears to play some role in increased IKBalpha; however, further research is needed to identify downstream effects of this increase.

Effects of Age and Sedentary Lifestyle on Skeletal Muscle NF-κB Signaling in Men

PubMed Central

Buford, Thomas W.; Cooke, Matthew B.; Manini, Todd M.; Leeuwenburgh, Christiaan

2010-01-01

Background. Nuclear factor kappa B (NF-κB) is a critical signaling molecule of disuse-induced skeletal muscle atrophy. However, few studies have carefully investigated whether similar pathways are modulated with physical activity and age. Methods. The present study examined lean mass, maximal force production, and skeletal muscle NF-κB signaling in 41 men categorized as sedentary (OS, N = 13, 63.85 ± 6.59 year), physically active (OA, N = 14, 60.71 ± 5.54 year), or young and sedentary (YS, N = 14, 21.35 ± 3.84 year). Muscle tissue from the vastus lateralis was assayed for messenger RNA (mRNA) expression of the β subunit of IkB kinase (IKKβ), cytosolic protein content of phosphorylated inhibitor of kappa B alpha (pIKBα), and nuclear content of NF-κB subunits p50 and p65. Results. When compared with YS, OS demonstrated age-related muscle atrophy and reduced isokinetic knee extension torque. Physical activity in older individuals preserved maximal isokinetic knee extension torque. OS muscle contained 50% more pIKBα than OA and 61% more pIKBα than YS. Furthermore, nuclear p65 was significantly elevated in OS compared with YS. OS muscle did not differ from either of the other two groups for nuclear p50 or for mRNA expression of IKKβ. Conclusions. These results indicate that skeletal muscle content of nuclear-bound p65 is elevated by age in humans. The elevation in nuclear-bound p65 appears to be at least partially due to significant increases in pIKBα. A sedentary lifestyle appears to play some role in increased IKBα; however, further research is needed to identify downstream effects of this increase. PMID:20045871

Synergetic Effect of Ultrasound, the Heterogeneous Fenton Reaction and Photocatalysis by TiO2 Loaded on Nickel Foam on the Degradation of Pollutants

PubMed Central

Qiu, Shan; Xu, Shanwen; Li, Guangming; Yang, Jixian

2016-01-01

The synergistic effect of ultrasound, the heterogeneous Fenton reaction and photocatalysis was studied using a nickel foam (NF)-supporting TiO2 system and rhodamine B (RhB) as a target. The NF-supporting TiO2 system was prepared by depositing TiO2 on the skeleton of NF repeatedly and then calcining it. To optimize the conditions and parameters, the catalytic activity was tested in four systems (ultrasound alone (US), nickel foam (NF), US/NF and NF/US/H2O2). The optimal conditions were fixed at 0.1 g/mL NF, initial 5.00 mg/L RhB, 300 W ultrasonic power, pH = 3 and 5.00 mg/L H2O2. The effects of the dissolution of nickel from NF and quenching of the Fenton reaction were studied on degradation efficiency. When the heterogeneous Fenton reaction is combined with TiO2-photocatalysis, the pollutant removal efficiency is enhanced significantly. Through this synergistic effect, 22% and 80% acetochlor was degraded within 10 min and 80 min, respectively. PMID:28773580

Polyamide nanofiltration membranes to remove aniline in aqueous solutions.

PubMed

Hidalgo, A M; León, G; Gómez, M; Murcia, M D; Bernal, M D; Ortega, S

2014-01-01

Aniline is commonly used in a number of industrial processes. It is known to be a harmful and persistent pollutant and its presence in wastewater requires treatment before disposal. In this paper, the effectiveness of nanofiltration (NF) to remove aniline from aqueous solutions is studied in a flat membrane test module using two thin-layer composite membranes of polyamide (NF97 and NF99HF). The influence of different operational variables (applied pressure, feed concentration and pH) on the removal of aniline from synthetic aqueous solutions was analysed. The experimental NF results are compared with results previously obtained by reverse osmosis. Based on this comparative study, the effective order for aniline rejection is: HR98PP > NF97 > DESAL3B > SEPA-MS05 > NF99HF.

18β-Glycyrrhetinic acid suppresses TNF-α induced matrix metalloproteinase-9 and vascular endothelial growth factor by suppressing the Akt-dependent NF-κB pathway.

PubMed

Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Dilshara, Matharage Gayani; Park, Sang Rul; Choi, Yung Hyun; Hyun, Jin-Won; Chang, Weon-Young; Kim, Gi-Young

2014-08-01

Little is known about the molecular mechanism through which 18β-glycyrrhetinic acid (GA) inhibits metastasis and invasion of cancer cells. Therefore, this study aimed to investigate the effects of GA on the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in various types of cancer cells. We found that treatment with GA reduces tumor necrosis factor-α (TNF-α)-induced Matrigel invasion with few cytotoxic effects. Our findings also showed that MMP-9 and VEGF expression increases in response to TNF-α; however, GA reverses their expression. In addition, GA inhibited inhibitory factor kappa B degradation, sustained nuclear factor-kappa B (NF-κB) subunits, p65 and p50, in the cytosol compartments, and consequently suppressed the TNF-α-induced DNA-binding activity and luciferase activity of NF-κB. Specific NF-κB inhibitors, pyrrolidine dithiocarbamate, MG132, and PS-1145, also attenuated TNF-α-mediated MMP-9 and VEGF expression as well as activity by suppressing their regulatory genes. Furthermore, phosphorylation of TNF-α-induced phosphatidyl-inositol 3 kinase (PI3K)/Akt was significantly downregulated in the presence of GA accompanying with the inhibition of NF-κB activity, and as presumed, the specific PI3K/Akt inhibitor LY294002 significantly decreased MMP-9 and VEGF expression as well as activity. These results suggest that GA operates as a potential anti-invasive agent by downregulating MMP-9 and VEGF via inhibition of PI3K/Akt-dependent NF-κB activity. Taken together, GA might be an effective anti-invasive agent by suppressing PI3K/Akt-mediated NF-κB activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Identification of known drugs that act as inhibitors of NF-kappaB signaling and their mechanism of action.

PubMed

Miller, Susanne C; Huang, Ruili; Sakamuru, Srilatha; Shukla, Sunita J; Attene-Ramos, Matias S; Shinn, Paul; Van Leer, Danielle; Leister, William; Austin, Christopher P; Xia, Menghang

2010-05-01

Nuclear factor-kappa B (NF-kappaB) is a transcription factor that plays a critical role across many cellular processes including embryonic and neuronal development, cell proliferation, apoptosis, and immune responses to infection and inflammation. Dysregulation of NF-kappaB signaling is associated with inflammatory diseases and certain cancers. Constitutive activation of NF-kappaB signaling has been found in some types of tumors including breast, colon, prostate, skin and lymphoid, hence therapeutic blockade of NF-kappaB signaling in cancer cells provides an attractive strategy for the development of anticancer drugs. To identify small molecule inhibitors of NF-kappaB signaling, we screened approximately 2800 clinically approved drugs and bioactive compounds from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC) in a NF-kappaB mediated beta-lactamase reporter gene assay. Each compound was tested at fifteen different concentrations in a quantitative high throughput screening format. We identified nineteen drugs that inhibited NF-kappaB signaling, with potencies as low as 20 nM. Many of these drugs, including emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, and lestaurtinib, inhibited NF-kappaB signaling via inhibition of IkappaBalpha phosphorylation. Others, such as ectinascidin 743, chromomycin A3 and bortezomib utilized other mechanisms. Furthermore, many of these drugs induced caspase 3/7 activity and had an inhibitory effect on cervical cancer cell growth. Our results indicate that many currently approved pharmaceuticals have previously unappreciated effects on NF-kappaB signaling, which may contribute to anticancer therapeutic effects. Comprehensive profiling of approved drugs provides insight into their molecular mechanisms, thus providing a basis for drug repurposing. Published by Elsevier Inc.

3D MnO2-graphene composites with large areal capacitance for high-performance asymmetric supercapacitors

NASA Astrophysics Data System (ADS)

Zhai, Teng; Wang, Fuxin; Yu, Minghao; Xie, Shilei; Liang, Chaolun; Li, Cheng; Xiao, Fangming; Tang, Renheng; Wu, Qixiu; Lu, Xihong; Tong, Yexiang

2013-07-01

In this paper, we reported an effective and simple strategy to prepare large areal mass loading of MnO2 on porous graphene gel/Ni foam (denoted as MnO2/G-gel/NF) for supercapacitors (SCs). The MnO2/G-gel/NF (MnO2 mass: 13.6 mg cm-2) delivered a large areal capacitance of 3.18 F cm-2 (234.2 F g-1) and good rate capability. The prominent electrochemical properties of MnO2/G-gel/NF are attributed to the enhanced conductivities and improved accessible area for ions in electrolytes. Moreover, an asymmetric supercapacitor (ASC) based on MnO2/G-gel/NF (MnO2 mass: 6.1 mg cm-2) as the positive electrode and G-gel/NF as the negative electrode achieved a remarkable energy density of 0.72 mW h cm-3. Additionally, the fabricated ASC device also exhibited excellent cycling stability, with less than 1.5% decay after 10 000 cycles. The ability to effectively develop SC electrodes with high mass loading should open up new opportunities for SCs with high areal capacitance and high energy density.In this paper, we reported an effective and simple strategy to prepare large areal mass loading of MnO2 on porous graphene gel/Ni foam (denoted as MnO2/G-gel/NF) for supercapacitors (SCs). The MnO2/G-gel/NF (MnO2 mass: 13.6 mg cm-2) delivered a large areal capacitance of 3.18 F cm-2 (234.2 F g-1) and good rate capability. The prominent electrochemical properties of MnO2/G-gel/NF are attributed to the enhanced conductivities and improved accessible area for ions in electrolytes. Moreover, an asymmetric supercapacitor (ASC) based on MnO2/G-gel/NF (MnO2 mass: 6.1 mg cm-2) as the positive electrode and G-gel/NF as the negative electrode achieved a remarkable energy density of 0.72 mW h cm-3. Additionally, the fabricated ASC device also exhibited excellent cycling stability, with less than 1.5% decay after 10 000 cycles. The ability to effectively develop SC electrodes with high mass loading should open up new opportunities for SCs with high areal capacitance and high energy density. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr01589k

Anti-inflammatory effect of tricin 4′-O-(threo-β-guaiacylglyceryl) ether, a novel flavonolignan compound isolated from Njavara on in RAW264.7 cells and in ear mice edema

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jung, Young-Suk; Kim, Dae Hwan; Hwang, Jae Yeon

Although recent study has shown tricin 4′-O-(threo-β-guaiacylglyceryl) ether (TTGE), an isolated compound from Njavara rice, to have the most potent anti-inflammatory effects, the action mechanism has not been fully understood. Here, we examined the effect of TTGE on the inflammation and elucidated the potential mechanism. We demonstrated that TTGE significantly inhibited LPS-induced NO and ROS generation in RAW264.7 cells, which was correlated with the down-regulating effect of TTGE on the iNOS and COX-2 expression via NF-κB and STAT3. TPA-induced ear edema was also efficiently inhibited by the TTGE treatment. TTGE blocked the induction of iNOS and COX-2 through the regulationmore » of NF-κB and STAT3, which could explain the reduced TPA-induced edema symptoms. Moreover, the introduction of ERK inhibitor abrogated the anti-inflammatory effect of TTGE via the recovery of NF-κB and STAT3 signalings. Taken together, these results suggest that TTGE has anti-inflammatory properties through down-regulation of NF-κB and STAT3 pathways. - Highlights: • TTGE inhibited expression of iNOS and COX-2, NF-kB activity and ear edema through inhibition of ERK pathway.« less

The p65 Subunit of NF-κB Inhibits COL1A1 Gene Transcription in Human Dermal and Scleroderma Fibroblasts through Its Recruitment on Promoter by Protein Interaction with Transcriptional Activators (c-Krox, Sp1, and Sp3)*

PubMed Central

Beauchef, Gallic; Bigot, Nicolas; Kypriotou, Magdalini; Renard, Emmanuelle; Porée, Benoît; Widom, Russell; Dompmartin-Blanchere, Anne; Oddos, Thierry; Maquart, François-Xavier; Demoor, Magali; Boumediene, Karim; Galera, Philippe

2012-01-01

Transcriptional mechanisms regulating type I collagen genes expression in physiopathological situations are not completely known. In this study, we have investigated the role of nuclear factor-κB (NF-κB) transcription factor on type I collagen expression in adult normal human (ANF) and scleroderma (SF) fibroblasts. We demonstrated that NF-κB, a master transcription factor playing a major role in immune response/apoptosis, down-regulates COL1A1 expression by a transcriptional control involving the −112/−61 bp sequence. This 51-bp region mediates the action of two zinc fingers, Sp1 (specific protein-1) and Sp3, acting as trans-activators of type I collagen expression in ANF and SF. Knockdown of each one of these trans factors by siRNA confirmed the trans-activating effect of Sp1/Sp3 and the p65 subunit of NF-κB trans-inhibiting effect on COL1A1 expression. Despite no existing κB consensus sequence in the COL1A1 promoter, we found that Sp1/Sp3/c-Krox and NF-κB bind and/or are recruited on the proximal promoter in chromatin immunoprecipitation (ChIP) assays. Attempts to elucidate whether interactions between Sp1/Sp3/c-Krox and p65 are necessary to mediate the NF-κB inhibitory effect on COL1A1 in ANF and SF were carried out; in this regard, immunoprecipitation assays revealed that they interact, and this was validated by re-ChIP. Finally, the knockdown of Sp1/Sp3/c-Krox prevents the p65 inhibitory effect on COL1A1 transcription in ANF, whereas only the siRNAs targeting Sp3 and c-Krox provoked the same effect in SF, suggesting that particular interactions are characteristic of the scleroderma phenotype. In conclusion, our findings highlight a new mechanism for COL1A1 transcriptional regulation by NF-κB, and these data could allow the development of new antifibrotic strategies. PMID:22139845

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

PubMed Central

Wu, Wen; Luo, Jie; Ye, Peng; Chen, Shao-liang; Hu, Zuo-ying

2016-01-01

Recent studies reported that atorvastatin (ATOR) alleviated progression of experimental diabetic cardiomyopathy (DCM), possibly by protecting against apoptosis. However, the underlying mechanisms of this protective effect remain unclear. Therefore, our study investigated the role of the glycogen synthase kinase (GSK)-3β-protein phosphatase 2A(PP2A)-NF-κB signaling pathway in the anti-apoptotic and cardioprotective effects of ATOR on cardiomyocytes cultured in high glucose (HG) and in DCM. Our results showed that, in HG-cultured cardiomyocytes, phosphorylation of GSK-3β was decreased, while that of the PP2A catalytic subunit C (PP2Ac) and IKK/IкBα was increased, followed by NF-кB nuclear translocation and apoptosis. IKK/IкBα phosphorylation and NF-кB nuclear translocation were also increased by treatment of cells with okadaic acid (OA), a selective PP2A inhibitor, or by silencing PP2Ac expression. The opposite results were obtained by silencing GSK-3β expression, which resulted in PP2Ac activation. Furthermore, IKK/IкBα phosphorylation and NF-кB nuclear translocation were markedly inhibited and apoptosis attenuated in cells treated with ATOR. These effects occurred through inactivation of GSK-3β and subsequent activation of PP2Ac. They were abolished by treatment of cells with OA or PP2Ac siRNA. In mice with type 1 diabetes mellitus, treatment with ATOR, at 10 mg-kg−1-d−1, significantly suppressed GSK-3β activation, IKK/IкBα phosphorylation, NF-кB nuclear translocation and caspase-3 activation, while also activating PP2Ac. Finally, improvements in histological abnormalities, fibrosis, apoptosis and cardiac dysfunction were observed in diabetic mice treated with ATOR. These findings demonstrated that ATOR protected against HG-induced apoptosis in cardiomyocytes and alleviated experimental DCM by regulating the GSK-3β-PP2A-NF-κB signaling pathway. PMID:27851811

Thermal reactions of uranium metal, UO 2, U 3O 8, UF 4, and UO 2F 2 with NF 3 to produce UF 6

NASA Astrophysics Data System (ADS)

McNamara, Bruce; Scheele, Randall; Kozelisky, Anne; Edwards, Matthew

2009-11-01

This paper demonstrates that NF 3 fluorinates uranium metal, UO 2, UF 4, UO 3, U 3O 8, and UO 2F 2·2H 2O to produce the volatile UF 6 at temperatures between 100 and 550 °C. Thermogravimetric and differential thermal analysis reaction profiles are described that reflect changes in the uranium fluorination/oxidation state, physiochemical effects, and instances of discrete chemical speciation. Large differences in the onset temperatures for each system investigated implicate changes in mode of the NF 3 gas-solid surface interaction. These studies also demonstrate that NF 3 is a potential replacement fluorinating agent in the existing nuclear fuel cycle and in actinide volatility reprocessing.

Exploring the mechanical behavior of single intermediate filaments.

PubMed

Kreplak, L; Bär, H; Leterrier, J F; Herrmann, H; Aebi, U

2005-12-02

Intermediate filaments (IFs) are structural elements of eukaryotic cells with distinct mechanical properties. Tissue integrity is severely impaired, in particular in skin and muscle, when IFs are either absent or malfunctioning due to mutations. Our knowledge on the mechanical properties of IFs is mainly based on tensile testing of macroscopic fibers and on the rheology of IF networks. At the single filament level, the only piece of data available is a measure of the persistence length of vimentin IFs. Here, we have employed an atomic force microscopy (AFM) based protocol to directly probe the mechanical properties of single cytoplasmic IFs when adsorbed to a solid support in physiological buffer environment. Three IF types were studied in vitro: recombinant murine desmin, recombinant human keratin K5/K14 and neurofilaments isolated from rat brains, which are composed of the neurofilament triplet proteins NF-L, NF-M and NF-H. Depending on the experimental conditions, the AFM tip was used to laterally displace or to stretch single IFs on the support they had been adsorbed to. Upon applying force, IFs were stretched on average 2.6-fold. The maximum stretching that we encountered was 3.6-fold. A large reduction of the apparent filament diameter was observed concomitantly. The observed mechanical properties therefore suggest that IFs may indeed function as mechanical shock absorbers in vivo.

Effects of Cot expression on the nuclear translocation of NF-kappaB in RBL-2H3 cells.

PubMed

Chikamatsu, Satomi; Furuno, Tadahide; Kinoshita, Yosuke; Inoh, Yoshikazu; Hirashima, Naohide; Teshima, Reiko; Nakanishi, Mamoru

2007-03-01

Cot is a serine/threonine protein kinase and is classified as a mitogen-activated protein (MAP) kinase kinase kinase. Overexpression of this protein has been shown to activate the extracellular signal-regulated kinase, the c-Jun N-terminal kinase, and the p38 MAP kinase pathways and to stimulate NF-AT and NF-kappaB-dependent transcription. Here we have shown that Cot kinase activity is intimately involved in the high affinity receptor for IgE (FcvarepsilonRI)-mediated nuclear translocation of NF-kappaB1 independent of NF-kappaB-inducing kinase (NIK) in rat basophilic leukemia (RBL-2H3) cells. A transfected green fluorescent protein-tagged NF-kappaB1 (GFP-NF-kappaB1) resided in the cytoplasm in RBL-2H3 cells and it remained in the cytoplasm even when Cot tagged with red fluorescent protein (Cot-RFP) was co-expressed. Western blotting analysis showed that IkappaB kinases (IKKs) were expressed in RBL-2H3 cells but NIK was not. GFP-NF-kappaB1 translocated from the cytoplasm to the nucleus after the aggregation of FcvarepsilonRI in Cot-transfected cells but not in kinase-deficient Cot-transfected cells. This finding gives a new insight into the role of Cot in the FcvarepsilonRI-mediated NF-kappaB activation in mast cells.

Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia-like Bone Phenotype.

PubMed

Kamiya, Nobuhiro; Yamaguchi, Ryosuke; Aruwajoye, Olumide; Kim, Audrey J; Kuroyanagi, Gen; Phipps, Matthew; Adapala, Naga Suresh; Feng, Jian Q; Kim, Harry Kw

2017-08-01

Neurofibromatosis type 1 (NF1, OMIM 162200), caused by NF1 gene mutations, exhibits multi-system abnormalities, including skeletal deformities in humans. Osteocytes play critical roles in controlling bone modeling and remodeling. However, the role of neurofibromin, the protein product of the NF1 gene, in osteocytes is largely unknown. This study investigated the role of neurofibromin in osteocytes by disrupting Nf1 under the Dmp1-promoter. The conditional knockout (Nf1 cKO) mice displayed serum profile of a metabolic bone disorder with an osteomalacia-like bone phenotype. Serum FGF23 levels were 4 times increased in cKO mice compared with age-matched controls. In addition, calcium-phosphorus metabolism was significantly altered (calcium reduced; phosphorus reduced; parathyroid hormone [PTH] increased; 1,25(OH) 2 D decreased). Bone histomorphometry showed dramatically increased osteoid parameters, including osteoid volume, surface, and thickness. Dynamic bone histomorphometry revealed reduced bone formation rate and mineral apposition rate in the cKO mice. TRAP staining showed a reduced osteoclast number. Micro-CT demonstrated thinner and porous cortical bones in the cKO mice, in which osteocyte dendrites were disorganized as assessed by electron microscopy. Interestingly, the cKO mice exhibited spontaneous fractures in long bones, as found in NF1 patients. Mechanical testing of femora revealed significantly reduced maximum force and stiffness. Immunohistochemistry showed significantly increased FGF23 protein in the cKO bones. Moreover, primary osteocytes from cKO femora showed about eightfold increase in FGF23 mRNA levels compared with control cells. The upregulation of FGF23 was specifically and significantly inhibited by PI3K inhibitor Ly294002, indicating upregulation of FGF23 through PI3K in Nf1-deficient osteocytes. Taken together, these results indicate that Nf1 deficiency in osteocytes dramatically increases FGF23 production and causes a mineralization defect (ie, hyperosteoidosis) via the alteration of calcium-phosphorus metabolism. This study demonstrates critical roles of neurofibromin in osteocytes for osteoid mineralization. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-κB and NF-κB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis

PubMed Central

Kim, Ji H.; Gupta, Subash C.; Park, Byoungduck; Yadav, Vivek R.; Aggarwal, Bharat B.

2012-01-01

Scope The incidence of cancer is significantly lower in regions where turmeric is heavily consumed. Whether lower cancer incidence is due to turmeric was investigated by examining its effects on tumor cell proliferation, on pro-inflammatory transcription factors NF-κB and STAT3, and on associated gene products. Methods and results Cell proliferation and cell cytotoxicity were measured by the MTT method, NF-κB activity by EMSA, protein expression by Western blot analysis, ROS generation by FACS analysis, and osteoclastogenesis by TRAP assay. Turmeric inhibited NF-κB activation and down-regulated NF-κB-regulated gene products linked to survival (Bcl-2, cFLIP, XIAP, and cIAP1), proliferation (cyclin D1 and c-Myc), and metastasis (CXCR4) of cancer cells. The spice suppressed the activation of STAT3, and induced the death receptors (DR)4 and DR5. Turmeric enhanced the production of ROS, and suppressed the growth of tumor cell lines. Furthermore, turmeric sensitized the tumor cells to chemotherapeutic agents capecitabine and taxol. Turmeric was found to be more potent than pure curcumin for cell growth inhibition. Turmeric also inhibited NF-κB activation induced by RANKL that correlated with the suppression of osteoclastogenesis. Conclusion Our results indicate that turmeric can effectively block the proliferation of tumor cells through the suppression of NF-κB and STAT3 pathways. PMID:22147524

Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-κB and NF-κB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis.

PubMed

Kim, Ji H; Gupta, Subash C; Park, Byoungduck; Yadav, Vivek R; Aggarwal, Bharat B

2012-03-01

The incidence of cancer is significantly lower in regions where turmeric is heavily consumed. Whether lower cancer incidence is due to turmeric was investigated by examining its effects on tumor cell proliferation, on pro-inflammatory transcription factors NF-κB and STAT3, and on associated gene products. Cell proliferation and cell cytotoxicity were measured by the MTT method, NF-κB activity by EMSA, protein expression by Western blot analysis, ROS generation by FACS analysis, and osteoclastogenesis by TRAP assay. Turmeric inhibited NF-κB activation and down-regulated NF-κB-regulated gene products linked to survival (Bcl-2, cFLIP, XIAP, and cIAP1), proliferation (cyclin D1 and c-Myc), and metastasis (CXCR4) of cancer cells. The spice suppressed the activation of STAT3, and induced the death receptors (DR)4 and DR5. Turmeric enhanced the production of ROS, and suppressed the growth of tumor cell lines. Furthermore, turmeric sensitized the tumor cells to chemotherapeutic agents capecitabine and taxol. Turmeric was found to be more potent than pure curcumin for cell growth inhibition. Turmeric also inhibited NF-κB activation induced by RANKL that correlated with the suppression of osteoclastogenesis. Our results indicate that turmeric can effectively block the proliferation of tumor cells through the suppression of NF-κB and STAT3 pathways. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury.

PubMed

Chen, Xiangrong; Chen, Chunnuan; Fan, Sining; Wu, Shukai; Yang, Fuxing; Fang, Zhongning; Fu, Huangde; Li, Yasong

2018-04-20

Microglial polarization and the subsequent neuroinflammatory response are contributing factors for traumatic brain injury (TBI)-induced secondary injury. High mobile group box 1 (HMGB1) mediates the activation of the NF-κB pathway, and it is considered to be pivotal in the late neuroinflammatory response. Activation of the HMGB1/NF-κB pathway is closely related to HMGB1 acetylation, which is regulated by the sirtuin (SIRT) family of proteins. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that ω-3 PUFA inhibited TBI-induced microglial activation and the subsequent neuroinflammatory response by regulating the HMGB1/NF-κB signaling pathway. However, no studies have elucidated if ω-3 PUFA affects the HMGB1/NF-κB pathway in a HMGB1 deacetylation of dependent SIRT1 manner, thus regulating microglial polarization and the subsequent neuroinflammatory response. The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and HMGB1, were used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1/NF-κB signaling pathway activation to evaluate the effects of ω-3 PUFA supplementation. The impact of SIRT1 deacetylase activity on HMGB1 acetylation and the interaction between HMGB1 and SIRT1 were assessed to evaluate anti-inflammation effects of ω-3 PUFAs, and also, whether these effects were dependent on a SIRT1-HMGB1/NF-κB axis to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. The results of our study showed that ω-3 PUFA supplementation promoted a shift from the M1 microglial phenotype to the M2 microglial phenotype and inhibited microglial activation, thus reducing TBI-induced inflammatory factors. In addition, ω-3 PUFA-mediated downregulation of HMGB1 acetylation and its extracellular secretion was found to be likely due to increased SIRT1 activity. We also found that treatment with ω-3 PUFA inhibited HMGB1 acetylation and induced direct interactions between SIRT1 and HMGB1 by elevating SIRT1 activity following TBI. These events lead to inhibition of HMGB1 nucleocytoplasmic translocation/extracellular secretion and alleviated HMGB1-mediated activation of the NF-κB pathway following TBI-induced microglial activation, thus inhibiting the subsequent inflammatory response. The results of this study suggest that ω-3 PUFA supplementation attenuates the inflammatory response by modulating microglial polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway, leading to neuroprotective effects following experimental traumatic brain injury.

Gastrin regulates ABCG2 to promote the migration, invasion and side populations in pancreatic cancer cells via activation of NF-κB signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Juan; Xin, Beibei; Wang, Hui

Gastrin is absent in most normal adult pancreatic tissues but is highly expressed in pancreatic cancer tissues. Although Gastrin expression was reported to be associated with tumor proliferation in human pancreatic cancer, studies on the relationship between Gastrin and tumor metastasis in pancreatic cancer are rare. In this study, we performed an analysis to determine the effects of Gastrin on modulating the side populations, cell proportion and tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. We indicated that Gastrin and ABCG2 were widely expressed in pancreatic cancer cell lines and overexpressed in cancer tissues.more » Gastrin induced ABCG2 expression, and this effect was mediated by NF-κB activation. Gastrin regulated the SP proportion of BxPC-3 cells via modulating ABCG2 expression. Through the regulation of the functions of NF-κB/ABCG2, Gastrin functionally promoted the migration and invasion in pancreatic cancer cell. The present study indicated that Gastrin induced ABCG2 expression by activating NF-κB and thereby modulated the SP proportion, tumor cell metastatic potential and invasion activity in pancreatic cancer. Gastrin could serve as an effective therapeutic target for the metastasis of pancreatic cancer. - Highlights: • Gastrin induces ABCG2 expression mediated by NF-κB activation. • Gastrin regulates NF-κB's function that binds to the ABCG2 promoter in BxPC-3 cells. • Gastrin promotes the SP proportion in BxPC-3 cells by modulating ABCG2 expression via activation of NF-κB molecule. • Gastrin induces an increase in migration and invasion potential in pancreatic cancer cell by regulating NF-κB/ABCG2 signaling.« less

Effects of Different Ratio of n-6/n-3 Polyunsaturated Fatty Acids on the PI3K/Akt Pathway in Rats with Reflux Esophagitis.

PubMed

Zhuang, Jia-Yuan; Chen, Zhi-Yao; Zhang, Tao; Tang, Du-Peng; Jiang, Xiao-Yin; Zhuang, Ze-Hao

2017-01-30

BACKGROUND We designed this study to investigate the influence of different ratios of n-6/n-3 polyunsaturated fatty acid in the diet of reflux esophagitis (RE) rats' and the effect on the PI3K/Akt pathway. MATERIAL AND METHODS RE rats were randomly divided into a sham group and modeling groups of different concentrations of n-6/n-3 polyunsaturated fatty acid (PUFA): 12:1 group, 10:1 group, 5:1 group, and 1:1 group. RT-PCR and Western-blot were used to detect the expression of PI3K, Akt, p-Akt, NF-κBp50, and NF-κBp65 proteins in esophageal tissue. RESULTS In the n-6/n-3 PUFAs groups the expression of PI3K, Akt, p-Akt, nf-κbp50, and NF-κBp65 mRNA decreased with the decrease in n-6/n-3 ratios in the diet. The lowest expression of each indicator occurred in the 1:1 n-6/n-3 group compared with other n-6/n-3 groups, the difference was statistically significant (p<0.05). CONCLUSIONS The inhibition of n-3 PUFAs in the development of esophageal inflammation in rats with RE was attributed to the function of PI3K/Akt-NF-κB signaling pathway.

Encephalomyocarditis Virus 3C Protease Relieves TRAF Family Member-associated NF-κB Activator (TANK) Inhibitory Effect on TRAF6-mediated NF-κB Signaling through Cleavage of TANK.

PubMed

Huang, Li; Liu, Qinfang; Zhang, Lijie; Zhang, Quan; Hu, Liang; Li, Changyao; Wang, Shengnan; Li, Jiangnan; Zhang, Yuanfeng; Yu, Huibin; Wang, Yan; Zhong, Zhaohua; Xiong, Tao; Xia, Xueshan; Wang, Xiaojun; Yu, Li; Deng, Guohua; Cai, Xuehui; Cui, Shangjin; Weng, Changjiang

2015-11-13

TRAF family member-associated NF-κB activator (TANK) is a negative regulator of canonical NF-κB signaling in the Toll-like receptor- and B-cell receptor-mediated signaling pathways. However, functions of TANK in viral infection-mediated NF-κB activation remain unclear. Here, we reported that TANK was cleaved by encephalomyocarditis virus 3C at the 197 and 291 glutamine residues, which depends on its cysteine protease activity. In addition, encephalomyocarditis virus 3C impaired the ability of TANK to inhibit TRAF6-mediated NF-κB signaling. Interestingly, we found that several viral proteases encoded by the foot and mouth disease virus, porcine reproductive and respiratory syndrome virus, and equine arteritis virus also cleaved TANK. Our results suggest that TANK is a novel target of some viral proteases, indicating that some positive RNA viruses have evolved to utilize their major proteases to regulate NF-κB activation. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Ophiopogonin D alleviates cardiac hypertrophy in rat by upregulating CYP2J3 in vitro and suppressing inflammation in vivo.

PubMed

Wang, Yuan; Huang, Xiaoyan; Ma, Zengchun; Wang, Yuguang; Chen, Xiangmei; Gao, Yue

2018-06-20

Ophiopogonin D (OPD) is the chief pharmacological active component of the traditional Chinese herbal prescription drug-Shenmai injection (SMI), which has been used to prevent and treat cardiovascular diseases. In the present study, we investigated whether OPD protectively relieve cardiac hypertrophy against inflammation via inhibiting the expression of NF-κB and examined whether cytochrome P450 2J3 (CYP2J3)was involved in this pathway. H9c2 cells were treated with Angiotensin II (Ang II). Hypertrophy in rat was induced by administration of Ang II infusion. To evaluate the effect of OPD on disease progression and the role of CYP2J3 in this way, inflammatory mediators (NF-κB), specific hypertrophic factors and pathological change were determined in this experiment. In addition, Ang II induced hypertrophy with the elevated expression of specific hypertrophy genes and NF-κB signaling molecules. However, these inductive effects were reversed by OPD in conjunction with Ang II. Overexpression of CYP2J3 prevented the excessive expression of NF-κB. In vivo, some pathological cardiac hypertrophy injuries were relieved after OPD treatment. OPD exerts a positive effect on alleviating cardiac hypertrophy. The mechanism is probably inhibiting the expression of NF-κB by upregulating CYP2J3 to suppressing inflammation. Copyright © 2018. Published by Elsevier Inc.

Porous Ni-Mn oxide nanosheets in situ formed on nickel foam as 3D hierarchical monolith de-NOx catalysts

NASA Astrophysics Data System (ADS)

Cai, Sixiang; Zhang, Dengsong; Shi, Liyi; Xu, Jing; Zhang, Lei; Huang, Lei; Li, Hongrui; Zhang, Jianping

2014-06-01

In this work, we successfully in situ decorated nickel foam with porous Ni-Mn oxide nanosheets (3DH-NM/NF) as 3D hierarchical monolith de-NOx catalysts via a simple hydrothermal reaction and calcination process. The catalysts were carefully examined by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, elemental mapping, X-ray photoelectron spectroscopy, H2 temperature-programmed reduction and NH3 temperature-programmed desorption measurements. The results indicated that the nanosheets are composed of a Ni6Mn1O8 spinel and the metal species are uniformly dispersed in bi-metal oxides. As a result, the strong synergistic effects between the Mn and Ni species have been observed. The active oxygen species, reducible species and acidity are enhanced by the in situ formation of the nanosheets on the surface of nickel foam. These desirable features of 3DH-NM/NF catalysts bring about the excellent de-NOx performance. Moreover, the 3DH-NM/NF catalysts also present good stability and H2O resistance. Based on these favorable properties, 3DH-NM/NF could be considered as a promising candidate for the monolith de-NOx catalysts.In this work, we successfully in situ decorated nickel foam with porous Ni-Mn oxide nanosheets (3DH-NM/NF) as 3D hierarchical monolith de-NOx catalysts via a simple hydrothermal reaction and calcination process. The catalysts were carefully examined by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, elemental mapping, X-ray photoelectron spectroscopy, H2 temperature-programmed reduction and NH3 temperature-programmed desorption measurements. The results indicated that the nanosheets are composed of a Ni6Mn1O8 spinel and the metal species are uniformly dispersed in bi-metal oxides. As a result, the strong synergistic effects between the Mn and Ni species have been observed. The active oxygen species, reducible species and acidity are enhanced by the in situ formation of the nanosheets on the surface of nickel foam. These desirable features of 3DH-NM/NF catalysts bring about the excellent de-NOx performance. Moreover, the 3DH-NM/NF catalysts also present good stability and H2O resistance. Based on these favorable properties, 3DH-NM/NF could be considered as a promising candidate for the monolith de-NOx catalysts. Electronic supplementary information (ESI) available: Experimental details and catalytic performance of the NM/cordierite catalysts, SEM image and EDX analysis of the NF and 3DH-N/NF catalysts, N2 selectivity and catalytic performance under different gas hourly space velocities of the 3DH-NM/NF catalysts. See DOI: 10.1039/c4nr00475b

Synergistic acceleration of experimental tooth movement by supplementary high-frequency vibration applied with a static force in rats.

PubMed

Takano-Yamamoto, Teruko; Sasaki, Kiyo; Fatemeh, Goudarzi; Fukunaga, Tomohiro; Seiryu, Masahiro; Daimaruya, Takayoshi; Takeshita, Nobuo; Kamioka, Hiroshi; Adachi, Taiji; Ida, Hiroto; Mayama, Atsushi

2017-10-25

Several recent prospective clinical trials have investigated the effect of supplementary vibration applied with fixed appliances in an attempt to accelerate tooth movement and shorten the duration of orthodontic treatment. Among them, some studies reported an increase in the rate of tooth movement, but others did not. This technique is still controversial, and the underlying cellular and molecular mechanisms remain unclear. In the present study, we developed a new vibration device for a tooth movement model in rats, and investigated the efficacy and safety of the device when used with fixed appliances. The most effective level of supplementary vibration to accelerate tooth movement stimulated by a continuous static force was 3 gf at 70 Hz for 3 minutes once a week. Furthermore, at this optimum-magnitude, high-frequency vibration could synergistically enhance osteoclastogenesis and osteoclast function via NF-κB activation, leading to alveolar bone resorption and finally, accelerated tooth movement, but only when a static force was continuously applied to the teeth. These findings contribute to a better understanding of the mechanism by which optimum-magnitude high-frequency vibration accelerates tooth movement, and may lead to novel approaches for the safe and effective treatment of malocclusion.

Effect of total-contact orthosis on medial longitudinal arch and lower extremities in flexible flatfoot subjects during walking.

PubMed

Prachgosin, Tulaya; Leelasamran, Wipawan; Smithmaitrie, Pruittikorn; Chatpun, Surapong

2017-12-01

Total-contact orthosis (TCO) is one kind of foot orthosis (FO) that is used to adjust biomechanics in flexible flatfoot. To determine the effects of a TCO on the MLA moment, MLA deformation angle and lower limb biomechanics. Cross-sectional study. Seven-flatfoot and thirteen-normal foot subjects were recruited by footprint and radiographs. The biomechanics of subjects with normal foot (NF), flatfoot with shoe only (FWOT) and flatfoot with TCO (FWT) were collected in a 3D motion analysis laboratory and force plates. The MLA and lower limb biomechanics in each condition during specific sub-phases of stance were analyzed. The NF had larger MLA eversion moment after shod walking ( p = 0.001). The FWT condition compared with the FWOT condition had a significantly larger peak MLA upward moment ( p = 0.035) during pre-swing, larger peak knee external rotation angle ( p = 0.040) during mid stance, smaller peak knee extension moment during terminal stance ( p = 0.035) and a larger ground reaction force in the anterior-posterior direction during early stance ( p < 0.05). Our study found positive effects from the customized TCOs which included an increased TCO angle that led to a decreased peak MLA moment in the frontal plane in flexible flatfoot subjects during walking. Clinical relevance Lower limb biomechanics is different from normal in subjects with flexible flatfoot. The design of a TCO affects MLA, ankle and knee biomechanics and may be used to clinically correct biomechanical changes in flexible flatfoot.

Non-classic multiscale modeling of manipulation based on AFM, in aqueous and humid ambient

NASA Astrophysics Data System (ADS)

Korayem, M. H.; Homayooni, A.; Hefzabad, R. N.

2018-05-01

To achieve a precise manipulation, it is important that an accurate model consisting the size effect and environmental conditions be employed. In this paper, the non-classical multiscale modeling is developed to investigate the manipulation in a vacuum, aqueous and humid ambient. The manipulation structure is considered into two parts as a macro-field (MF) and a nano-field (NF). The governing equations of the AFM components (consist of the cantilever and tip) in the MF are derived based on the modified couple stress theory. The material length scale parameter is used to study the size effect. The fluid flow in the MF is assumed as the Couette and Creeping flows. Moreover, the NF is modeled using the molecular dynamics. The Electro-Based (ELBA) model is considered to model the ambient condition in the NF. The nanoparticle in the different conditions is taken into account to study the manipulation. The results of the manipulation indicate that the predicted deflection of the non-classical model is less than the classical one. Comparison of the nanoparticle travelled distance on substrate shows that the manipulation in the submerged condition is close to the ideal manipulation. The results of humid condition illustrate that by increasing the relative humidity (RH) the manipulation force decreases. Furthermore, Root Mean Square (RMS) as a criterion of damage demonstrates that the submerged nanoparticle has the minimum damage, however, the minimum manipulation force occurs in superlative humid ambient.

Mind-body therapy via videoconferencing in patients with neurofibromatosis: An RCT.

PubMed

Vranceanu, Ana-Maria; Riklin, Eric; Merker, Vanessa L; Macklin, Eric A; Park, Elyse R; Plotkin, Scott R

2016-08-23

To test, within a single-blind randomized controlled trial, the feasibility, acceptability, efficacy, and durability of a mind-body program (the Relaxation Response Resiliency Program for neurofibromatosis [3RP-NF]) vs an attention placebo control (Health Enhancement Program for NF [HEP-NF]), both delivered via group videoconferencing. Sixty-three patients completed baseline assessments and were randomized. Primary outcomes were physical health and psychological quality of life (QoL), measured by the WHOQOL-BREF (World Health Organization QoL abbreviated instrument). Secondary outcomes were social relations and environment QoL, depression, anxiety, pain intensity, and pain interference. Sixty-three participants completed the intervention (100%) and 52 the 6-month follow-up (82.5%). Acceptability was 4.1 (5-point scale). Patients in the 3RP-NF showed greater improvement in physical health QoL (7.69; 95% confidence interval [CI]: 0.29-15.10; p = 0.040), psychological QoL (5.57; 95% CI: 0.17-11.34; p = 0.056), social relations QoL (10.95; 95% CI: 1.57-20.31; p = 0.021), environment QoL (8.02; 95% CI: 2.57-13.48; p = 0.005), and anxiety (-2.32; 95% CI: -3.96 to 0.69; p = 0.006) compared to those in HEP-NF, and gains were maintained at follow-up. Patients in the 3RP-NF did not improve more than those in HEP-NF on depression, with both groups showing improvement. Patients in the 3RP-NF with baseline pain ≥5 of 10 showed improvement in pain intensity from baseline to posttest (1.30; 95% CI: -2.26 to -0.34; p = 0.009) with effects maintained at follow-up; this improvement was not greater than that in HEP-NF. There were more treatment responders in the 3RP-NF group (p < 0.05). The 3RP-NF delivered via videoconferencing was highly feasible and accepted by patients, and resulted in sustained improvement in QoL. This study provides Class II evidence that for patients with NF, a mind-body program is superior to an attention placebo control in improving QoL. © 2016 American Academy of Neurology.

Pre-S2 Start Codon Mutation of Hepatitis B Virus Subgenotype B3 Effects on NF-κB Expression and Activation in Huh7 Cell Lines.

PubMed

Siburian, Marlinang Diarta; Suriapranata, Ivet Marita; Wanandi, Septelia Inawati

2018-03-19

A cross-sectional study on hepatitis B patients in Indonesia showed association of pre-S2 start codon mutation (M120 V) with cirrhosis and hepatocellular carcinoma (HCC), which was dissimilar from studies from other populations where pre-S2 deletion mutation was more prevalent. Different mutation patterns were attributed to different hepatitis B virus (HBV) subgenotypes in each population study. HBV surface proteins are reported to induce the activation of NF-κB, a transcriptional factor known to play an important role in the development of liver disease. This study aimed to see the effects of HBs variants in HBV subgenotype B3 on the expression and activation of NF-κB as one of the mechanisms in inducing advanced liver disease. HBV subgenotypes B3, each carrying wild-type (wt) HBs, M120 V, and pre-S2 deletion mutation were isolated from three HCC patients. HBs genes were amplified and cloned into pcDNA3.1 and were transfected using Lipofectamine into a Huh7 cell line. NF-κB activation was measured through IκB-α expression, which is regulated by NF-κB. RNA expressions for HBs, IκB-α, and NF-κB subunit (p50) were evaluated using real-time PCR. M120 V mutant had a significantly higher mRNA level compared with wt and pre-S2 deletion mutant; however, there were no significant differences in HBs protein expressions. The transcription level of p50 was higher in M120 V mutation compared with HBs wild-type and pre-S2 deletion mutant. NF-κB activation was higher in HBs wild-type compared with the two mutant variants. Pre-S2 mutations had no effect on the increment of NF-κB activation. However, M120 V mutation may utilize a different pathway in liver disease progression that involves high expression of NF-κB subunit, p50.

Nicotine promotes cervical carcinoma cell line HeLa migration and invasion by activating PI3k/Akt/NF-κB pathway in vitro.

PubMed

Wang, Chengze; Gu, Weiting; Zhang, Yunpeng; Ji, Yawen; Wen, Yong; Xu, Xin

2017-07-05

Cigarette smoking is one of highly risk factors of cervical cancer. Recently nicotine has been reported to increase proliferation and invasion in some smoking related cancers, like non-small cell lung cancer and esophageal squamous cell cancer. However, the effects and mechanisms of nicotine stimulation on cervical cancer cells are not clear. Here, we investigated the effects and mechanisms of nicotine stimulation on HeLa cells in vitro. In our study, we found that nicotine could accelerate HeLa cells migration and invasion, activate PI3K/Akt and NF-κB pathways and increase the expression of Vimentin in vitro. Moreover, we demonstrated that the specific PI3K inhibitor LY294002 could reverse nicotine-induced cell migration and invasion, NF-κB activation and up-regulation of Vimentin. Inhibition of NF-κB by Pyrrolidine dithiocarbamate (PDTC) also antagonized nicotine-induced cell migration, invasion and up-regulation of Vimentin. Simply put, these findings suggest that nicotine promotes cervical carcinoma cell line HeLa migration and invasion by activating PI3k/Akt/NF-κB pathway in vitro. Copyright © 2017 Elsevier GmbH. All rights reserved.

Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related kinase 1/2.

PubMed

Rodríguez-Calvo, Ricardo; Serrano, Lucía; Coll, Teresa; Moullan, Norman; Sánchez, Rosa M; Merlos, Manuel; Palomer, Xavier; Laguna, Juan C; Michalik, Liliane; Wahli, Walter; Vázquez-Carrera, Manuel

2008-08-01

Chronic activation of the nuclear factor-kappaB (NF-kappaB) in white adipose tissue leads to increased production of pro-inflammatory cytokines, which are involved in the development of insulin resistance. It is presently unknown whether peroxisome proliferator-activated receptor (PPAR) beta/delta activation prevents inflammation in adipocytes. First, we examined whether the PPARbeta/delta agonist GW501516 prevents lipopolysaccharide (LPS)-induced cytokine production in differentiated 3T3-L1 adipocytes. Treatment with GW501516 blocked LPS-induced IL-6 expression and secretion by adipocytes and the subsequent activation of the signal transducer and activator of transcription 3 (STAT3)-Suppressor of cytokine signaling 3 (SOCS3) pathway. This effect was associated with the capacity of GW501516 to impede LPS-induced NF-kappaB activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPARbeta/delta expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-kappaB DNA-binding activity. Furthermore, IL-6 expression and NF-kappaB DNA-binding activity was higher in white adipose tissue from PPARbeta/delta-null mice than in wild-type mice. Because mitogen-activated protein kinase-extracellular signal-related kinase (ERK)1/2 (MEK1/2) is involved in LPS-induced NF-kappaB activation in adipocytes, we explored whether PPARbeta/delta prevented NF-kappaB activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylation by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-kappaB activity, such as ZDF rats and PPARbeta/delta-null mice, also showed enhanced phospho-ERK1/2 levels. These findings indicate that activation of PPARbeta/delta inhibits enhanced cytokine production in adipocytes by preventing NF-kappaB activation via ERK1/2, an effect that may help prevent insulin resistance.

Effect of Pendant Side-Chain Sterics and Dipole Forces on Short Range Ordering in Random Polyelectrolytes

NASA Astrophysics Data System (ADS)

Nwosu, Chinomso; Pandey, Tara; Herring, Andrew; Coughlin, Edward; University of Massachusetts, Amherst Collaboration; Colorado School of Mines Collaboration

Backbone-to-backbone spacing in polymers is known to be dictated by the length of the pendant side-chains. Dipole forces in random polyelectrolytes lead to ionic clusters with a characteristic spacing that can be observed by SAXS. Repulsion due to side-chain sterics will compete with dipole forces driving cluster formation in random polyelectrolytes. A model study on short range order in anion exchange membranes (AEMs) of quaternized P4VP-ran-PI is presented. Quaternization of P4VP with alkyl bromides having different numbers of carbons, CnBr, introduces pendant side-chains as well as charges. X-ray scattering performed on PQ4VP-ran-PI(CnBr) show that when n <5 the dipole forces dominate leading to the formation of ionic clusters. However, when n >4, the chains remain separated due to sterics, forming a distinct backbone-to-backbone spacing morphology. For n=3, both dipole clustering and backbone spacing can coexist. Crosslinking of the isoprene units increased the coexistence window from n=3 to n=6. Impedance measurements show that a maximum conductivity of 110mS/cm was obtained for PQ4VP-ran-PI(C3Br). A discussion on short range order due to competition, or counter balancing, of steric repulsion and dipole forces will be presented. US Army MURI project (W911NF1010520).

Fluorimetric study on the interaction between Norfloxacin and Proflavine hemisulphate.

PubMed

More, Vishalkumar R; Anbhule, Prashant V; Lee, Sang H; Patil, Shivajirao R; Kolekar, Govind B

2011-07-01

The interaction between Norfloxacin (NF) and Proflavine hemisulphate (PF) was investigated by spectroscopic tools like UV-VIS absorption and Fluorescence spectroscopy. It was proved that fluorescence quenching of NF by PF is due to the formation of NF-PF complex which was supported by UV-VIS absorption study. The study of thermodynamic parameters suggested that the key interacting forces are hydrogen bond and van der Waal's interactions and the binding interaction was spontaneous. The distance r between NF and PF was obtained according to the Förster's theory of non-radiative energy transfer. The fluorescence quenching mechanism was applied to estimate PF directly from pharmaceutical samples. © Springer Science+Business Media, LLC 2011

BRAF activated non-coding RNA (BANCR) promoting gastric cancer cells proliferation via regulation of NF-κB1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Zhi-Xin; Liu, Zhi-Qiang; Jiang, Biao

Background and objective: Long non-coding RNA, BANCR, has been demonstrated to contribute to the proliferation and migration of tumors. However, its molecular mechanism underlying gastric cancer is still unknown. In present study, we investigated whether BANCR was involved in the development of gastric cancer cells via regulation of NF-κB1. Methods: Human gastric cancer tissues were isolated as well as human gastric cell lines MGC803 and BGC823 were cultured to investigate the role of BANCR in gastric cancer. Results: BANCR expression was significantly up-regulated in gastric tumor tissues and gastric cell lines. Down-regulation of BANCR inhibited gastric cancer cell growth andmore » promoted cell apoptosis, and it also contributed to a significant decrease of NF-κB1 (P50/105) expression and 3′UTR of NF-κB1 activity. Overexpression of NF-κB1 reversed the effect of BANCR on cancer cell growth and apoptosis. MiroRNA-9 (miR-9) targeted NF-κB1, and miR-9 inhibitor also reversed the effects of BANCR on gastric cancer cell growth and apoptosis. Conclusion: BANCR was highly expressed both in gastric tumor tissues and in cancer cells. NF-κB1 and miR-9 were involved in the role of BANCR in gastric cancer cell growth and apoptosis. - Highlights: • BANCR up-regulated in gastric cancer (GC) tissues and cell lines MGC803 and BGC823. • Down-regulation of BANCR inhibited GC cell growth and promoted cell apoptosis. • Down-regulation of BANCR contributed to decreased 3′UTR of NF-κB1 and its expression. • Overexpressed NF-κB1 reversed the effect of BANCR on GC cell growth. • miR-9 inhibitor reversed the effect of BANCR on cancer GC cell growth.« less

Developing Non-Somatotopic Phantom Finger Sensation to Comparable Levels of Somatotopic Sensation through User Training With Electrotactile Stimulation.

PubMed

Chai, Guohong; Zhang, Dingguo; Zhu, Xiangyang

2017-05-01

Cutaneous electrical stimulation can provide tactile feedback for upper-limb amputees through somatotopic feedback (SF) or non-somatotopic feedback (NF). The SF delivers electrotactile stimulus to projection finger maps (PFMs) on the stumps of amputees, which outperforms NF that transfers stimulus to other human intact skin areas in general. However, the SF areas on stumps are very limited and often occupied by electromyography (EMG) sensors in application of myoelectric prosthesis. This work aims at improving NF performance on human upper arms through user training with electrotactile stimulation. The experiments were conducted over seven consecutive days on nine able-bodied subjects and two forearm amputees. The performance measures of NF/SF included the correct identification rates (CIR s ), the response time and the NASA-TLX questionnaire. The between-day CIR s on NF sites increased logarithmically with a mean course of 3-day rapid-improving phase and plateaued in the relative-steady phase. The response time and NASA-TLX scores could also rapidly reduce to the comparable levels of the SF areas during the same mean period of 3-day rapid-improving phase, respectively. These results indicated that the performance of NF could be highly improved to the equivalent level as that of SF through 3-day electrotactile training, which we named as "3-day effect". It provides important insights that intact skin areas without phantom sensations can effectively replace SF sites to transfer tactile feedback after continuous user training, which validates effectiveness of non-invasive interfaces of tactile feedback for upper-limb amputees in practice.

Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF-κB signaling in LPS-induced PC3 cells.

PubMed

Ogut, Deniz; Reel, Buket; Gonen Korkmaz, Ceren; Arun, Mehmet Zuhuri; Cilaker Micili, Serap; Ergur, Bekir Ugur

2016-01-01

Matrix metalloproteinase enzymes (MMPs) play important role in inflammation, malignant cell proliferation, invasion and angiogenesis by mediating extracellular matrix degradation. Doxycycline, a synthetic tetracycline, behaves as a MMP inhibitor at a subantimicrobial dose and inhibits tumor cell proliferation, invasion and angiogenesis. The aberrant activity of nuclear factor kappa B (NF-κB) causes activation of MMPs and thereby proliferation and invasion of cancer cells. The aim of this study was to investigate the effects of doxycycline on the expression of MMPs in lipopolysaccharide (LPS)-induced PC3 human prostate cancer cells and the possible role of NF-κB signaling. PC3 cells were incubated with LPS (0.5 μg/mL) for 24 h in the presence or absence of doxycycline (5 μg/mL). The effects of LPS and doxycycline on the expressions of MMP-2, MMP-8, MMP-9, MMP-10, NF-κB/p65, IκB-α, p-IκB-α, IKK-β were examined by Western blotting and immunohistochemistry in PC3 cells. Furthermore, relative proteinase activities of MMP-2 and MMP-9 were determined by gelatin zymography. LPS increased expression and activity of MMP-9 and expression of MMP-8, MMP-10, NF-κB /p65, p-IκB-α, IKK-β and doxycycline down-regulated its effects with the exception of MMP-10 expression. The expression of MMP-2 and IκB-α was affected by neither LPS nor doxycycline. Our findings indicate that doxycycline inhibits the expression of various MMPs and NF-κB signaling may play a role in the regulation of MMPs expression in LPS-induced PC3 human prostate cancer cells.

Capacity of omega-3 fatty acids or eicosapentaenoic acid to counteract weightlessness-induced bone loss by inhibiting NF-kappaB activation: from cells to bed rest to astronauts.

PubMed

Zwart, Sara R; Pierson, Duane; Mehta, Satish; Gonda, Steve; Smith, Scott M

2010-05-01

NF-kappaB is a transcriptional activator of many genes, including some that lead to muscle atrophy and bone resorption-significant concerns for astronauts. NF-kappaB activation is inhibited by eicosapentaenoic acid (EPA), but the influence of this omega-3 fatty acid on the effects of weightlessness are unknown. We report here cellular, ground analogue, and spaceflight findings. We investigated the effects of EPA on differentiation of RAW264.7 monocyte/macrophage cells induced by receptor activator of NF-kappaB ligand (RANKL) and on activation of NF-kappaB by tumor necrosis factor alpha (TNF-alpha) or exposure to modeled weightlessness. EPA (50 microM for 24 hours) inhibited RANKL-induced differentiation and decreased activation of NF-kappaB induced by 0.2 microg/mL of TNF-alpha for 30 minutes or by modeled weightlessness for 24 hours (p < .05). In human studies, we evaluated whether NF-kappaB activation was altered after short-duration spaceflight and determined the relationship between intake of omega-3 fatty acids and markers of bone resorption during bed rest and the relationship between fish intake and bone mineral density after long-duration spaceflight. NF-kappaB was elevated in crew members after short-duration spaceflight, and higher consumption of fish (a rich source of omega-3 fatty acids) was associated with reduced loss of bone mineral density after flight (p < .05). Also supporting the cell study findings, a higher intake of omega-3 fatty acids was associated with less N-telopeptide excretion during bed rest (Pearson r = -0.62, p < .05). Together these data provide mechanistic cellular and preliminary human evidence of the potential for EPA to counteract bone loss associated with spaceflight. (c) 2010 American Society for Bone and Mineral Research.

Microtrenching-free two-step reactive ion etching of 4H-SiC using NF{sub 3}/HBr/O{sub 2} and Cl{sub 2}/O{sub 2}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tseng, Yuan-Hung, E-mail: yhtseng.ee99g@nctu.edu.tw; Tsui, Bing-Yue

2014-05-15

In this paper, the authors performed a reactive ion etch of a 4H-SiC substrate with a gas mixture of NF{sub 3}, HBr, and O{sub 2}, resulting in a microtrenching-free etch. The etch rate was 107.8 nm/min, and the selectivity over the oxide hard mask was ∼3.85. Cross-sectional scanning electron microscopy showed no microtrenching compared with etches using plasmas of NF{sub 3}, NF{sub 3}/HBr, and NF{sub 3}/O{sub 2}. Analyzing a variety of HBr/O{sub 2} mixing ratios, the authors discuss the additive effect of each gas and their respective potential mechanisms for alleviating microtrenching. To increase the radius of gyration of the bottommore » corners, they introduced a second etch step with Cl{sub 2}/O{sub 2} plasma. Fabricating simple metal-oxide-semiconductor capacitors on the two-step etched surface, the authors found that the electrical characteristics of the etched sample were nearly the same as the nonetched sample.« less

Ultrafast and large scale preparation of superior catalyst for oxygen evolution reaction

NASA Astrophysics Data System (ADS)

Tian, Xianqing; Liu, Yunhua; Xiao, Dan; Sun, Jie

2017-10-01

The development of efficient and earth abundant catalyst for the oxygen evolution reaction (OER) is a key challenge for the renewable energy research community. Here, we report a facile and ultrafast route to immobilize nickel-iron layered double hydroxide (NiFe-LDH) nanoparticles on nickel foam (NF) via soaking the direct electroless deposited prussian blue analogue (PBA) on NF in 1 M KOH. This NiFe-LDH/NF electrode can be prepared in a few seconds without further treatments. It has three-dimensional interpenetrating network originated from its PBA precursor which facilitate the diffusion and ad/desorption of the reactants and producing for OER. And further characterization of the Faradaic efficiency and forced convection tests show direct evidence to demonstrate the formation of free intermediate(s) in the OER process. This electrode (typically NiFe-LDH-20s/NF) exhibits outstanding electrocatalytic activity with low overpotential of ∼0.240 V at 10 mA cm-2, low Tafel slope of 38 mV dec-1, and great stability. This feasible strategy affords a new strategy for the large scale manufacture of low-cost, effective and robust OER electrodes.

NF-kB activation and its downstream target genes expression after heavy ions exposure

NASA Astrophysics Data System (ADS)

Chishti, Arif Ali; Baumstark-Khan, Christa; Hellweg, Christine; Schmitz, Claudia; Koch, Kristina; Feles, Sebastian

2016-07-01

To enable long-term human space flight cellular radiation response to densely ionizing radiation needs to be better understood for developing appropriate countermeasures to mitigate acute effects and late radiation risks for the astronaut. The biological effectiveness of accelerated heavy ions (which constitute the most important radiation type in space) with high linear energy transfer (LET) for effecting DNA damage response pathways as a gateway to cell death or survival is of major concern not only for space missions but also for new regimes of tumor radiotherapy. In the current research study, the contribution of NF-κB in response to space-relevant radiation qualities was determined by a NF-κB reporter cell line (HEK-pNF-κB-d2EGFP/Neo L2). The NF-κB dependent reporter gene expression (d2EGFP) after ionizing radiation (X-rays and heavy ions) exposure was evaluated by flow cytometry. Because of differences in the extent of NF-κB activation after X-irradiation and heavy ions exposure, it was expected that radiation quality (LET) might play an important role in the cellular radiation response. In addition, the biological effectiveness (RBE) of NF-κB activation and reduction of cellular survival was examined for heavy ions having a broad range of LET (˜0.3 - 9674 keV/µm). Furthermore, the effect of LET on NF-κB target gene expression was analyzed by real time reverse transcriptase quantitative PCR (RT-qPCR). In this study it was proven that NF-κB activation and NF-κB dependent gene expression comprises an early step in cellular radiation response. Taken together, this study clearly demonstrates that NF-κB activation and NF-κB-dependent gene expression by heavy ions are highest in the LET range of ˜50-200 keV/μupm. The up-regulated chemokines and cytokines (CXCL1, CXCL2, CXCL10, IL-8 and TNF) might be important for cell-cell communication among hit as well as unhit cells (bystander effect). The results obtained suggest the NF-κB pathway to be a promising target for pharmacological modulation of cellular radiation response either to improve tumor cell killing during radiotherapy with heavy ions or to mitigate radiation late effects in astronauts or irradiated healthy tissue.

Does Nissen fundoplication improve deglutition in children?

PubMed

Soyer, Tutku; Yalçın, Şule; Demir, Numan; Karhan, Asuman Nur; Saltık-Temizel, İnci Nur; Demir, Hülya; Tanyel, Feridun Cahit

2017-01-01

Soyer T, Yalçın Ş, Demir N, Karhan AN, Saltık-Temizel İN, Demir H, Tanyel FC. Does Nissen fundoplication improve deglutition in children? Turk J Pediatr 2017; 59: 28-34. A prospective study was performed to evaluate the effect of Nissen fundoplication (NF) on deglutition in children. Children who underwent NF between 2011-2015 were evaluated for demographic features, clinical findings, diagnostic methods for gastroesophageal reflux (GER) and indications for NF. Penetration aspiration scale (PAS), functional oral intake scale (FOIS) and esophageal functions were evaluated by videoflouroscopy (VFS). Preoperative and postoperative VFS findings were compared to evaluate the effect of NF on clinical findings and deglutition. Twenty-three children with a mean age of 5.08 ± 3.7 years were included. Female to male ratio was 15:8. Recurrent respiratory infections (RTI) (n: 14, 60.8%), swallowing dysfunction (n:13, 56.5%) and vomiting (n:10, 43.4%) were the most common symptoms. Preoperatively GER was diagnosed with barium swallowing study (BSS) contrast graphs (n:20, 87%) and with 24-hour esophageal pH monitorization (n:8, 34.8%). In 39.1% of patients, medical treatment for GER was used with a mean duration of 8 ± 5.8 months. Indications for NF were swallowing dysfunction (n: 18, 78%), GER complications (n:6, 26%), associated anatomical problems (n:4, 17.3%) and unresponsiveness to medical treatment (n: 3, 13%). Postoperative barium swallowing study and 24-hour esophageal pH monitorization showed no GER after NF in 95% of patients. Number of RTI were significantly decreased after NF (preoperative vs postoperative infection rate 4.21 vs 1.6 respectively, p < 0.05). VFS findings showed that PAS was significantly decreased after NF during both liquid and semi-liquid swallowing (p < 0.05). After NF, upper esophageal opening (UEO) was decreased when compared to preoperative VFS findings (p < 0.05 Esophageal cleaning, esophageal motility, esophageal backflow and lower esophageal sphincter narrowing did not alter after NF (p > 0.05). FOIS were significantly improved after NF (p < 0.05). VFS findings showed that penetration and aspiration were significantly decreased after NF and children had less RTI. Although, esophageal motility evaluated by VFS did not changed after NF, functional oral intake significantly improved in children.

Ferulic acid inhibits neuro-inflammation in mice exposed to chronic unpredictable mild stress.

PubMed

Liu, Ya-Min; Shen, Ji-Duo; Xu, Li-Ping; Li, Han-Bing; Li, Yu-Cheng; Yi, Li-Tao

2017-04-01

Ferulic acid is a hydroxycinnamic acid that widely presents in plant cell wall components. It has been demonstrated that ferulic acid can attenuate depressive-like behaviors in both forced swimming test and tail suspension test. Considering that depression is an inflammatory related mental disease, our present study was aimed to investigate the role of ferulic acid in the regulation of microglia activation, pro-inflammatory cytokines, nuclear factor kappa B (NF-κB) and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in mice exposed to chronic unpredictable mild stress (CUMS). Our results firstly showed that decreased sucrose preference and increased immobility time were completely reversed by administration with ferulic acid and fluoxetine for four weeks. Then, we found that CUMS significantly caused interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) up-regulation, microglia, NF-κB signaling and NLRP3 inflammasome activation in the prefrontal cortex. On the contrary, these activated inflammatory response induced by CUMS were reversed by ferulic acid and fluoxetine as well, suggesting that anti-inflammatory related mechanism was involved in the antidepressant-like effects of ferulic acid in stressed mice. Copyright © 2017 Elsevier B.V. All rights reserved.

3,4,5-Tricaffeoylquinic acid inhibits tumor necrosis factor-α-stimulated production of inflammatory mediators in keratinocytes via suppression of Akt- and NF-κB-pathways.

PubMed

Lee, Chung Soo; Lee, Seon Ae; Kim, Yun Jeong; Seo, Seong Jun; Lee, Min Won

2011-11-01

Keratinocytes may play an important role in the pathogenesis of skin disease in atopic dermatitis. Caffeoyl derivatives are demonstrated to have anti-inflammatory and anti-oxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid prepared from Aconium koreanum on the pro-inflammatory cytokine-stimulated keratinocyte responses remains uncertain. In human keratinocytes, we investigated the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor (TNF)-α-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-κB and cell signaling Akt, which regulates the transcription genes involved in immune and inflammatory responses. 3,4,5-Tricaffeoylquinic acid inhibited the TNF-α-stimulated production of cytokines (IL-1β and IL-8) and chemokine (CCL17 and CCL27) in keratinocytes. Bay 11-7085 (an inhibitor of NF-κB activation) and Akt inhibitor attenuated the TNF-α-induced formation of inflammatory mediators. 3,4,5-Tricaffeoylquinic acid, Bay 11-7085, Akt inhibitor and N-acetylcysteine inhibited the TNF-α-induced activation of NF-κB, activation of Akt, and formation of reactive oxygen and nitrogen species. The results show that 3,4,5-tricaffeoylquinic acid seems to attenuate the TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of Akt and NF-κB pathways which may be mediated by reactive oxygen species. The findings suggest that 3,4,5-tricaffeoylquinic acid may exert an inhibitory effect against the pro-inflammatory mediator-induced skin disease. Copyright © 2011 Elsevier B.V. All rights reserved.

The Influenza A Virus Genotype Determines the Antiviral Function of NF-κB

PubMed Central

Dam, Sharmistha; Kracht, Michael; Pleschka, Stephan

2016-01-01

ABSTRACT The role of NF-κB in influenza A virus (IAV) infection does not reveal a coherent picture, as pro- and also antiviral functions of this transcription factor have been described. To address this issue, we used clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9)-mediated genome engineering to generate murine MLE-15 cells lacking two essential components of the NF-κB pathway. Cells devoid of either the central NF-κB essential modulator (NEMO) scaffold protein and thus defective in IκB kinase (IKK) activation or cells not expressing the NF-κB DNA-binding and transactivation subunit p65 were tested for propagation of the SC35 virus, which has an avian host range, and its mouse-adapted variant, SC35M. While NF-κB was not relevant for replication of SC35M, the absence of NF-κB activity increased replication of the nonadapted SC35 virus. This antiviral effect of NF-κB was most prominent upon infection of cells with low virus titers as they usually occur during the initiation phase of IAV infection. The defect in NF-κB signaling resulted in diminished IAV-triggered phosphorylation of interferon regulatory factor 3 (IRF3) and expression of the antiviral beta interferon (IFN-β) gene. To identify the viral proteins responsible for NF-κB dependency, reassortant viruses were generated by reverse genetics. SC35 viruses containing the SC35M segment encoding neuraminidase (NA) were completely inert to the inhibitory effect of NF-κB, emphasizing the importance of the viral genotype for susceptibility to the antiviral functions of NF-κB. IMPORTANCE This study addresses two different issues. First, we investigated the role of the host cell transcription factor NF-κB in IAV replication by genetic manipulation of IAVs by reverse genetics combined with targeted genome engineering of host cells using CRISPR-Cas9. The analysis of these two highly defined genetic systems indicated that the IAV genotype can influence whether NF-κB displays an antiviral function and thus might in part explain incoherent results from the literature. Second, we found that perturbation of NF-κB function greatly improved the growth of a nonadapted IAV, suggesting that NF-κB may contribute to the maintenance of the host species barrier. PMID:27356900

The AhR and NF-κB/Rel Proteins Mediate the Inhibitory Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the 3′ Immunoglobulin Heavy Chain Regulatory Region

PubMed Central

Salisbury, Richard L.; Sulentic, Courtney E. W.

2015-01-01

Transcriptional regulation of the murine immunoglobulin (Ig) heavy chain gene (Igh) involves several regulatory elements including the 3′Igh regulatory region (3′IghRR), which is composed of at least 4 enhancers (hs3A, hs1.2, hs3B, and hs4). The hs1.2 and hs4 enhancers exhibit the greatest transcriptional activity and contain binding sites for several transcription factors including nuclear factor kappaB/Rel (NF-κB/Rel) proteins and the aryl hydrocarbon receptor (AhR). Interestingly, the environmental immunosuppressant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which potently inhibits antibody secretion, also profoundly inhibits 3′IghRR and hs1.2 enhancer activation induced by the B-lymphocyte activator lipopolysaccharide (LPS), but enhances LPS-induced activation of the hs4 enhancer. Within the hs1.2 and hs4 enhancers, the AhR binding site is in close proximity or overlaps an NF-κB/Rel binding site suggesting a potential reciprocal modulation of the 3′IghRR by AhR and NF-κB/Rel. The objective of the current study was to evaluate the role of NF-κB/Rel and the AhR on the 3′IghRR and its enhancers using the AhR ligand TCDD, the AhR antagonist CH223191, and toll-like receptor agonists LPS, Resiquimod (R848), or cytosine-phosphate-guanine-oligodeoxynucleotides (CpG). Utilizing the CH12.LX B-lymphocyte cell line and variants expressing either a 3′IghRR-regulated transgene reporter or an inducible IκBα (inhibitor kappa B-alpha protein) superrepressor (IκBαAA), we demonstrate an AhR- and NF-κB/Rel-dependent modulation of 3′IghRR and hs4 activity. Additionally, in mouse splenocytes or CH12.LX cells, binding within the hs1.2 and hs4 enhancer of the AhR and the NF-κB/Rel proteins RelA and RelB was differentially altered by the cotreatment of LPS and TCDD. These results suggest that the AhR and NF-κB/Rel protein binding profile within the 3′IghRR mediates the inhibitory effects of TCDD on Ig expression and therefore antibody levels. PMID:26377645

Effect of UBE2L3 genotype on regulation of the linear ubiquitin chain assembly complex in systemic lupus erythematosus.

PubMed

Lewis, Myles; Vyse, Simon; Shields, Adrian; Boeltz, Sebastian; Gordon, Patrick; Spector, Timothy; Lehner, Paul; Walczak, Henning; Vyse, Timothy

2015-02-26

A single risk haplotype across UBE2L3 is strongly associated with systemic lupus erythematosus (SLE) and many other autoimmune diseases. UBE2L3 is an E2 ubiquitin-conjugating enzyme with specificity for RING-in-between-RING E3 ligases, including HOIL-1 and HOIP, components of the linear ubiquitin chain assembly complex (LUBAC), which has a pivotal role in inflammation, through crucial regulation of NF-κB. We aimed to determine whether UBE2L3 regulates LUBAC-mediated activation of NF-κB, and determine the effect of UBE2L3 genotype on NF-κB activation and B-cell differentiation. UBE2L3 genotype data from SLE genome-wide association studies was imputed by use of 1000 Genomes data. UBE2L3 function was studied in a HEK293-NF-κB reporter cell line with standard molecular biology techniques. p65 NF-κB translocation in ex-vivo B cells and monocytes from genotyped healthy individuals was quantified by imaging flow cytometry. B-cell subsets from healthy individuals and patients with SLE, stratified by UBE2L3 genotype, were determined by multicolour flow cytometry. rs140490, located at -270 base pairs of the UBE2L3 promoter, was identified as the most strongly associated single nucleotide polymorphism (p=8·6 × 10(-14), odds ratio 1·30, 95% CI 1·21-1·39). The rs140490 risk allele increased UBE2L3 expression in B cells and monocytes. Marked upregulation of NF-κB was observed with combined overexpression of UBE2L3 and LUBAC, but abolished by dominant-negative mutant UBE2L3 (C86S), or UBE2L3 silencing. The rs140490 genotype correlated with basal NF-κB activation in ex-vivo human B cells and monocytes, as well as NF-κB sensitivity to CD40 or tumour necrosis factor (TNF) stimulation. UBE2L3 expression was 3-4 times higher in circulating plasmablasts and plasma cells than in other B-cell subsets, with higher levels in patients with SLE than in controls. The rs140490 genotype correlated with increasing plasmablast and plasma cell differentiation in patients with SLE. This study shows that NF-κB activation mediated by LUBAC is exquisitely sensitive to the expression level of UBE2L3. The UBE2L3 risk haplotype is correlated with TNF and CD40 induced NF-κB activation in primary human cells, and with plasmablast and plasma cell expansion in SLE, consistent with the dependence of these cells on NF-κB as a survival factor. Since UBE2L3 is highly expressed in plasma cells, UBE2L3 could be a novel therapeutic target in SLE. Arthritis Research UK, Wellcome Trust, George Koukis Foundation, European Community's Seventh Framework Programme. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cyanidin-3-o-β-Glucoside Induces Megakaryocyte Apoptosis via PI3K/Akt- and MAPKs-Mediated Inhibition of NF-κB Signalling.

PubMed

Ya, Fuli; Li, Qing; Wang, Dongliang; Xie, Shuangfeng; Song, Fenglin; Gallant, Reid C; Tian, Zezhong; Wan, Jianbo; Ling, Wenhua; Yang, Yan

2018-06-04

Apoptotic-like phase is an essential step in thrombopoiesis from megakaryocytes. Anthocyanins are natural flavonoid pigments that possess a wide range of biological activities, including protection against cardiovascular diseases and induction of tumour cell apoptosis. We investigated the effects and underlying mechanisms of cyanidin-3-o-β-glucoside (Cy-3-g, the major bioactive compound in anthocyanins) on the apoptosis of human primary megakaryocytes and Meg-01 cell line in vitro . We found that Cy-3-g dose-dependently increased the dissipation of the mitochondrial membrane potential, caspase-9 and caspase-3 activity in megakaryocytes from patients with newly diagnosed acute myeloid leukaemia but not in those from healthy volunteers. In Meg-01 cells, Cy-3-g regulated the distribution of Bak, Bax and Bcl-xL proteins in the mitochondria and cytosol, subsequently increasing cytochrome c release and stimulating caspase-9 and caspase-3 activation and phosphatidylserine exposure. However, Cy-3-g did not exert significant effects on factor-associated suicide (Fas), Fas ligand, caspase-8 or Bid expression. Cy-3-g inhibited nuclear factor kappa B (NF-κB) p65 activation by down-regulating inhibitor of NF-κB kinase (IKK)α and IKKβ expression, followed by the inhibition of inhibitor of NF-κB (IκB)α phosphorylation and degradation and subsequent inhibition of the translocation of the p65 sub-unit into the nucleus, and finally stimulating caspase-3 activation and phosphatidylserine exposure. The inhibitory effect of Cy-3-g on NF-κB activation was mediated by the activation of extracellular signal-regulated kinases (Erk1/2) and p38 mitogen-activated protein kinase (MAPK) and the inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling. U0126 (Erk1/2 inhibitor), SB203580 (p38 MAPK inhibitor) and 740 Y-P (PI3K agonist) significantly reversed Cy-3-g-reduced phosphorylation of p65. Taken together, our data indicate that Cy-3-g induces megakaryocyte apoptosis via the inhibition of NF-κB signalling, which may play important roles in regulating thrombopoiesis. Schattauer GmbH Stuttgart.

Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1beta-induced NF-kappaB-mediated inflammation and apoptosis.

PubMed

Csaki, Constanze; Mobasheri, Ali; Shakibaei, Mehdi

2009-01-01

Currently available treatments for osteoarthritis (OA) are restricted to nonsteroidal anti-inflammatory drugs, which exhibit numerous side effects and are only temporarily effective. Thus novel, safe and more efficacious anti-inflammatory agents are needed for OA. Naturally occurring polyphenolic compounds, such as curcumin and resveratrol, are potent agents for modulating inflammation. Both compounds mediate their effects by targeting the NF-kappaB signalling pathway. We have recently demonstrated that in chondrocytes resveratrol modulates the NF-kappaB pathway by inhibiting the proteasome, while curcumin modulates the activation of NF-kappaB by inhibiting upstream kinases (Akt). However, the combinational effects of these compounds in chondrocytes has not been studied and/or compared with their individual effects. The aim of this study was to investigate the potential synergistic effects of curcumin and resveratrol on IL-1beta-stimulated human chondrocytes in vitro using immunoblotting and electron microscopy. Treatment with curcumin and resveratrol suppressed NF-kappaB-regulated gene products involved in inflammation (cyclooxygenase-2, matrix metalloproteinase (MMP)-3, MMP-9, vascular endothelial growth factor), inhibited apoptosis (Bcl-2, Bcl-xL, and TNF-alpha receptor-associated factor 1) and prevented activation of caspase-3. IL-1beta-induced NF-kappaB activation was suppressed directly by cocktails of curcumin and resveratrol through inhibition of Ikappakappa and proteasome activation, inhibition of IkappaBalpha phosphorylation and degradation, and inhibition of nuclear translocation of NF-kappaB. The modulatory effects of curcumin and resveratrol on IL-1beta-induced expression of cartilage specific matrix and proinflammatory enzymes were mediated in part by the cartilage-specific transcription factor Sox-9. We propose that combining these natural compounds may be a useful strategy in OA therapy as compared with separate treatment with each individual compound.

Proinflammatory Cytokine Tumor Necrosis Factor (TNF)-like Weak Inducer of Apoptosis (TWEAK) Suppresses Satellite Cell Self-renewal through Inversely Modulating Notch and NF-κB Signaling Pathways*

PubMed Central

Ogura, Yuji; Mishra, Vivek; Hindi, Sajedah M.; Kuang, Shihuan; Kumar, Ashok

2013-01-01

Satellite cell self-renewal is an essential process to maintaining the robustness of skeletal muscle regenerative capacity. However, extrinsic factors that regulate self-renewal of satellite cells are not well understood. Here, we demonstrate that TWEAK cytokine reduces the proportion of Pax7+/MyoD− cells (an index of self-renewal) on myofiber explants and represses multiple components of Notch signaling in satellite cell cultures. The number of Pax7+ cells is significantly increased in skeletal muscle of TWEAK knock-out (KO) mice compared with wild-type in response to injury. Furthermore, Notch signaling is significantly elevated in cultured satellite cells and in regenerating myofibers of TWEAK-KO mice. Forced activation of Notch signaling through overexpression of the Notch1 intracellular domain (N1ICD) rescued the TWEAK-mediated inhibition of satellite cell self-renewal. TWEAK also activates the NF-κB transcription factor in satellite cells and inhibition of NF-κB significantly improved the number of Pax7+ cells in TWEAK-treated cultures. Furthermore, our results demonstrate that a reciprocal interaction between NF-κB and Notch signaling governs the inhibitory effect of TWEAK on satellite cell self-renewal. Collectively, our study demonstrates that TWEAK suppresses satellite cell self-renewal through activating NF-κB and repressing Notch signaling. PMID:24151074

Proinflammatory cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) suppresses satellite cell self-renewal through inversely modulating Notch and NF-κB signaling pathways.

PubMed

Ogura, Yuji; Mishra, Vivek; Hindi, Sajedah M; Kuang, Shihuan; Kumar, Ashok

2013-12-06

Satellite cell self-renewal is an essential process to maintaining the robustness of skeletal muscle regenerative capacity. However, extrinsic factors that regulate self-renewal of satellite cells are not well understood. Here, we demonstrate that TWEAK cytokine reduces the proportion of Pax7(+)/MyoD(-) cells (an index of self-renewal) on myofiber explants and represses multiple components of Notch signaling in satellite cell cultures. The number of Pax7(+) cells is significantly increased in skeletal muscle of TWEAK knock-out (KO) mice compared with wild-type in response to injury. Furthermore, Notch signaling is significantly elevated in cultured satellite cells and in regenerating myofibers of TWEAK-KO mice. Forced activation of Notch signaling through overexpression of the Notch1 intracellular domain (N1ICD) rescued the TWEAK-mediated inhibition of satellite cell self-renewal. TWEAK also activates the NF-κB transcription factor in satellite cells and inhibition of NF-κB significantly improved the number of Pax7(+) cells in TWEAK-treated cultures. Furthermore, our results demonstrate that a reciprocal interaction between NF-κB and Notch signaling governs the inhibitory effect of TWEAK on satellite cell self-renewal. Collectively, our study demonstrates that TWEAK suppresses satellite cell self-renewal through activating NF-κB and repressing Notch signaling.

Connective tissue growth factor enhances the migration of gastric cancer through downregulation of E-cadherin via the NF-κB pathway.

PubMed

Mao, Zhengfa; Ma, Xiaoyan; Rong, Yefei; Cui, Lei; Wang, Xuqing; Wu, Wenchuan; Zhang, Jianxin; Jin, Dayong

2011-01-01

Local invasion and distant metastasis are difficult problems for surgical intervention and treatment in gastric cancer. Connective tissue growth factor (CTGF/CCN2) was considered to have an important role in this process. In this study, we demonstrated that expression of CTGF was significantly upregulated in clinical tissue samples of gastric carcinoma (GC) samples. Forced expression of CTGF in AGS GC cells promoted their migration in culture and significantly increased tumor metastasis in nude mice, whereas RNA interference-mediated knockdown of CTGF in GC cells significantly inhibited cell migration in vitro. We disclose that CTGF downregulated the expression of E-cadherin through activation of the nuclear factor-κappa B (NF-κB) pathway. The effects of CTGF in GC cells were abolished by dominant negative IκappaB. Collectively, these data reported here demonstrate CTGF could modulate the NF-κappaB pathway and perhaps be a promising therapeutic target for gastric cancer invasion and metastasis. © 2010 Japanese Cancer Association.

3D MnO2-graphene composites with large areal capacitance for high-performance asymmetric supercapacitors.

PubMed

Zhai, Teng; Wang, Fuxin; Yu, Minghao; Xie, Shilei; Liang, Chaolun; Li, Cheng; Xiao, Fangming; Tang, Renheng; Wu, Qixiu; Lu, Xihong; Tong, Yexiang

2013-08-07

In this paper, we reported an effective and simple strategy to prepare large areal mass loading of MnO2 on porous graphene gel/Ni foam (denoted as MnO2/G-gel/NF) for supercapacitors (SCs). The MnO2/G-gel/NF (MnO2 mass: 13.6 mg cm(-2)) delivered a large areal capacitance of 3.18 F cm(-2) (234.2 F g(-1)) and good rate capability. The prominent electrochemical properties of MnO2/G-gel/NF are attributed to the enhanced conductivities and improved accessible area for ions in electrolytes. Moreover, an asymmetric supercapacitor (ASC) based on MnO2/G-gel/NF (MnO2 mass: 6.1 mg cm(-2)) as the positive electrode and G-gel/NF as the negative electrode achieved a remarkable energy density of 0.72 mW h cm(-3). Additionally, the fabricated ASC device also exhibited excellent cycling stability, with less than 1.5% decay after 10,000 cycles. The ability to effectively develop SC electrodes with high mass loading should open up new opportunities for SCs with high areal capacitance and high energy density.

Divergent Effects of Arsenic on NF-κB Signaling in Different Cells or Tissues: A Systematic Review and Meta-Analysis.

PubMed

Wei, Meng; Liu, Jiaming; Xu, Mengchuan; Rui, Dongsheng; Xu, Shangzhi; Feng, Gangling; Ding, Yusong; Li, Shugang; Guo, Shuxia

2016-01-26

Arsenic is ubiquitously present in human lives, including in the environment and organisms, and has divergent effects between different cells and tissues and between different exposure times and doses. These observed effects have been attributed to the nuclear transcription factor kappa B(NF-κB) signaling pathway. Herein, a meta-analysis was performed by independently searching databases including the Cochrane Library, PubMed, Springer, Embase, and China National Knowledge Infrastructure, to analyze effects of arsenic exposure on NF-κB signaling. Compared to controls, in the exposed group, p-IκB levels were found to be 8.13-fold higher (95% CI, 2.40-13.85; Z = 2.78; p = 0.005), IκB levels were 16.19-fold lower (95% CI, -27.44--4.94; Z = 2.78; p = 0.005), and NF-κBp65 levels were 0.77-fold higher (95% CI, 0.13-1.42; Z = 2.34; p = 0.02) for normal cells and tissue, while NF-κBp65 levels were 4.90-fold lower (95% CI, -8.49-1.31; Z = 2.62; p = 0.009), NF-κB activity was 2.45-fold lower (95% CI, -3.66-1.25; Z = 4.00; p < 0.0001), and DNA-binding activity of NF-κB was 9.75-fold lower (95% CI, -18.66-4.54; Z = 2.15; p = 0.03) for abnormal cells and tissue. Short exposure to high arsenic doses activated the NF-κB signaling pathway, while long exposure to low arsenic doses suppressed NF-κB signaling pathway activation. These findings may provide a theoretical basis for injurious and therapeutic mechanisms of divergent effects of arsenic.

Regulation of NF-κB oscillation by spatial parameters in true intracellular space (TiCS)

NASA Astrophysics Data System (ADS)

Ohshima, Daisuke; Sagara, Hiroshi; Ichikawa, Kazuhisa

2013-10-01

Transcription factor NF-κB is activated by cytokine stimulation, viral infection, or hypoxic environment leading to its translocation to the nucleus. The nuclear NF-κB is exported from the nucleus to the cytoplasm again, and by repetitive import and export, NF-κB shows damped oscillation with the period of 1.5-2.0 h. Oscillation pattern of NF-κB is thought to determine the gene expression profile. We published a report on a computational simulation for the oscillation of nuclear NF-κB in a 3D spherical cell, and showed the importance of spatial parameters such as diffusion coefficient and locus of translation for determining the oscillation pattern. Although the value of diffusion coefficient is inherent to protein species, its effective value can be modified by organelle crowding in intracellular space. Here we tested this possibility by computer simulation. The results indicate that the effective value of diffusion coefficient is significantly changed by the organelle crowding, and this alters the oscillation pattern of nuclear NF-κB.

Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury.

PubMed

Chen, Xiangrong; Wu, Shukai; Chen, Chunnuan; Xie, Baoyuan; Fang, Zhongning; Hu, Weipeng; Chen, Junyan; Fu, Huangde; He, Hefan

2017-07-24

Microglial activation and the subsequent inflammatory response in the central nervous system play important roles in secondary damage after traumatic brain injury (TBI). High-mobility group box 1 (HMGB1) protein, an important mediator in late inflammatory responses, interacts with transmembrane receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) to activate downstream signaling pathways, such as the nuclear factor (NF)-κB signaling pathway, leading to a cascade amplification of inflammatory responses, which are related to neuronal damage after TBI. Omega-3 polyunsaturated fatty acid (ω-3 PUFA) is a commonly used clinical immunonutrient, which has antioxidative and anti-inflammatory effects. However, the effects of ω-3 PUFA on HMGB1 expression and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway are not clear. The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglial activation in lesioned sites and protein markers for proinflammatory, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and HMGB1 were used to evaluate neuroinflammatory responses and anti-inflammation effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway to evaluate the effects of ω-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. It was found that ω-3 PUFA supplementation inhibited TBI-induced microglial activation and expression of inflammatory factors (TNF-α, IL-1β, IL-6, and IFN-γ), reduced brain edema, decreased neuronal apoptosis, and improved neurological functions after TBI. We further demonstrated that ω-3 PUFA supplementation inhibited HMGB1 nuclear translocation and secretion and decreased expression of HMGB1 in neurons and microglia in the lesioned areas. Moreover, ω-3 PUFA supplementation inhibited microglial activation and the subsequent inflammatory response by regulating HMGB1 and the TLR4/NF-κB signaling pathway. The results of this study suggest that microglial activation and the subsequent neuroinflammatory response as well as the related HMGB1/TLR4/NF-κB signaling pathway play essential roles in secondary injury after TBI. Furthermore, ω-3 PUFA supplementation inhibited TBI-induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1-mediated activation of the TLR4/NF-κB signaling pathway, leading to neuroprotective effects.

Bioremediation of contaminated groundwater

DOEpatents

Hazen, T.C.; Fliermans, C.B.

1994-01-01

Disclosed is an apparatus and method for in situ remediation of contaminated subsurface soil or groundwater contaminated by chlorinated hydrocarbons. A nutrient fluid (NF) is selected to simulated the growth and reproduction of indigenous subsurface microorganisms capable of degrading the contaminants; an oxygenated fluid (OF) is selected to create an aerobic environment with anaerobic pockets. NF is injected periodically while OF is injected continuously and both are extracted so that both are drawn across the plume. NF stimulates microbial colony growth; withholding it periodically forces the larger, healthy colony of microbes to degrade the contaminants. Treatment is continued until the subsurface concentration of contaminants is acceptable. NF can be methane and OF be air, for stimulating production of methanotrophs to break down chlorohydrocarbons, especially TCE and tetrachloroethylene.

Effect of natural and semi-synthetic cadinanes from Heterotheca inuloides on NF-κB, Nrf2 and STAT3 signaling pathways and evaluation of their in vitro cytotoxicity in human cancer cell lines.

PubMed

Egas, Verónica; Millán, Estrella; Collado, Juan A; Ramírez-Apan, Teresa; Méndez-Cuesta, Carlos A; Muñoz, Eduardo; Delgado, Guillermo

2017-06-15

The effects of ten natural cadinane sesquiterpenoids isolated from Heterotheca inuloides on the pathways of the NF-κB, Nrf2 and STAT3 transcription factors were studied for the first time. The main constituent in this species, 7-hydroxy-3,4-dihydrocadalene (1), showed anti-NF-κB activity and activated the antioxidant Nrf2 pathway, which may explain the properties reported for the traditional use of the plant. In addition to the main metabolite, a structurally similar compound, 7-hydroxy-cadalene (2), also displayed anti-NF-κB activity. Thus, both natural compounds were used as templates for the preparation of a novel semi-synthetic derivative set, including esters and carbamates, which were evaluated for their potential in vitro antiproliferative activities against six human cancer cell lines. Carbamate derivatives 32 and 33 were found to exhibit potent activity against human colorectal adenocarcinoma and showed important selectivity in cancer cells. Among ester derivatives, compound 13 was determined to be a more potent NF-κB inhibitor and Nrf2 activator than its parent, 7-hydroxy-3,4-dihydrocadalene (1). Furthermore, this compound decreases levels of phospho-IκBα, a protein complex involved in the NF-κB activation pathway. Molecular simulations suggest that all active compounds interact with the activation loop of the IKKβ subunit in the IKK complex, which is the responsible of IκBα phosphorylation. Thus, we identified two natural, and one semi-synthetic, NF-κB and Nrf2 modulators and two new promising cytotoxic compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibition of IκB Kinase-Nuclear Factor-κB Signaling Pathway by 3,5-Bis(2-flurobenzylidene)piperidin-4-one (EF24), a Novel Monoketone Analog of Curcumin*

PubMed Central

Kasinski, Andrea L.; Du, Yuhong; Thomas, Shala L.; Zhao, Jing; Sun, Shi-Yong; Khuri, Fadlo R.; Wang, Cun-Yu; Shoji, Mamoru; Sun, Aiming; Snyder, James P.; Liotta, Dennis; Fu, Haian

2009-01-01

The nuclear factor-κB (NF-κB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-κB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-κB signaling pathway through direct action on IκB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-κB, with an IC50 value of 1.3 μM compared with curcumin, with an IC50 value of 13 μM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-α-induced IκB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-α-induced NF-κB signaling by EF24 extends the therapeutic application of EF24 to other NF-κB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis. PMID:18577686

Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin.

PubMed

Kasinski, Andrea L; Du, Yuhong; Thomas, Shala L; Zhao, Jing; Sun, Shi-Yong; Khuri, Fadlo R; Wang, Cun-Yu; Shoji, Mamoru; Sun, Aiming; Snyder, James P; Liotta, Dennis; Fu, Haian

2008-09-01

The nuclear factor-kappaB (NF-kappaB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-kappaB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-kappaB signaling pathway through direct action on IkappaB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-kappaB, with an IC(50) value of 1.3 microM compared with curcumin, with an IC(50) value of 13 microM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-alpha-induced IkappaB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-alpha-induced NF-kappaB signaling by EF24 extends the therapeutic application of EF24 to other NF-kappaB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis.

Surface-modified Ba(Zr0.3Ti0.7)O3 nanofibers by polyvinylpyrrolidone filler for poly(vinylidene fluoride) composites with enhanced dielectric constant and energy storage density.

PubMed

Liu, Shaohui; Xue, Shuangxi; Xiu, Shaomei; Shen, Bo; Zhai, Jiwei

2016-05-17

Ferroelectric-relaxor behavior of Ba(Zr0.3Ti0.7)O3 nanofibers (BZT NF) with a large aspect ratio were prepared via electrospinning and surface modified by PVP as dielectric fillers. The nanocomposite flexible films based on surface modified BZT NF and polyvinylidene fluoride (PVDF) were fabricated via a solution casting. The results show that the surface-modified BZT NF fillers are highly dispersed and well integrated in the PVDF nanocomposites. The nanocomposites exhibit enhanced dielectric constant and reduced loss tangents at a low volume fraction of surface-modified BZT NF. The polymer nanocomposites maintain a relatively high breakdown strength, which is favorable for enhancing energy storage density in the nanocomposites. The nanocomposite containing of 2.5 vol. % of PVP modified BZT NF exhibits energy density as high as 6.3 J/cm(3) at 3800 kV/cm, which is more than doubled that of the pure PVDF of 2.8 J/cm(3) at 4000 kV/cm. Such significant enhancement could be attributed to the combined effects of the surface modification and large aspect ratio of the BZT NF. This work may provide a route for using the surface modified ferroelectric-relaxor behavior of ceramic nanofibers to enhance the dielectric energy density in ceramic-polymer nanocomposites.

Synergistic effect of baicalein, wogonin and oroxylin A mixture: multistep inhibition of the NF-κB signalling pathway contributes to an anti-inflammatory effect of Scutellaria root flavonoids.

PubMed

Shimizu, Tomofumi; Shibuya, Nobuhiko; Narukawa, Yuji; Oshima, Naohiro; Hada, Noriyasu; Kiuchi, Fumiyuki

2018-01-01

Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids contained in Scutellaria root have been found to inhibit PGE 2 production more strongly than individual flavonoids. Here, to investigate the mechanism of the synergistic effect, we examined the effects of an equimolar mixture (F-mix) of baicalein (1), wogonin (2) and oroxylin A (3) on the production of PGE 2 in LPS-treated J774.1 cells. Although 1 and 3 inhibited COX-2 activity, the F-mix showed no synergistic effect on COX-2 inhibition. Therefore, we investigated the steps leading to the activation of COX-2 protein. Compounds 1-3 and F-mix inhibited the expression of COX-2 protein. However, only 2 inhibited the expression of COX-2 mRNA among the flavonoids, and the F-mix showed no synergistic effect. Only 1 inhibited NF-κB translocation into the nucleus, and the F-mix showed no synergistic effect. Although 2 did not affect NF-κB translocation, it strongly inhibited NF-κB-dependent transcriptional activity, and the F-mix inhibited the activity slightly more than 2. Compounds 1-3 also inhibited NO production, and the F-mix showed a synergistic effect. However, the effects of each flavonoid on the expression of iNOS mRNA were not consistent with those on COX-2 mRNA. Because the flavonoids inhibit different steps in the production of PGE 2 and NO, and their mixture did not show apparent synergistic effects in each step, we conclude that the synergistic effect of the flavonoid mixture reflects the total effect of the flavonoids inhibiting different steps in the NF-κB signalling pathway.

A Randomized Controlled Study of Neurofeedback for Chronic PTSD

PubMed Central

van der Kolk, Bessel A.; Hodgdon, Hilary; Gapen, Mark; Musicaro, Regina; Suvak, Michael K.; Hamlin, Ed; Spinazzola, Joseph

2016-01-01

Introduction Brain/Computer Interaction (BCI) devices are designed to alter neural signals and, thereby, mental activity. This study was a randomized, waitlist (TAU) controlled trial of a BCI, EEG neurofeedback training (NF), in patients with chronic PTSD to explore the capacity of NF to reduce PTSD symptoms and increase affect regulation capacities. Study Design 52 individuals with chronic PTSD were randomized to either NF (n = 28) or waitlist (WL) (n = 24). They completed four evaluations, at baseline (T1), after week 6 (T2), at post-treatment (T3), and at one month follow up (T4). Assessment measures were:1. Traumatic Events Screening Inventory (T1); 2. the Clinician Administered PTSD Scale (CAPS; T1, T3, T4); 3. the Davidson Trauma Scale (DTS; T1-T4) and 4. the Inventory of Altered Self-Capacities (IASC; T1-T4). NF training occurred two times per week for 12 weeks and involved a sequential placement with T4 as the active site, P4 as the reference site. Results Participants had experienced an average of 9.29 (SD = 2.90) different traumatic events. Post-treatment a significantly smaller proportion of NF (6/22, 27.3%) met criteria for PTSD than the WL condition (15/22, 68.2%), χ2 (n = 44, df = 1) = 7.38, p = .007. There was a significant treatment condition x time interaction (b = -10.45, t = -5.10, p< .001). Measures of tension reduction activities, affect dysregulation, and affect instability exhibited a significant Time x Condition interaction. The effect sizes of NF (d = -2.33 within, d = - 1.71 between groups) are comparable to those reported for the most effective evidence based treatments for PTSD. Discussion Compared with the control group NF produced significant PTSD symptom improvement in individuals with chronic PTSD, as well as in affect regulation capacities. NF deserves further investigation for its potential to ameliorate PTSD and to improve affect regulation, and to clarify its mechanisms of action. PMID:27992435

A Novel Pentamethoxyflavone Down-Regulates Tumor Cell Survival and Proliferative and Angiogenic Gene Products through Inhibition of IκB Kinase Activation and Sensitizes Tumor Cells to Apoptosis by Cytokines and Chemotherapeutic Agents

PubMed Central

Phromnoi, Kanokkarn; Reuter, Simone; Sung, Bokyung; Prasad, Sahdeo; Kannappan, Ramaswamy; Yadav, Vivek R.; Chanmahasathien, Wisinee; Limtrakul, Pornngarm

2011-01-01

Most anticancer drugs have their origin in traditional medicinal plants. We describe here a flavone, 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone (PMF), from the leaves of the Thai plant Gardenia obtusifolia, that has anti-inflammatory and anticancer potential. Because the nuclear factor-κB (NF-κB) pathway is linked to inflammation and tumorigenesis, we investigated the effect of PMF on this pathway. We found that PMF suppressed NF-κB activation induced by inflammatory agents, tumor promoters, and carcinogens. This suppression was not specific to the cell type. Although PMF did not directly modify the ability of NF-κB proteins to bind to DNA, it inhibited IκBα (inhibitory subunit of NF-κB) kinase, leading to suppression of phosphorylation and degradation of IκBα, and suppressed consequent p65 nuclear translocation, thus abrogating NF-κB-dependent reporter gene expression. Suppression of the NF-κB cell signaling pathway by the flavone led to the inhibition of expression of NF-κB-regulated gene products that mediate inflammation (cyclooxygenase-2), survival (XIAP, survivin, Bcl-xL, and cFLIP), proliferation (cyclin D1), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of antiapoptotic gene products by PMF correlated with the enhancement of apoptosis induced by tumor necrosis factor-α and the chemotherapeutic agents cisplatin, paclitaxel, and 5-flurouracil. Overall, our results indicate that PMF suppresses the activation of NF-κB and NF-κB-regulated gene expression, leading to the enhancement of apoptosis. This is the first report to demonstrate that this novel flavone has anti-inflammatory and anticancer effects by targeting the IKK complex. PMID:20930110

Magnesium Isoglycyrrhizinate attenuates lipopolysaccharide-induced depressive-like behavior in mice.

PubMed

Jiang, Wenjiao; Chen, Qianying; Li, Peijin; Lu, Qianfeng; Pei, Xue; Sun, Yilin; Wang, Guangji; Hao, Kun

2017-02-01

Magnesium Isoglycyrrhizinate (MI) is a magnesium salt of 18α-GA stereoisomer which has been reported to exert hepatoprotective activity. The aim of the present study was to ascertain the underlying mechanisms behind the action of Magnesium Isoglycyrrhizinate on neuroinflammatation and oxidative stress in LPS-stimulated mice. Mice were pretreated with Magnesium Isoglycyrrhizinate (MI, 25, 50mg/kg) as well as fluoxetine (Flu, positive control, 20mg/kg) once daily for one week before intraperitoneal injection of LPS (0.83mg/kg). Pretreatments with MI and Flu significantly improved immobility time in tail suspension test (TST) and forced swim test (FST) as well as locomotor activity in open-field test (OFT). In addition, the levels of pro-inflammatory cytokines and oxidative stress in serum and hippocampus were also suppressed effectively by MI and Flu administrations. Western blot analysis showed the up-regulated levels of p-Jak3, p-STAT3, p-NF-κBp65, and p-IκBα in mice exposed to LPS, while different degrees of down-regulation in these expression were observed in MI (25, 50mg/kg) and Flu (20mg/kg) groups respectively. Taken together, our obtained results demonstrated that Magnesium Isoglycyrrhizinate (MI) exhibited an antidepressant-like effect in LPS-induced mice, which might be mediated by JAK/STAT/NF-κB signaling pathway. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Activation of Peroxisome Proliferator–Activated Receptor β/δ Inhibits Lipopolysaccharide-Induced Cytokine Production in Adipocytes by Lowering Nuclear Factor-κB Activity via Extracellular Signal–Related Kinase 1/2

PubMed Central

Rodríguez-Calvo, Ricardo; Serrano, Lucía; Coll, Teresa; Moullan, Norman; Sánchez, Rosa M.; Merlos, Manuel; Palomer, Xavier; Laguna, Juan C.; Michalik, Liliane; Wahli, Walter; Vázquez-Carrera, Manuel

2008-01-01

OBJECTIVE—Chronic activation of the nuclear factor-κB (NF-κB) in white adipose tissue leads to increased production of pro-inflammatory cytokines, which are involved in the development of insulin resistance. It is presently unknown whether peroxisome proliferator–activated receptor (PPAR) β/δ activation prevents inflammation in adipocytes. RESEARCH DESIGN AND METHODS AND RESULTS—First, we examined whether the PPARβ/δ agonist GW501516 prevents lipopolysaccharide (LPS)-induced cytokine production in differentiated 3T3-L1 adipocytes. Treatment with GW501516 blocked LPS-induced IL-6 expression and secretion by adipocytes and the subsequent activation of the signal transducer and activator of transcription 3 (STAT3)–Suppressor of cytokine signaling 3 (SOCS3) pathway. This effect was associated with the capacity of GW501516 to impede LPS-induced NF-κB activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPARβ/δ expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-κB DNA-binding activity. Furthermore, IL-6 expression and NF-κB DNA-binding activity was higher in white adipose tissue from PPARβ/δ-null mice than in wild-type mice. Because mitogen-activated protein kinase–extracellular signal–related kinase (ERK)1/2 (MEK1/2) is involved in LPS-induced NF-κB activation in adipocytes, we explored whether PPARβ/δ prevented NF-κB activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylation by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-κB activity, such as ZDF rats and PPARβ/δ-null mice, also showed enhanced phospho-ERK1/2 levels. CONCLUSIONS—These findings indicate that activation of PPARβ/δ inhibits enhanced cytokine production in adipocytes by preventing NF-κB activation via ERK1/2, an effect that may help prevent insulin resistance. PMID:18443198

Astragaloside IV Attenuated 3,4-Benzopyrene-Induced Abdominal Aortic Aneurysm by Ameliorating Macrophage-Mediated Inflammation.

PubMed

Wang, Jiaoni; Zhou, Yingying; Wu, Shaoze; Huang, Kaiyu; Thapa, Saroj; Tao, Luyuan; Wang, Jie; Shen, Yigen; Wang, Jinsheng; Xue, Yangjing; Ji, Kangting

2018-01-01

Abdominal aortic aneurysm (AAA), characterized by macrophage infiltration-mediated inflammation and oxidative stress, is a potentially fatal disease. Astragaloside IV (AS-IV) has been acknowledged to exhibit antioxidant and anti-inflammatory properties. This study was designed to investigate the protective effect of AS-IV against AAA formation induced by 3,4-benzopyrene (Bap) and angiotensin II (Ang II), and to explore probable mechanisms. Results showed that AS-IV decreased AAA formation, and reduced macrophage infiltration and expression of matrix metalloproteinase. Furthermore, AS-IV abrogated Bap-/Ang II-induced NF-κB activation and oxidative stress. In vitro , AS-IV inhibition of macrophage activation and NF-κB was correlated with increased phosphorylation of phosphatidylinositol 3-kinase (PI3-K)/AKT. Together, our findings suggest that AS-IV has potential as an intervention in the formation of AAA. (1)The protective effect of Astragaloside IV (AS-IV) on abdominal aortic aneurysm (AAA) is associated with its suppressing effects on inflammation in the aortic wall.(2)AS-IV abrogated 3,4-benzopyrene (Bap)/angiotensin II (Ang II)-induced nuclear factor-κB (NF-κB) activation and oxidative stress.(3)AS-IV inhibited Bap-induced RAW264.7 macrophage cells activation by inhibiting oxidative stress and NF-κB activation through phosphatidylinositol 3-kinase (PI3-K)/AKT pathway.AS-IV is a potential preventive agent for cigarette smoking-related AAA.

Tumor Necrosis Factor-α– and Interleukin-1β–Dependent Matrix Metalloproteinase-3 Expression in Nucleus Pulposus Cells Requires Cooperative Signaling via Syndecan 4 and Mitogen-Activated Protein Kinase–NF-κB Axis

PubMed Central

Wang, Xin; Wang, Hua; Yang, Hao; Li, Jun; Cai, Qiqing; Shapiro, Irving M.; Risbud, Makarand V.

2015-01-01

Matrix metalloproteinase-3 (MMP-3) plays an important role in intervertebral disc degeneration, a ubiquitous condition closely linked to low back pain and disability. Elevated expression of syndecan 4, a cell surface heparan sulfate proteoglycan, actively controls disc matrix catabolism. However, the relationship between MMP-3 expression and syndecan 4 in the context of inflammatory disc disease has not been clearly defined. We investigated the mechanisms by which cytokines control MMP-3 expression in rat and human nucleus pulposus cells. Cytokine treatment increased MMP-3 expression and promoter activity. Stable silencing of syndecan 4 blocked cytokine-mediated MMP-3 expression; more important, syndecan 4 did not mediate its effects through NF-κB or mitogen-activated protein kinase (MAPK) pathways. However, treatment with MAPK and NF-κB inhibitors resulted in partial blocking of the inductive effect of cytokines on MMP-3 expression. Loss-of-function studies confirmed that NF-κB, p38α/β2/γ/δ, and extracellular signal–regulated kinase (ERK) 2, but not ERK1, contributed to cytokine-dependent induction of MMP3 promoter activity. Similarly, inhibitor treatments, lentiviral short hairpin-p65, and short hairpin-IκB kinase β significantly decreased cytokine-dependent up-regulation in MMP-3 expression. Finally, we show that transforming growth factor-β can block the up-regulation of MMP-3 induced by tumor necrosis factor (TNF)-α by counteracting the NF-κB pathway and syndecan 4 expression. Taken together, our results suggest that cooperative signaling through syndecan 4 and the TNF receptor 1–MAPK–NF-κB axis is required for TNF-α–dependent expression of MMP-3 in nucleus pulposus cells. Controlling these pathways may slow the progression of intervertebral disc degeneration and matrix catabolism. PMID:25063530

Upstream regulators and downstream effectors of NF-κB in Alzheimer's disease.

PubMed

Shi, Zhe-Min; Han, Ya-Wei; Han, Xiao-Hui; Zhang, Kun; Chang, Ya-Nan; Hu, Zhi-Mei; Qi, Hai-Xia; Ting, Chen; Zhen, Zhang; Hong, Wei

2016-07-15

Since Alzheimer's disease (AD) is becoming the prevalent dementia in the whole world, more underlying mechanisms are emerging. Long time has the transcription factor NF-κB been identified to participate in AD pathogenesis, various studies have focused on the causes and effects of AD that are linked to NF-κB. In this review we discuss diverse environmental stimuli including oxidative stress, neuroinflammation and metabolism, involved signaling pathways such as PI3K/AKT, MAPK and AGE/RAGE/GSK-3 and newly found ncRNAs that mediate neuron toxicity or neuron protection through NF-κB activation and the following response associated with the same factors in AD. These may provide future orientation of investigation at transcription level and support efficient treatment to AD by a better understanding of the upstream regulators and downstream effectors of NF-κB. Copyright © 2016 Elsevier B.V. All rights reserved.

NF-{kappa}B inhibition is involved in tobacco smoke-induced apoptosis in the lungs of rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhong Caiyun; Zhou Yamei; Pinkerton, Kent E.

2008-07-15

Apoptosis is a vital mechanism for the regulation of cell turnover and plays a critical role in tissue homeostasis and development of many disease processes. Previous studies have demonstrated the apoptotic effect of tobacco smoke; however, the molecular mechanisms by which tobacco smoke triggers apoptosis remain unclear. In the present study we investigated the effects of tobacco smoke on the induction of apoptosis in the lungs of rats and modulation of nuclear factor-kappa B (NF-{kappa}B) in this process. Exposure of rats to 80 mg/m{sup 3} tobacco smoke significantly induced apoptosis in the lungs. Tobacco smoke resulted in inhibition of NF-{kappa}Bmore » activity, noted by suppression of inhibitor of {kappa}B (I{kappa}B) kinase (IKK), accumulation of I{kappa}B{alpha}, decrease of NF-{kappa}B DNA binding activity, and downregulation of NF-{kappa}B-dependent anti-apoptotic proteins, including Bcl-2, Bcl-xl, and inhibitors of apoptosis. Initiator caspases for the death receptor pathway (caspase 8) and the mitochondrial pathway (caspase 9) as well as effector caspase 3 were activated following tobacco smoke exposure. Tobacco smoke exposure did not alter the levels of p53 and Bax proteins. These findings suggest the role of NF-{kappa}B pathway in tobacco smoke-induced apoptosis.« less

Transforming growth factor-beta 1 (TGF-beta1) promotes IL-2 mRNA expression through the up-regulation of NF-kappaB, AP-1 and NF-AT in EL4 cells.

PubMed

Han, S H; Yea, S S; Jeon, Y J; Yang, K H; Kaminski, N E

1998-12-01

Transforming growth factor beta1 (TGF-beta1) has been previously shown to modulate interleukin 2 (IL-2) secretion by activated T-cells. In the present studies, we determined that TGF-beta1 induced IL-2 mRNA expression in the murine T-cell line EL4, in the absence of other stimuli. IL-2 mRNA expression was significantly induced by TGF-beta1 (0.1-1 ng/ml) over a relatively narrow concentration range, which led to the induction of IL-2 secretion. Under identical condition, we examined the effect of TGF-beta1 on the activity of nuclear factor AT (NF-AT), nuclear factor kappaB (NF-kappaB), activator protein-1 (AP-1) and octamer, all of which contribute to the regulation of IL-2 gene expression. Electrophoretic mobility shift assays showed that TGF-beta1 markedly increased NF-AT, NF-kappaB and AP-1 binding to their respective cognate DNA binding sites, whereas octamer binding remained constant, as compared with untreated cells. Employing a reporter gene expression system with p(NF-kappaB)3-CAT, p(NF-AT)3-CAT and p(AP-1)3-CAT, TGF-beta1 treatment of transfected EL4 cells induced a dose-related increase in chloramphenicol acetyltransferase activity that correlated well with the DNA binding profile found in the electrophoretic mobility shift assay studies. These results show that TGF-beta1, in the absence of any additional stimuli, up-regulates the activity of key transcription factors involved in IL-2 gene expression, including NF-AT, NF-kappaB and AP-1, to help promote IL-2 mRNA expression by EL4 cells.

OsNF-YC2 and OsNF-YC4 proteins inhibit flowering under long-day conditions in rice.

PubMed

Kim, Soon-Kap; Park, Hyo-Young; Jang, Yun Hee; Lee, Keh Chien; Chung, Young Soo; Lee, Jeong Hwan; Kim, Jeong-Kook

2016-03-01

OsNF-YC2 and OsNF-YC4 proteins regulate the photoperiodic flowering response through the modulation of three flowering-time genes ( Ehd1, Hd3a , and RFT1 ) in rice. Plant NUCLEAR FACTOR Y (NF-Y) transcription factors control numerous developmental processes by forming heterotrimeric complexes, but little is known about their roles in flowering in rice. In this study, it is shown that some subunits of OsNF-YB and OsNF-YC interact with each other, and among them, OsNF-YC2 and OsNF-YC4 proteins regulate the photoperiodic flowering response of rice. Protein interaction studies showed that the physical interactions occurred between the three OsNF-YC proteins (OsNF-YC2, OsNF-YC4 and OsNF-YC6) and three OsNF-YB proteins (OsNF-YB8, OsNF-YB10 and OsNF-YB11). Repression and overexpression of the OsNF-YC2 and OsNF-YC4 genes revealed that they act as inhibitors of flowering only under long-day (LD) conditions. Overexpression of OsNF-YC6, however, promoted flowering only under LD conditions, suggesting it could function as a flowering promoter. These phenotypes correlated with the changes in the expression of three rice flowering-time genes [Early heading date 1 (Ehd1), Heading date 3a (Hd3a) and RICE FLOWERING LOCUS T1 (RFT1)]. The diurnal and tissue-specific expression patterns of the subsets of OsNF-YB and OsNF-YC genes were similar to those of CCT domain encoding genes such as OsCO3, Heading date 1 (Hd1) and Ghd7. We propose that OsNF-YC2 and OsNF-YC4 proteins regulate the photoperiodic flowering response by interacting directly with OsNF-YB8, OsNF-YB10 or OsNF-YB11 proteins in rice.

Neurofeedback ineffective in paediatric brain tumour survivors: Results of a double-blind randomised placebo-controlled trial.

PubMed

de Ruiter, Marieke Anna; Oosterlaan, Jaap; Schouten-van Meeteren, Antoinette Yvonne Narda; Maurice-Stam, Heleen; van Vuurden, Dannis Gilbert; Gidding, Corrie; Beek, Laura Rachel; Granzen, Bernd; Caron, Huib N; Grootenhuis, Martha Alexandra

2016-09-01

Many paediatric brain tumour survivors (PBTS) suffer from neurocognitive impairments. Promising effects of neurofeedback (NF) on neurocognitive functioning have been reported, however research into NF for PBTS has not been conducted. We investigated the effects of NF on neurocognitive functioning in PBTS using a double-blind randomised placebo-controlled trial with a parallel-group design (Pediatric Research on Improving Speed, Memory, and Attention; the PRISMA study). Eligible for inclusion were PBTS with neurocognitive complaints, aged 8-18 years, >2 years post-treatment. They were recruited from five medical centres in the Netherlands. A randomisation table assigned participants to 30 sessions (two per week) of either NF or placebo feedback (PF) (ratio 1:1). Participants, parents, trainers, and researchers handling the data were blinded to group assignment. Participants were assessed pre-, post- and 6 months post-training to determine whether NF training would lead to improved functioning as compared with PF training. Primary outcome measures were attention, processing speed, memory, executive functioning, visuomotor integration, and intelligence. Linear mixed models analyses were used to test differences between NF and PF training over time. A total of 82 children were enrolled (mean age 13.9 years, standard deviation = 3.2, 49% males); 80 participants were randomised (NF: n = 40, PF n = 40); 71 participants completed the training (NF: n = 34, PF: n = 37); 68 participants completed training and 6 months post-training assessment (NF: n = 33, PF: n = 35). Similar improvements were found over time for the two treatment groups on the primary outcomes (all p's > 0.15). Results indicated no specific treatment-effects of NF on neurocognitive functioning of PBTS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Knockdown of NF-κB1 by shRNA Inhibits the Growth of Renal Cell Carcinoma In Vitro and In Vivo.

PubMed

Ikegami, Amanda; Teixeira, Luiz Felipe S; Braga, Marina S; Dias, Matheus Henrique Dos S; Lopes, Eduardo C; Bellini, Maria Helena

2018-06-11

Renal cell carcinoma (RCC) accounts for approximately 2%-3% of human malignancies and is the most aggressive among urologic tumors. Biological heterogeneity, drug resistance, and chemotherapy side effects are the biggest obstacles to the effective treatment of RCC. The NF-κB transcription factor is one of several molecules identified to be responsible for the aggressive phenotype of this tumor. In the past decade, several studies have demonstrated the activation of NF-κB in RCC, and many have implicated NF-κB1 (p50) as an important molecule in tumor progression and metastasis. In the present study, a lentivirus was used to deliver shRNA targeting NF-κB1 into mouse RCC (Renca) cells. It was determined that the knockdown of the NF-κB1 gene led to a reduction in cell proliferation and late apoptosis/necrosis in vitro. Flow cytometry analysis demonstrated G2/M arrest in the cells. In addition, immunoblotting analysis revealed a significant increase in cyclin B1 and Bax. In vivo experiments showed that Renca-shRNA-NF-κB1 cells have significantly diminished tumorigenicity. Moreover, immunohistochemical analysis revealed an increase in necrotic areas of Renca-shRNA-NF-κB1 tumors. Thus, this study indicates that downregulation of NF-κB1 can suppress RCC tumorigenesis by inducing late apoptosis/necrosis. Therefore, NF-κB1 may be a potential therapeutic target for RCC.

The impact of a mind-body program on multiple dimensions of resiliency among geographically diverse patients with neurofibromatosis.

PubMed

Zale, Emily L; Pierre-Louis, Catherine; Macklin, Eric A; Riklin, Eric; Vranceanu, Ana-Maria

2018-04-01

The neurofibromatoses (NF) are incurable genetic disorders that can cause nerve sheath tumors, chronic pain, and disfiguration. Patients with NF report lower quality of life and greater distress, and may benefit from programs that promote resiliency. To test effects of an 8-week mind-body program (Relaxation Response Resiliency Program for NF [3RP-NF]) on resiliency, using data derived from a larger randomized controlled trial of the 3RP-NF versus attention placebo control (Vranceanu et al. in Neurology 87:806-814, 2016). Participants (N = 63; 46 female; 52 White) were randomized to 3RP-NF (n = 32, M age = 42.86) or control (n = 31, M age = 39.90), completed intervention sessions via group videoconferencing, and provided self-report measures of resiliency (i.e., perceived coping abilities, perceived social support, gratitude, optimism, spiritual well-being, mindfulness) at baseline, post-intervention, and 6-month follow-up. All participants attended at least 6/8 sessions and 83% (N = 52) provided 6-month follow-up data. The 3RP-NF (vs. control) produced greater improvements from pre- to post-intervention in perceived coping abilities (M difference = 6.68; p = .008), perceived social support (M difference = 9.16; p = .032), and mindfulness (M difference = 2.23; p = .035), which were maintained at 6-month follow up. We did not observe group differences in spiritual well-being, optimism, or gratitude. The 3RP-NF produced sustained increases in multiple dimensions of resiliency (perceived coping abilities, perceived social support, and mindfulness). Promoting resiliency may be particularly important for a population that is underserved and living with a chronic, incurable illness.

Corneal NF-kappaB activity is necessary for the retention of transparency in the cornea of UV-B-exposed transgenic reporter mice.

PubMed

Alexander, George; Carlsen, Harald; Blomhoff, Rune

2006-04-01

To determine the dynamics of Nuclear Factor-kappaB (NF-kappaB) in murine corneal pathology and the role of NF-kappaB in maintaining corneal clarity after ultraviolet B radiation insult, transgenic mice containing NF-kappaB-luciferase reporter were exposed to LPS (bacterial lipopolysaccharide), TNF-alpha (Tumor Necrosis Factor-alpha) or 4 kJ m(-2) UV-B radiation. NF-kappaB decoy oligonucleotides were also administered in some of the UV-B experiments. Following various exposure times, the mice were sacrificed and whole eyes or corneal tissues were obtained. Whole eyes were examined for scattering using a point-source optical imaging technique. Tissue homogenates were examined for luciferase activity using a luminometer. TNF-alpha and LPS-injected NF-kappaB-luciferase transgenic mice demonstrated 3-10-fold increases in cornea NF-kappaB with peak activities at 4 and 6 hr post-injection, respectively. Mice exposed to 4 kJ m(-2) UV-B exhibited a 3-fold increase in NF-kappaB activity 4 hr post-exposure. The administration of NF-kappaB-decoy oligonucleotides to mice had the effect of reducing UV-B-induced NF-kappaB activity in the cornea and significantly increasing the amount of light scattering in UV-B exposed corneas 7 days post-UV-B exposure when compared to sham injected mice. These results indicate that NF-kappaB is activated in cornea in pathologies that involves increased plasma levels of LPS and TNF-alpha, as well as direct UV-B exposure, and suggest that NF-kappaB activation play an essential part in the corneal healing process.

Myelodysplastic syndrome patients present more severe respiratory muscle impairment and reduced forced vital capacity: Is disordered inflammatory signaling the culprit?

PubMed

Okubo, Bruno Memória; Matos, Anacélia Gomes de; Ribeiro Junior, Howard Lopes; Borges, Daniela de Paula; Oliveira, Roberta Taiane Germano de; de Castro, Marilena Facundo; Martins, Manoel Ricardo Alves; Gonçalves, Romélia Pinheiro; Bruin, Pedro Felipe Carvalhedo; Pinheiro, Ronald Feitosa; Magalhães, Silvia Maria Meira

2017-01-01

The ageing process is associated with gradual decline in respiratory system performance. Anemia is highly prevalent among older adults and usually associated with adverse outcomes. Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies with increasing incidence with age and characterized by anemia and other cytopenias. The main objectives of this study were to evaluate respiratory muscle strength and lung function in elderly patients with anemia, compare data between myelodysplastic syndromes and non-clonal anemias and evaluate the influence of serum IL-8 level and NF-kB activity on deteriorate pulmonary function in this specific population. Individuals aged 60 and older with anemia secondary to MDS, non-clonal anemia and healthy elderly individuals. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/ FVC ratio were measured by spirometry. Respiratory muscle strength was evaluated by maximal static respiratory pressures measurement. IL-8 analysis was performed by ELISA and activity of NF-kB by chemiluminescent assay. Mean Hb concentration was comparable between patients with anemia. Significant differences were detected between all patients with anemia and controls for maximum-effort inspiratory mouth pressure (PImax) and also for maximum-effort expiratory mouth pressure (PEmax). The MDS group recorded a significantly lower PImax and PEmax percent predicted when compared to non-clonal anemia group. For FVC and FEV1, a significant difference was found in anemic patients, with even significantly lower values for FVC and FEV1 in MDS group. No significant differences were detected for PImax and PEmax and spirometry parameters when anemic patients were stratified according to the degree of anemia. A significant negative impact in FVC (% pred), PImax (% pred) and PEmax (% pred) was observed in patients with MDS and higher levels of IL-8 or increased activity of NF-kB. A negative impact of anemia, independent of its degree, was demonstrated in respiratory muscle strength and lung function particularly in MDS. The well known elevated proinflammatory cytokines in MDS patients were proposed to play a role as was demonstrated by detrimental effect of higher IL-8 and NF-kB in pulmonary function tests in this population.

The Influenza A Virus Genotype Determines the Antiviral Function of NF-κB.

PubMed

Dam, Sharmistha; Kracht, Michael; Pleschka, Stephan; Schmitz, M Lienhard

2016-09-01

The role of NF-κB in influenza A virus (IAV) infection does not reveal a coherent picture, as pro- and also antiviral functions of this transcription factor have been described. To address this issue, we used clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9)-mediated genome engineering to generate murine MLE-15 cells lacking two essential components of the NF-κB pathway. Cells devoid of either the central NF-κB essential modulator (NEMO) scaffold protein and thus defective in IκB kinase (IKK) activation or cells not expressing the NF-κB DNA-binding and transactivation subunit p65 were tested for propagation of the SC35 virus, which has an avian host range, and its mouse-adapted variant, SC35M. While NF-κB was not relevant for replication of SC35M, the absence of NF-κB activity increased replication of the nonadapted SC35 virus. This antiviral effect of NF-κB was most prominent upon infection of cells with low virus titers as they usually occur during the initiation phase of IAV infection. The defect in NF-κB signaling resulted in diminished IAV-triggered phosphorylation of interferon regulatory factor 3 (IRF3) and expression of the antiviral beta interferon (IFN-β) gene. To identify the viral proteins responsible for NF-κB dependency, reassortant viruses were generated by reverse genetics. SC35 viruses containing the SC35M segment encoding neuraminidase (NA) were completely inert to the inhibitory effect of NF-κB, emphasizing the importance of the viral genotype for susceptibility to the antiviral functions of NF-κB. This study addresses two different issues. First, we investigated the role of the host cell transcription factor NF-κB in IAV replication by genetic manipulation of IAVs by reverse genetics combined with targeted genome engineering of host cells using CRISPR-Cas9. The analysis of these two highly defined genetic systems indicated that the IAV genotype can influence whether NF-κB displays an antiviral function and thus might in part explain incoherent results from the literature. Second, we found that perturbation of NF-κB function greatly improved the growth of a nonadapted IAV, suggesting that NF-κB may contribute to the maintenance of the host species barrier. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Inhibition of NF-κB prevents the acidic bile-induced oncogenic mRNA phenotype, in human hypopharyngeal cells

PubMed Central

Vageli, Dimitra P.; Doukas, Sotirios G.; Sasaki, Clarence T.

2018-01-01

Bile-containing gastro-duodenal reflux has been clinically considered an independent risk factor in hypopharyngeal carcinogenesis. We recently showed that the chronic effect of acidic bile, at pH 4.0, selectively induces NF-κB activation and accelerates the transcriptional levels of genes, linked to head and neck cancer, in normal hypopharyngeal epithelial cells. Here, we hypothesize that NF-κB inhibition is capable of preventing the acidic bile-induced and cancer-related mRNA phenotype, in treated normal human hypopharyngeal cells. In this setting we used BAY 11-7082, a specific and well documented pharmacologic inhibitor of NF-κB, and we observed that BAY 11-7082 effectively inhibits the acidic bile-induced gene expression profiling of the NF-κB signaling pathway (down-regulation of 72 out of 84 analyzed genes). NF-κB inhibition significantly prevents the acidic bile-induced transcriptional activation of NF-κB transcriptional factors, RELA (p65) and c-REL, as well as genes related to and commonly found in established HNSCC cell lines. These include anti-apoptotic bcl-2, oncogenic STAT3, EGFR, ∆Np63, TNF-α and WNT5A, as well as cytokines IL-1β and IL-6. Our findings are consistent with our hypothesis demonstrating that NF-κB inhibition effectively prevents the acidic bile-induced cancer-related mRNA phenotype in normal human hypopharyngeal epithelial cells supporting an understanding that NF-κB may be a critical link between acidic bile and early preneoplastic events in this setting. PMID:29464041

[Effect of NF-κB activation on the radiation response of esophageal cancer cells].

PubMed

Li, Baozhong; Chen, Zhaoli; Zhou, Fang; He, Jie

2014-07-01

To investigate the effect of NF-κB activation on radiation response of esophageal carcinoma. The expression of NF-κB was detected in pretreatment and posttreatment specimens of patients with ESCC by immunohistochemistry. Electrophoretic mobility shift assay (EMSA) and Western blot were used to detect the activation of NF-κB in esophageal cancer cell line KYSE150 cells. SN50, a specific NF-κB inhibitor, was applied to inhibit the activation of NF-κB. Clone formation test was used to detect the radiosensitivity of esophageal cancer cells. The median survival time of patients with activated and inactivated NF-κB in the pretreatment specimens were 16 and 19 months, respectively, with a non-significant difference between the two groups (P > 0.05). As to the patients with activated and inactivated NF-κB in posttreatment specimens, the median survival times were 13 and 35 months, respectively, with a significant difference (P < 0.01) between them. Western blot showed that the cytoplasmic expression of NF-κB was reduced with increasing radiation dose at 1.5 and 3 hours after radiation treatment. However, the expression of NF-κB in the cell nuclei was increased under the same condition, showing a trend of increased nucleus/cytoplasm ratio. The clone number in SN50 group was 96.66, 64.66, 76.66 and 10.00 under 0, 2, 4 and 12 Gy irradiation, which demonstrated a significant difference compared with the control groups (P < 0.001). Our results show that activation of NF-κB is induced by radiotherapy. Activation of NF-κB reduces the outcome of radiation treatment of esophageal cancer patients.

Molecular Imaging of Smoke-Induced Changes in Nuclear Factor-Kappa B Expression in Murine Tissues Including the Lung.

PubMed

Syrkina, Olga; Hales, Charles H; Bonab, Ali A; Hamrahi, Victoria; Paul, Kasie; Jung, Walter J; Tompkins, Ronald G; Fischman, Alan J; Carter, Edward A

Many inflammatory responses are mediated by activation of the transcription factor, nuclear factor-kappa B (NF-κB), and a wide variety of human diseases involve abnormal regulation of its expression. In this investigation, we evaluated the effect of smoke inhalation injury on NF-κB expression in lung using two strains of NF-κB reporter mice. Groups of reporter mice with viral thymidine kinase (TK) or "fire fly" luciferase (Luc) genes under control by the NF-κB promoter (TK/NF-κB mice and Luc/NF-κB mice) were subjected to nonlethal smoke inhalation injury. Sham-treated animals served as controls. Twenty-four hours (each animal was injected intravenously with either 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine (FHBG) (~ 1.0 mCi) or luciferin (1.0 mg). One hour later, the TK/NF-κB mice were studied by micro-positron emission tomography (µ-PET) imaging using a Concord P4 µ-PET camera, and the Luc/NF-κB mice were studied by bioluminescence imaging with a charge-coupled device camera. The µ-PET data demonstrated that smoke injury produced massive increases in NF-κB expression (FHBG-standardized uptake value: 3.1 vs 0.0) 24 hours after smoke inhalation, which was reduced 48 hours after smoke inhalation, but still significantly different than the control. Qualitative analysis of the bioluminescence data revealed a remarkably similar effect of burn NF-κB luciferase expression in vivo. Biodistribution studies of FHBG uptake and luciferase activity in lung tissue demonstrated a similar increase 24 hours after injury, which was reduced 48 hours later, but still significantly higher than the sham. The present data with these models providing longitudinal imaging data on the same mouse may prove useful in the examination of the factors producing lung injury by smoke inhalation, as well as the treatment(s) for the damage produced with and without burn injury.

Swelling and morphology of the skin layer of polyamide composite membranes: an atomic force microscopy study.

PubMed

Freger, Viatcheslav

2004-06-01

The paper introduces a new methodology for studying polyamide composite membranes for reverse osmosis (RO) and nanofiltration (NF) in liquid environments. The methodology is based on atomic force microscopy of the active layer, which had been separated from the support and placed on a solid substrate. The approach was employed to determine the thickness, interfacial morphology, and dimensional changes in solution (swelling) of polyamide films. The face (active) and back (facing the support) surfaces of the RO films appeared morphologically similar, in agreement with the recently proposed model of skin formation. Measured thickness and swelling data in conjunction with the intrinsic permeability of the membranes suggest that the selective barrier in RO membrane constitutes only a fraction of the polyamide skin, whereas NF membranes behave as nearly uniform films. For NF membranes, there was reasonable correlation between the changes in the swelling and in the permeability of the membrane and the salinity and pH of the feed.

α-Naphthoflavone Increases Lipid Accumulation in Mature Adipocytes and Enhances Adipocyte-Stimulated Endothelial Tube Formation.

PubMed

Wang, Mei-Lin; Lin, Shyh-Hsiang; Hou, Yuan-Yu; Chen, Yue-Hwa

2015-04-30

The aryl hydrocarbon receptor (AhR) is a ligand-activated factor that regulates biological effects associated with obesity. The AhR agonists, such as environmental contaminants 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and β-naphthoflavone (BNF), inhibit preadipocyte differentiation and interfere with the functions of adipose tissue, whereas the antagonist may have opposite or protective effects in obesity. This study investigated the effects of α-naphthoflavone (α-NF), an AhR antagonist, on adipogenesis- and angiogenesis-associated factors in mature adipocytes and on cross-talk of mature adipocytes with endothelial cells (ECs). Besides, the roles of the AhR on lipid accumulation and on secretion of vascular endothelial growth factor were also determined by introducing siRNA of AhR. Differentiated 3T3-L1 cells were treated with α-naphthoflavone (α-NF) (1-5 μM) for 16 h. Lipid accumulation and the expressions of AhR-associated factors in the cells were determined. The interaction between adipocytes and ECs was investigated by cultivating ECs with conditioned medium (CM) from α-NF-treated mature adipocytes, followed by the determination of endothelial tube formation. The results showed that α-NF significantly increased triglyceride (TG) accumulation in mature adipocytes, which was associated with increased expression of hormone-sensitive lipase (HSL), estrogen receptor (ER), as well as decreased expression of AhR, AhR nuclear translocator (ARNT), cytochrome P4501B1 (CYP1B1), and nuclear factor erythroid-2-related factor (NRF-2) proteins. In addition, CM stimulated formation of tube-like structures in ECs, and α-NF further enhanced such stimulation in association with modulated the secretions of various angiogenic mediators by mature adipocytes. Similarly, increased TG accumulation and vascular endothelial growth factor (VEGF) secretion were observed in AhR-knockout cells. In conclusion, α-NF increased TG accumulation in mature adipocytes and enhanced mature adipocyte-stimulated tube formation in ECs, suggesting that the AhR may suppress obesity-induced adverse effects, and α-NF abolished the protective effects of the AhR.

Antitumor activity of IL-32β through the activation of lymphocytes, and the inactivation of NF-κB and STAT3 signals.

PubMed

Yun, H-M; Oh, J H; Shim, J-H; Ban, J O; Park, K-R; Kim, J-H; Lee, D H; Kang, J-W; Park, Y H; Yu, D; Kim, Y; Han, S B; Yoon, D-Y; Hong, J T

2013-05-23

Cytokine and activation of lymphocytes are critical for tumor growth. We investigated whether interleukin (IL)-32β overexpression changes other cytokine levels and activates cytotoxic lymphocyte, and thus modify tumor growth. Herein, IL-32β inhibited B16 melanoma growth in IL-32β-overexpressing transgenic mice (IL-32β mice), and downregulated the expressions of anti-apoptotic proteins (bcl-2, IAP, and XIAP) and cell growth regulatory proteins (Ki-67 antigen (Ki-67) and proliferating cell nuclear antigen (PCNA)), but upregulated the expressions of pro-apoptotic proteins (bax, cleaved caspase-3, and cleaved caspase-9). IL-32β also inhibited colon and prostate tumor growth in athymic nude mice inoculated with IL-32β-transfected SW620 colon or PC3 prostate cancer cells. The forced expression of IL-32β also inhibited cell growth in cultured colon and prostate cancer cells, and these inhibitory effects were abolished by IL-32 small interfering RNA (siRNA). IL-10 levels were elevated, but IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels were reduced in the tumor tissues and spleens of IL-32β mice, and athymic nude mice. The number of cytotoxic T (CD8(+)) and natural killer (NK) cells in tumor tissues, spleen, and blood was significantly elevated in IL-32β mice and athymic nude mice inoculated with IL-32β-transfected cancer cells. Constituted activated NF-κB and STAT3 levels were reduced in the tumor tissues of IL-32β mice and athymic nude mice, as well as in IL-32β-transfected cultured cancer cells. These findings suggest that IL-32β inhibits tumor growth by increasing cytotoxic lymphocyte numbers, and by inactivating the NF-κB and STAT3 pathways through changing of cytokine levels in tumor tissues.

Open Reading Frame 3 of Genotype 1 Hepatitis E Virus Inhibits Nuclear Factor-κappa B Signaling Induced by Tumor Necrosis Factor-α in Human A549 Lung Epithelial Cells

PubMed Central

Tian, Deying; Wang, Jingjing; Zheng, Zizheng; Xia, Ningshao

2014-01-01

Hepatitis E virus (HEV) is one of the primary causative agents of acute hepatitis, and represents a major cause of severe public health problems in developing countries. The pathogenesis of HEV is not well characterized, however, primarily due to the lack of well-defined cell and animal models. Here, we investigated the effects of genotype 1 HEV open reading frame 3 (ORF3) on TNF-α-induced nucleus factor-κappa B (NF-κB) signaling. Human lung epithelial cells (A549) were transiently transfected with ORF3 containing plasmids. These cells were then stimulated with TNF-α and the nucleus translocation of the p65 NF-κB subunit was assessed using western blot and laser confocal microscopy. DNA-binding activity of p65 was also examined using electrophoretic mobility shift assay (EMSA), and the suppression of NF-κB target genes were detected using real-time RT-PCR and ELISA. These results enabled us to identify the decreased phosphorylation levels of IKBα. We focused on the gene of negative regulation of NF-κB, represented by TNF-α-induced protein 3 (TNFAIP3, also known as A20). Reducing the levels of A20 with siRNAs significantly enhances luciferase activation of NF-κB. Furthermore, HEV ORF3 regulated A20 primarily via activating transcription factor 6 (ATF6), involved in unfolded protein response (UPR), resulting in the degradation or inactivation of the receptor interacting protein 1 (RIP1), a major upstream activator of IKB kinase compounds (IKKs). Consequently, the phosphorylation of IKBα and the nucleus translocation of p65 are blocked, which contributes to diminished NF-κB DNA-binding activation and NF-κB-dependent gene expression. The findings suggest that genotype 1 HEV, through ORF3, may transiently activate NF-κB through UPR in early stage, and subsequently inhibit TNF-α-induced NF-κB signaling in late phase so as to create a favorable virus replication environment. PMID:24959724

Effects of decoy molecules targeting NF-kappaB transcription factors in Cystic fibrosis IB3–1 cells

PubMed Central

Finotti, Alessia; Borgatti, Monica; Bezzerri, Valentino; Nicolis, Elena; Lampronti, Ilaria; Dechecchi, Maria; Mancini, Irene; Cabrini, Giulio; Saviano, Michele; Avitabile, Concetta; Romanelli, Alessandra; Gambari, Roberto

2012-01-01

One of the clinical features of cystic fibrosis (CF) is a deep inflammatory process, which is characterized by production and release of cytokines and chemokines, among which interleukin 8 (IL-8) represents one of the most important. Accordingly, there is a growing interest in developing therapies against CF to reduce the excessive inflammatory response in the airways of CF patients. Since transcription factor NF-kappaB plays a critical role in IL-8 expression, the transcription factor decoy (TFD) strategy might be of interest. In order to demonstrate that TFD against NF-kappaB interferes with the NF-kappaB pathway we proved, by chromatin immunoprecipitation (ChIP) that treatment with TFD oligodeoxyribonucleotides of cystic fibrosis IB3–1 cells infected with Pseudomonas aeruginosa leads to a decrease occupancy of the Il-8 gene promoter by NF-kappaB factors. In order to develop more stable therapeutic molecules, peptide nucleic acids (PNAs) based agents were considered. In this respect PNA-DNA-PNA (PDP) chimeras are molecules of great interest from several points of view: (1) they can be complexed with liposomes and microspheres; (2) they are resistant to DNases, serum and cytoplasmic extracts; (3) they are potent decoy molecules. By using electrophoretic mobility shift assay and RT-PCR analysis we have demonstrated that (1) the effects of PDP/PDP NF-kappaB decoy chimera on accumulation of pro-inflammatory mRNAs in P.aeruginosa infected IB3–1 cells reproduce that of decoy oligonucleotides; in particular (2) the PDP/PDP chimera is a strong inhibitor of IL-8 gene expression; (3) the effect of PDP/PDP chimeras, unlike those of ODN-based decoys, are observed even in the absence of protection with lipofectamine. These informations are of great impact, in our opinion, for the development of stable molecules to be used in non-viral gene therapy of cystic fibrosis. PMID:22772035

Multiple NUCLEAR FACTOR Y transcription factors respond to abiotic stress in Brassica napus L.

PubMed

Xu, Li; Lin, Zhongyuan; Tao, Qing; Liang, Mingxiang; Zhao, Gengmao; Yin, Xiangzhen; Fu, Ruixin

2014-01-01

Members of the plant NUCLEAR FACTOR Y (NF-Y) family are composed of the NF-YA, NF-YB, and NF-YC subunits. In Brassica napus (canola), each of these subunits forms a multimember subfamily. Plant NF-Ys were reported to be involved in several abiotic stresses. In this study, we demonstrated that multiple members of thirty three BnNF-Ys responded rapidly to salinity, drought, or ABA treatments. Transcripts of five BnNF-YAs, seven BnNF-YBs, and two BnNF-YCs were up-regulated by salinity stress, whereas the expression of thirteen BnNF-YAs, ten BnNF-YBs, and four BnNF-YCs were induced by drought stress. Under NaCl treatments, the expression of one BnNF-YA10 and four NF-YBs (BnNF-YB3, BnNF-YB7, BnNF-YB10, and BnNF-YB14) were greatly increased. Under PEG treatments, the expression levels of four NF-YAs (BnNF-YA9, BnNF-YA10, BnNF-YA11, and BnNF-YA12) and five NF-YBs (BnNF-YB1, BnNF-YB8, BnNF-YB10, BnNF-YB13, and BnNF-YB14) were greatly induced. The expression profiles of 20 of the 27 salinity- or drought-induced BnNF-Ys were also affected by ABA treatment. The expression levels of six NF-YAs (BnNF-YA1, BnNF-YA7, BnNF-YA8, BnNF-YA9, BnNF-YA10, and BnNF-YA12) and seven BnNF-YB members (BnNF-YB2, BnNF-YB3, BnNF-YB7, BnNF-YB10, BnNF-YB11, BnNF-YB13, and BnNF-YB14) and two NF-YC members (BnNF-YC2 and BnNF-YC3) were greatly up-regulated by ABA treatments. Only a few BnNF-Ys were inhibited by the above three treatments. Several NF-Y subfamily members exhibited collinear expression patterns. The promoters of all stress-responsive BnNF-Ys harbored at least two types of stress-related cis-elements, such as ABRE, DRE, MYB, or MYC. The cis-element organization of BnNF-Ys was similar to that of Arabidopsis thaliana, and the promoter regions exhibited higher levels of nucleotide sequence identity with Brassica rapa than with Brassica oleracea. This work represents an entry point for investigating the roles of canola NF-Y proteins during abiotic stress responses and provides insight into the genetic evolution of Brassica NF-Ys.

Effect of composites based nickel foam anode in microbial fuel cell using Acetobacter aceti and Gluconobacter roseus as a biocatalysts.

PubMed

Karthikeyan, Rengasamy; Krishnaraj, Navanietha; Selvam, Ammaiyappan; Wong, Jonathan Woon-Chung; Lee, Patrick K H; Leung, Michael K H; Berchmans, Sheela

2016-10-01

This study explores the use of materials such as chitosan (chit), polyaniline (PANI) and titanium carbide (TC) as anode materials for microbial fuel cells. Nickel foam (NF) was used as the base anode substrate. Four different types of anodes (NF, NF/PANI, NF/PANI/TC, NF/PANI/TC/Chit) are thus prepared and used in batch type microbial fuel cells operated with a mixed consortium of Acetobacter aceti and Gluconobacter roseus as the biocatalysts and bad wine as a feedstock. A maximum power density of 18.8Wm(-3) (≈2.3 times higher than NF) was obtained in the case of the anode modified with a composite of PANI/TC/Chit. The MFCs running under a constant external resistance of (50Ω) yielded 14.7% coulombic efficiency with a maximum chemical oxygen demand (COD) removal of 87-93%. The overall results suggest that the catalytic materials embedded in the chitosan matrix show the best performance and have potentials for further development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Myricetin down-regulates phorbol ester-induced cyclooxygenase-2 expression in mouse epidermal cells by blocking activation of nuclear factor kappa B.

PubMed

Lee, Kyung Mi; Kang, Nam Joo; Han, Jin Hee; Lee, Ki Won; Lee, Hyong Joo

2007-11-14

Abnormal expression of cyclooxygenase-2 (COX-2) has been implicated in the development of cancer. There are multiple lines of evidence that red wine exerts chemopreventive effects, and 3,5,4'-trihydroxy- trans-stilbene (resveratrol), which is a non-flavonoid polyphenol found in red wine, has been reported to be a natural chemopreventive agent. However, other phytochemicals might contribute to the cancer-preventive activities of red wine, and the flavonol content of red wines is about 30 times higher than that of resveratrol. Here we report that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, inhibits 12-O-tetradecanoylphorbol-13-acetate (phorbol ester)-induced COX-2 expression in JB6 P+ mouse epidermal (JB6 P+) cells by suppressing activation of nuclear factor kappa B (NF-kappaB). Myricetin at 10 and 20 microM inhibited phorbol ester-induced upregulation of COX-2 protein, while resveratrol at the same concentration did not exert significant effects. The phorbol ester-induced production of prostaglandin E 2 was also attenuated by myricetin treatment. Myricetin inhibited both COX-2 and NF-kappaB transactivation in phorbol ester-treated JB6 P+ cells, as determined using a luciferase assay. Myricetin blocked the phorbol ester-stimulated DNA binding activity of NF-kappaB, as determined using an electrophoretic mobility shift assay. Moreover, TPCK (N-tosyl-l-phenylalanine chloromethyl ketone), a NF-kappaB inhibitor, significantly attenuated COX-2 expression and NF-kappaB promoter activity in phorbol ester-treated JB6 P+ cells. In addition, red wine extract inhibited phorbol ester-induced COX-2 expression and NF-kappaB transactivation in JB6 P+ cells. Collectively, these data suggest that myricetin contributes to the chemopreventive effects of red wine through inhibition of COX-2 expression by blocking the activation of NF-kappaB.

Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1.

PubMed

Plotkin, Scott R; Davis, Stephanie D; Robertson, Kent A; Akshintala, Srivandana; Allen, Julian; Fisher, Michael J; Blakeley, Jaishri O; Widemann, Brigitte C; Ferner, Rosalie E; Marcus, Carole L

2016-08-16

Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs. © 2016 American Academy of Neurology.

INTERFERON α ACTIVATES NF-κ B IN JAK1-DEFICIENT CELLS THROUGH A TYK2-DEPENDENT PATHWAY

PubMed Central

Yang, Chuan He; Murti, Aruna; Valentine, William J.; Du, Ziyun; Pfeffer, Lawrence M.

2005-01-01

In addition to activating members of the STAT transcription factor family, IFN α/β activates the NF-κ B transcription factor. To determine the role of the JAK-STAT pathway in NF-κ B activation by IFN, we examined NF-κ B activation in JAK1-deficient mutant human fibrosarcoma cells. In wild-type fibrosarcoma cells (2fTGH) IFN activates STAT1, STAT2 and STAT3, as well as NF-κB complexes comprised of p50 and p65. In contrast, in JAK1-deficient cells IFN induces NF-κB activation and NF-κB dependent gene transcription, but does not activate these STAT proteins and has no effect on STAT-dependent gene transcription. Expression of a catalytically-inactive TYK2 tyrosine kinase in JAK1-deficient cells, as well as in the highly IFN-sensitive Daudi lymphoblastoid cell line, abrogates NF-κB activation by IFN. Moreover, IFN does not promote NF-κB activation in TYK2-deficient mutant fibrosarcoma cells. Our results demonstrate a dichotomy between the classical JAK-STAT pathway and the NF-κB signaling pathway. In the IFN signaling pathway leading to STAT activation both JAK1 and TYK2 are essential, while NF-κB activation requires only TYK2. PMID:15883164

Regorafenib inhibits tumor progression through suppression of ERK/NF-κB activation in hepatocellular carcinoma bearing mice.

PubMed

Weng, Mao-Chi; Wang, Mei-Hui; Tsai, Jai-Jen; Kuo, Yu-Cheng; Liu, Yu-Chang; Hsu, Fei-Ting; Wang, Hsin-Ell

2018-06-29

Regorafenib has been demonstrated in our previous study to trigger apoptosis through suppression of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) activation in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro However, the effect of regorafenib on NF-κB-modulated tumor progression in HCC in vivo is ambiguous. The aim of the present study is to investigate the effect of regorafenib on NF-κB-modulated tumor progression in HCC bearing mouse model. pGL4.50 luciferase reporter vector transfected SK-Hep1 (SK-Hep1/ luc2 ) and Hep3B 2.1-7 tumor bearing mice were established and used for the present study. Mice were treated with vehicle or regorafenib (20 mg/kg/day by gavage) for 14 days. Effects of regorafenib on tumor growth and protein expression together with toxicity of regorafenib were evaluated with digital caliper and bioluminescence imaging (BLI), ex vivo Western blotting immunohistochemistry (IHC) staining, and measurement of body weight and pathological examination of liver tissue, respectively, in SK-Hep1/ luc2 and Hep3B 2.1-7 tumor bearing mice. The results indicated regorafenib significantly reduced tumor growth and expression of phosphorylated ERK, NF-κB p65 (Ser536), phosphorylated AKT, and tumor progression-associated proteins. In addition, we found regorafenib induced both extrinsic and intrinsic apoptotic pathways. Body weight and liver morphology were not affected by regorafenib treatment. Our findings present the mechanism of tumor progression inhibition by regorafenib is linked to suppression of ERK/NF-κB signaling in SK-Hep1/ luc2 and Hep3B 2.1-7 tumor bearing mice. © 2018 The Author(s).

A Randomized Controlled Trial Investigating the Effects of Neurofeedback, Methylphenidate, and Physical Activity on Event-Related Potentials in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Janssen, Tieme Willem Pieter; Bink, Marleen; Geladé, Katleen; van Mourik, Rosa; Maras, Athanasios; Oosterlaan, Jaap

2016-05-01

Electroencephalographic (EEG) neurofeedback (NF) is considered a nonpharmacological alternative for medication in attention-deficit/hyperactivity disorder (ADHD). Comparisons of the behavioral efficacy of NF and medication have produced inconsistent results. EEG measures can provide insight into treatment mechanisms, but have received little consideration. In this randomized controlled trial (RCT), effects of NF were compared with methylphenidate (MPH), and physical activity (PA) in children with ADHD on event-related potential (ERP) indices of response inhibition, which are involved in ADHD psychopathology. Using a multicenter three way parallel group RCT design, 112 children with a Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) (American Psychiatric Association 1994 ) diagnosis of ADHD, between 7 and 13 years of age, were initially included. NF training consisted of 30 sessions of theta/beta training at Cz over a 10 week period. PA training was a semiactive control group, matched in frequency and duration. MPH was titrated using a double-blind placebo controlled procedure in 6 weeks, followed by a stable dose for 4 weeks. ERP measures of response inhibition, N2 and P3, were available for 81 children at pre- and postintervention (n = 32 NF, n = 25 MPH, n = 24 PA). Only the medication group showed a specific increase in P3 amplitude compared with NF (partial eta-squared [ηp(2) ] = 0.121) and PA (ηp(2) = 0.283), which was related to improved response inhibition. Source localization of medication effects on P3 amplitude indicated increased activation primarily in thalamic and striatal nuclei. This is the first study that simultaneously compared NF with stimulant treatment and a semiactive control group. Only stimulant treatment demonstrated specific improvements in brain function related to response inhibition. These results are in line with recent doubts on the efficacy and specificity of NF as treatment for ADHD. Train Your Brain? Exercise and Neurofeedback Intervention for ADHD, https://clinicaltrials.gov/show/NCT01363544 , Ref. No. NCT01363544.

Nanostructured Co3O4 grown on nickel foam: An efficient and readily recyclable 3D catalyst for heterogeneous peroxymonosulfate activation.

PubMed

Yuan, Ruixia; Hu, Lin; Yu, Peng; Wang, Huaiyuan; Wang, Zhaohui; Fang, Jingyun

2018-05-01

Cobalt-based heterogeneous catalyst has been recognized as one of most efficient activators for peroxymonosulfate (PMS) decomposition, but usually suffers from the poor stability and difficulty to recover and reuse. Here easily recyclable cobalt oxide (Co 3 O 4 ) nanowires and nanoflowers grown on nickel foam (NF) are fabricated by a hydrothermal and calcination method. The prepared 3D Co 3 O 4 /NF catalyst is characterized and applied as a heterogeneous catalyst for PMS activation to generate sulfate radicals for decomposition of Acid Orange 7 (AO7). The results show that the AO7 degradation rate increases with cobalt loading and PMS dosage, but decreases with the increase of solution pH. The Co 3 O 4 /NF catalyst using 2 mM Co(NO 3 ) 2 ·6H 2 O as cobalt source exhibits highest activity, and almost complete decolorization could be achieved within 30 min. The diverse effects of coexisting anions (SO 4 2- , HCO 3 - , NO 3 - and Cl - ) on AO7 degradation are observed and explained. After 10 consecutive runs, excellent catalytic reactivity of the catalyst remains while the level of leached cobalt during the catalyst usage is much lower than the maximum allowable concentration in drinking and natural water. More importantly, the macroscopic Co 3 O 4 /NF catalyst shows advantage of easy recycling after application compared to traditional catalysts. It is believed that the as-prepared Co 3 O 4 /NF is promising to be an effective and green heterogeneous catalyst for PMS activation to degrade organic pollutants for environmental application. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effects of open-top chambers on Valencia' orange trees. [Citrus sinensis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olszyk, D.M.; Takemoto, B.K.; Kats, G.

Open-top field chambers are the most widely used technology for evaluating the impacts of air pollutants on vegetation. This study was conducted to evaluate the long-term effects of chambers on Valencia orange trees (Citrus sinensis (L.) Osbeck). The trees were exposed to ambient ozone (O{sub 3}) for 51 months in large (4.3-m diam. by 2.9-m high) nonfiltered open-top chambers (NF) and in ambient air without chambers (AA). Results suggest that the yield increases for NF compared to AA trees could, in part, be accounted for by decreased flux of O{sub 3} into leaves (based on decreased O{sub 3} exposure andmore » leaf conductance). However, other factors, i.e., increased tree growth, altered leaf C allocation, and lack of wind stress occurring only in chambers, likely contributed to higher NF tree yields.« less

Quenching Rate Constants of NF(A1 Delta) by N2F4, NF3, NF(X), SiF4, HNCO and NCO at Room Temperature

DTIC Science & Technology

1993-01-01

F., ill; Helvajian . H .; Holloway. J. S.; Koffend, .3. J.1 base interaction between NF(aaA) and NF(X3Z-). Although the PAys. Chem. 1969, 93, 7818. 4...Since NF(a’&) possibly could be generated by the H + NF2 mis Metuho ieems reaction in practical laser devices. there is a need to know the reEimoM...and NF(b’Z+) are of a 30% CF4/Ar mixture together with additional A& tiahMb h • f also of practical interest. Since these reactions involve ground

Cyanidin-3-O-glucoside inhibits NF-kB signalling in intestinal epithelial cells exposed to TNF-α and exerts protective effects via Nrf2 pathway activation.

PubMed

Ferrari, Daniela; Speciale, Antonio; Cristani, Mariateresa; Fratantonio, Deborah; Molonia, Maria Sofia; Ranaldi, Giulia; Saija, Antonella; Cimino, Francesco

2016-12-15

Chronic intestinal inflammatory disorders, such as Inflammatory Bowel Diseases (IBDs), are characterized by excessive release of proinflammatory mediators, intestinal barrier dysfunction and excessive activation of NF-kB cascade. Previous studies shown that TNF-α plays a central role in intestinal inflammation of IBDs and supported beneficial effects of flavonoids against chronic inflammatory diseases. In this study, we employed an in vitro model of acute intestinal inflammation using intestinal Caco-2 cells exposed to TNF-α. The protective effects of cyanidin-3-glucoside (C3G), an anthocyanin widely distributed in mediterranean diet, were then evaluated. Caco-2 cells exposure to TNF-α activated NF-kB proinflammatory pathway and induced IL6 and COX-2 expression. Cells pretreatment for 24h with C3G (20-40μM) prevented TNF-α-induced changes, and improved intracellular redox status. Our results demonstrated that C3G, also without any kind of stimulus, increased the translocation of the transcription factor Nrf2 into the nucleus so activating antioxidant and detoxifying genes. In conclusion, C3G exhibited protective effects through the inhibition of NF-kB signalling in Caco-2 cells and these beneficial effects appear to be due to its ability to activate cellular protective responses modulated by Nrf2. These data suggest that anthocyanins could contribute, as complementary or preventive approaches, to the management of chronic inflammatory diseases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effect of purification method of β-chitin from squid pen on the properties of β-chitin nanofibers.

PubMed

Suenaga, Shin; Nikaido, Nozomi; Totani, Kazuhide; Kawasaki, Kazunori; Ito, Yoshihito; Yamashita, Kazuhiko; Osada, Mitsumasa

2016-10-01

The relationship between purification methods of β-chitin from squid pen and the physicochemical properties of β-chitin nanofibers (NFs) were investigated. Two types of β-chitin were prepared, with β-chitin (a→b) subjected to acid treatment for decalcification and then base treatment for deproteinization, while β-chitin (b→a) was treated in the opposite order. These β-chitins were disintegrated into NFs using wet pulverization. The β-chitin (b→a) NF dispersion has higher transmittance and viscosity than the β-chitin (a→b) NF dispersion. For the first time, we succeeded in obtaining 3D images of the β-chitin NF dispersion in water by using quick-freeze deep-etch replication with high-angle annular dark field scanning transmission electron microscopy. The β-chitin (b→a) NF dispersion has a denser and more uniform 3D network structure than the β-chitin (a→b) NF dispersion. Widths of the β-chitin (a→b) and (b→a) NFs were approximately 8-25 and 3-10nm, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

Semi-in situ atomic force microscopy imaging of intracellular neurofilaments under physiological conditions through the 'sandwich' method.

PubMed

Sato, Fumiya; Asakawa, Hitoshi; Fukuma, Takeshi; Terada, Sumio

2016-08-01

Neurofilaments are intermediate filament proteins specific for neurons and characterized by formation of biochemically stable, obligate heteropolymers in vivo While purified or reassembled neurofilaments have been subjected to morphological analyses by electron microscopy and atomic force microscopy, there has been a need for direct imaging of cytoplasmic genuine intermediate filaments with minimal risk of artefactualization. In this study, we applied the modified 'cells on glass sandwich' method to exteriorize intracellular neurofilaments, reducing the risk of causing artefacts through sample preparation. SW13vim(-) cells were double transduced with neurofilament medium polypeptide (NF-M) and alpha-internexin (α-inx). Cultured cells were covered with a cationized coverslip after prestabilization with tannic acid to form a sandwich and then split into two. After confirming that neurofilaments could be deposited on ventral plasma membranes exposed via unroofing, we performed atomic force microscopy imaging semi-in situ in aqueous solution. The observed thin filaments, considered to retain native structures of the neurofilaments, exhibited an approximate periodicity of 50-60 nm along their length. Their structural property appeared to reflect the morphology formed by their constituents, i.e. NF-M and α-inx. The success of semi-in situ atomic force microscopy of exposed bona fide assembled neurofilaments through separating the sandwich suggests that it can be an effective and alternative method for investigating cytoplasmic intermediate filaments under physiological conditions by atomic force microscopy. © The Author 2016. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

BAG3 protects against hyperthermic stress by modulating NF-κB and ERK activities in human retinoblastoma cells.

PubMed

Yunoki, Tatsuya; Tabuchi, Yoshiaki; Hayashi, Atsushi; Kondo, Takashi

2015-03-01

BCL2-associated athanogene 3 (BAG3), a co-chaperone of HSP70, is a cytoprotective and anti-apoptotic protein that acts against various stresses, including heat stress. Here, we examined the effect of BAG3 on the sensitivity of human retinoblastoma cells to hyperthermia (HT). We examined the effects of BAG3 knockdown on the sensitivity of Y79 and WERI-Rb-1cells to HT (44 °C, 1 h) by evaluating apoptosis and cell proliferation using western blotting, real-time quantitative PCR (qPCR), flow cytometry, and a WST-8 assay kit. Furthermore, we examined the effects of activating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) using western blotting and real time qPCR. HT induced considerable apoptosis along with the activation of caspase-3 and chromatin condensation. The sensitivity of Y79 and WERI-Rb-1 cells to HT was significantly enhanced by BAG3 knockdown. Compared to HT alone, the combination of BAG3 knockdown and HT reduced phosphorylation of the inhibitors of kappa B α (IκBα) and p65, a subunit of NF-κB, and degraded IκB kinase γ (IKKγ) during the recovery period after HT. Furthermore, BAG3 knockdown increased the HT-induced phosphorylation of ERK after HT treatment, and the ERK inhibitor U0126 significantly improved the viability of the cells treated with a combination of BAG3 knockdown and HT. The silencing of BAG3 seems to enhance the effects of HT, at least in part, by maintaining HT-induced inactivity of NF-κB and the phosphorylation of ERK. These findings indicate that BAG3 may be a potential molecular target for modifying the outcomes of HT in retinoblastoma.

Corn Silk Extract and Its Bioactive Peptide Ameliorated Lipopolysaccharide-Induced Inflammation in Mice via the Nuclear Factor-κB Signaling Pathway.

PubMed

Ho, Tin-Yun; Li, Chia-Cheng; Lo, Hsin-Yi; Chen, Feng-Yuan; Hsiang, Chien-Yun

2017-02-01

Bioactive peptides derived from foods have shown beneficial anti-inflammatory potential. Inhibitory κB kinase-β (IKKβ) plays a crucial role in the activation of nuclear factor-κB (NF-κB), a transcription factor involved in inflammation. Here we applied proteomic and bioinformatics approaches to identify anti-inflammatory peptides that target IKKβ from corn silk. Corn silk extract significantly suppressed lipopolysaccharide (LPS)-induced NF-κB activities [(1.7 ± 0.2)-fold vs (3.0 ± 0.6)-fold, p < 0.05] in cells. Trypsin hydrolysate of corn silk also suppressed LPS-induced NF-κB activities [(1.1 ± 0.3)-fold vs 3.3 ± 0.5 fold, p < 0.01]. In addition, both corn silk extract and trypsin hydrolysate significantly inhibited LPS-induced interleukin-1β (IL-1β) production by 58.3 ± 4.5 and 55.1 ± 7.4%, respectively. A novel peptide, FK2, docked into the ATP-binding pocket of IKKβ, was further identified from trypsin hydrolysis of corn silk. FK2 inhibited IKKβ activities, IκB phosphorylation, and subsequent NF-κB activation [(2.3 ± 0.4)-fold vs (5.5 ± 0.4)-fold, p < 0.001]. Moreover, FK2 significantly reduced NF-κB-driven luminescent signals in organs by 5-11-fold and suppressed LPS-induced NF-κB activities and IL-β production in tissues. In conclusion, our findings indicated that corn silk displayed anti-inflammatory abilities. In addition, we first identified an anti-inflammatory peptide FK2 from corn silk. Moreover, the anti-inflammatory effect of FK2 might be through IKKβ-NF-κB signaling pathways.

Influence of nitrogen fertilization and defoliation frequency on nitrogen constituents and feeding value of annual ryegrass.

PubMed

Zhang, Y; Bunting, L D; Kappel, L C; Hafley, J L

1995-08-01

Two experiments were conducted to determine the seasonal effects of N fertilizer (NF) and defoliation interval (DI) on specific N fractions within annual ryegrass (AR) and overall usage of AR N by growing lambs. In Exp. 1, NF (0, 112, 224, and 336 kg of N/ha) and DI of 2, 4, or 6 wk were factorially applied to AR plots. Both decreasing DI and increasing NF increased N levels in AR in a manner that depended on harvest date (NF or DI x harvest date interaction, P < .05). The proportions of .2% NaOH soluble N or soluble protein N were not affected (P > .05) by NF or DI. Although NF had no effect (P > .05) on in situ disappearance of DM, decreasing the DI seemed to reduce the severity of the season-induced reduction in DM disappearance (DI x harvest date interaction, P = .04). In Exp. 2, NF (0 or 224 kg of N/ha) and a DI of 2 or 6 wk were factorially applied to AR plots. Fresh, frozen AR was fed in semipurified diets (48% of DM as AR) to four wether lambs (23 +/- 1.3 kg) using a 4 x 4 Latin square. Diets including AR had greater ruminal DM and plant N digestibilities when AR had a 2-wk vs a 6-wk DI with NF but had reduced digestibilities when AR had a 2-wk vs a 6-wk DI without NF.(ABSTRACT TRUNCATED AT 250 WORDS)

Fouling characteristics and cleaning strategies of NF membranes for the advanced treatment of antibiotic production wastewater.

PubMed

Wang, Jianxing; Li, Kun; Yu, Dawei; Zhang, Junya; Wei, Yuansong

2017-04-01

The nanofiltration (NF) membrane fouling characteristics and cleaning strategies were investigated through a laboratory-scale NF fouling test treating membrane bioreactor (MBR) effluent and MBR-granular activated carbon (GAC) effluent of an antibiotic production wastewater by DK and NF90 membranes, respectively. Results showed that organic fouling is the main NF membrane fouling for treating both the MBR effluent and MBR-GAC effluent. Soluble microbial by-product (SMP)-like and aromatic protein-like substances were the dominant components in the foulants, whereas humic-like substances had little contribution to the NF fouling. The fouling of DK was more severe than that of NF90. However, foulants respond by UV 254 were more easily to foul NF90 membrane. It could get satisfactory effect using combined cleaning of acid (HCl, pH 2.0∼2.5) and alkali (NaOH + 0.3 wt% NaDS, pH 10.0∼10.5). The favorable cleaning strategy is "acid + alkali" for treating MBR-GAC effluent, while it is "alkali + acid" for treating MBR effluent.

Specific LPA receptor subtype mediation of LPA-induced hypertrophy of cardiac myocytes and involvement of Akt and NFkappaB signal pathways.

PubMed

Chen, Jinghai; Chen, Yuefeng; Zhu, Weiquan; Han, Yu; Han, Bianmei; Xu, Ruixia; Deng, Linzi; Cai, Yan; Cong, Xiangfeng; Yang, Yuejing; Hu, Shengshou; Chen, Xi

2008-04-15

Lysophosphatidic acid (LPA) is a bioactive phospholipid with diverse functions mediated via G-protein-coupled receptors (GPCRs). In view of the elevated levels of LPA in acute myocardial infarction (MI) patients we have conducted studies aimed at identifying specific LPA receptor subtypes and signaling events that may mediate its actions in hypertrophic remodeling. Experiments were carried out in cultured neonatal rat cardiomyocytes (NRCMs) exposed to LPA and in a rat MI model. In NRCMs, LPA-induced hypertrophic growth was completely abrogated by DGPP, an LPA1/LPA3 antagonist. The LPA3 agonist OMPT, but not the LPA2 agonist dodecylphosphate, promoted hypertrophy as examined by 3[H]-Leucine incorporation, ANF-luciferase expression and cell area. In in vivo experiments, LPA1, LPA2 and LPA3 mRNA levels as well as LPA1 and LPA3 protein levels increased together with left ventricular remodeling (LVRM) after MI. In addition, LPA stimulated the phosphorylation of Akt and p65 protein and activated NF-kappaB-luciferase expression. Inhibitors of PI3K (wortmannin), mTOR (rapamycin), and NF-kappaB (PDTC or SN50) effectively prevented LPA-induced 3[H]-Leucine incorporation and ANF-luciferase expression. Furthermore, ERK inhibitors (U0126 and PD98059) suppressed LPA-stimulated activation of NF-kappaB and p65 phosphorylation whereas wortmannin showed no effect on NF-kappaB activation. Our findings indicate that LPA3 and/or LPA1 mediate LPA-induced hypertrophy of NRCMs and that LPA1 and LPA3 may be involved in LVRM of MI rats. Moreover, Akt and NF-kappaB signaling pathways independently implicate in LPA-stimulated myocardial hypertrophic growth.

Isolation, structural analysis, and expression characteristics of the maize nuclear factor Y gene families.

PubMed

Zhang, Zhongbao; Li, Xianglong; Zhang, Chun; Zou, Huawen; Wu, Zhongyi

2016-09-16

NUCLEAR FACTOR-Y (NF-Y) has been shown to play an important role in growth, development, and response to environmental stress. A NF-Y complex, which consists of three subunits, NF-YA, NF-YB, and, NF-YC, binds to CCAAT sequences in a promoter to control the expression of target genes. Although NF-Y proteins have been reported in Arabidopsis and rice, a comprehensive and systematic analysis of ZmNF-Y genes has not yet been performed. To examine the functions of ZmNF-Y genes in this family, we isolated and characterized 50 ZmNF-Y (14 ZmNF-YA, 18 ZmNF-YB, and 18 ZmNF-YC) genes in an analysis of the maize genome. The 50 ZmNF-Y genes were distributed on all 10 maize chromosomes, and 12 paralogs were identified. Multiple alignments showed that maize ZmNF-Y family proteins had conserved regions and relatively variable N-terminal or C-terminal domains. The comparative syntenic map illustrated 40 paralogous NF-Y gene pairs among the 10 maize chromosomes. Microarray data showed that the ZmNF-Y genes had tissue-specific expression patterns in various maize developmental stages and in response to biotic and abiotic stresses. The results suggested that ZmNF-YB2, 4, 8, 10, 13, and 16 and ZmNF-YC6, 8, and 15 were induced, while ZmNF-YA1, 3, 4, 6, 7, 10, 12, and 13, ZmNF-YB15, and ZmNF-YC3 and 9 were suppressed by drought stress. ZmNF-YA3, ZmNF-YA8 and ZmNF-YA12 were upregulated after infection by the three pathogens, while ZmNF-YA1 and ZmNF-YB2 were suppressed. These results indicate that the ZmNF-Ys may have significant roles in the response to abiotic and biotic stresses. Copyright © 2016 Elsevier Inc. All rights reserved.

Rosmanol potently inhibits lipopolysaccharide-induced iNOS and COX-2 expression through downregulating MAPK, NF-kappaB, STAT3 and C/EBP signaling pathways.

PubMed

Lai, Ching-Shu; Lee, Jong Hun; Ho, Chi-Tang; Liu, Cheng Bin; Wang, Ju-Ming; Wang, Ying-Jan; Pan, Min-Hsiung

2009-11-25

Rosmanol is a natural polyphenol from the herb rosemary (Rosmarinus officinalis L.) with high antioxidant activity. In this study, we investigated the inhibitory effects of rosmanol on the induction of NO synthase (NOS) and COX-2 in RAW 264.7 cells induced by lipopolysaccharide (LPS). Rosmanol markedly inhibited LPS-stimulated iNOS and COX-2 protein and gene expression, as well as the downstream products, NO and PGE2. Treatment with rosmanol also reduced translocation of the nuclear factor-kappaB (NF-kappaB) subunits by prevention of the degradation and phosphorylation of inhibitor kappaB (IkappaB). Western blot analysis showed that rosmanol significantly inhibited translocation and phosphorylation of NF-kappaB, signal transducer and activator of transcription-3 (STAT3), and the protein expression of C/EBPbeta and C/EBPdelta. We also found that rosmanol suppressed LPS-induced phosphorylation of ERK1/2, p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Our results demonstrate that rosmanol downregulates inflammatory iNOS and COX-2 gene expression by inhibiting the activation of NF-kappaB and STAT3 through interfering with the activation of PI3K/Akt and MAPK signaling. Taken together, rosmanol might contribute to the potent anti-inflammatory effect of rosemary and may have potential to be developed into an effective anti-inflammatory agent.

NF-kappaB signaling blockade by Bay 11-7085 during early cardiac morphogenesis induces alterations of the outflow tract in chicken heart.

PubMed

Hernández-Gutierrez, S; García-Peláez, I; Zentella-Dehesa, A; Ramos-Kuri, M; Hernández-Franco, P; Hernández-Sánchez, F; Rojas, E

2006-07-01

Nuclear factor kappaB (NF-kappaB) is a pleiotropic transcription factor implicated in the regulation of diverse morphologic cardiac alterations, for which the p50 and p65 subunits form the most prevalent dimeric form in the heart. NF-kappaB is inactivated by proteins of the IkappaB family, which trap it in the cytoplasm. It is not known whether NF-kappaB influences cardiac development. Here we investigated the role of NF-kappaB in regulating transcription in chicken heart morphogenesis. Specifically, we tested whether NF-kappaB activation is required for normal formation of the outflow tract (OFT) during a critical stage of heart development. We designed a reporter vector with kappaB binding sites for Rel family members in the promoter, upstream from the cDNA of Green Fluorescent Protein (GFP). This construct was injected directly into the developing heart of chicken embryos. NF-kappaB activation was subsequently inhibited by administration of the specific pharmacological agent Bay 11-7085. We found that forced NF-kappaB expression was associated with multiple congenital cardiac alterations of the OFT (mainly IVC, DORV and great arteries stenosis). These findings indicate that blockade of NF-kappaB induces apoptosis and is an important factor in the development of OFT during cardiogenesis. However, it remains unknown which members of the Rel family are relevant in this process.

Curcumin Regulates Low-Linear Energy Transfer {gamma}-Radiation-Induced NF{kappa}B-Dependent Telomerase Activity in Human Neuroblastoma Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aravindan, Natarajan, E-mail: naravind@ouhsc.ed; Veeraraghavan, Jamunarani; Madhusoodhanan, Rakhesh

2011-03-15

Purpose: We recently reported that curcumin attenuates ionizing radiation (IR)-induced survival signaling and proliferation in human neuroblastoma cells. Also, in the endothelial system, we have demonstrated that NF{kappa}B regulates IR-induced telomerase activity (TA). Accordingly, we investigated the effect of curcumin in inhibiting IR-induced NF{kappa}B-dependent hTERT transcription, TA, and cell survival in neuroblastoma cells. Methods and Materials: SK-N-MC or SH-SY5Y cells exposed to IR and treated with curcumin (10-100 nM) with or without IR were harvested after 1 h through 24 h. NF{kappa}B-dependent regulation was investigated either by luciferase reporter assays using pNF{kappa}B-, pGL3-354-, pGL3-347-, or pUSE-I{kappa}B{alpha}-Luc, p50/p65, or RelA siRNA-transfectedmore » cells. NF{kappa}B activity was analyzed using an electrophoretic mobility shift assay and hTERT expression using the quantitative polymerase chain reaction. TA was determined using the telomerase repeat amplification protocol assay and cell survival using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium bromide and clonogenic assay. Results: Curcumin profoundly inhibited IR-induced NF{kappa}B. Consequently, curcumin significantly inhibited IR-induced TA and hTERT mRNA at all points investigated. Furthermore, IR-induced TA is regulated at the transcriptional level by triggering telomerase reverse transcriptase (TERT) promoter activation. Moreover, NF{kappa}B becomes functionally activated after IR and mediates TA upregulation by binding to the {kappa}B-binding region in the promoter region of the TERT gene. Consistently, elimination of the NF{kappa}B-recognition site on the telomerase promoter or inhibition of NF{kappa}B by the I{kappa}B{alpha} mutant compromises IR-induced telomerase promoter activation. Significantly, curcumin inhibited IR-induced TERT transcription. Consequently, curcumin inhibited hTERT mRNA and TA in NF{kappa}B overexpressed cells. Furthermore, curcumin enhanced the IR-induced inhibition of cell survival. Conclusions: These results strongly suggest that curcumin inhibits IR-induced TA in an NF{kappa}B dependent manner in human neuroblastoma cells.« less

Short-term effects of a nicotine-free e-cigarette compared to a traditional cigarette in smokers and non-smokers.

PubMed

Ferrari, Marco; Zanasi, Alessandro; Nardi, Elena; Morselli Labate, Antonio Maria; Ceriana, Piero; Balestrino, Antonella; Pisani, Lara; Corcione, Nadia; Nava, Stefano

2015-10-12

A few studies have assessed the short-term effects of low-dose nicotine e-cigarettes, while data about nicotine-free e-cigarettes (NF e-cigarettes) are scanty. Concerns have been expressed about the use of NF e-cigarettes, because of the high concentrations of propylene glycol and other compounds in the e-cigarette vapor. This laboratory-based study was aimed to compare the effects of ad libitum use of a NF e-cigarette or and a traditional cigarette for 5 min in healthy adult smokers (n = 10) and non-smokers (n = 10). The main outcome measures were pulmonary function tests, fraction of exhaled nitric oxide (FeNO) and fractional concentration of carbon monoxide (FeCO) in exhaled breath. The traditional cigarette induced statistically significant increases in FeCO in both smokers and non-smokers, while no significant changes were observed in FeNO. In non-smokers, the traditional cigarette induced a significant decrease from baseline in FEF75 (81 % ± 35 % vs 70.2 % ± 28.2 %, P = 0.013), while in smokers significant decreases were observed in FEF25 (101.3 % ± 16.4 % vs 93.5 % ± 31.7 %, P = 0.037), FEV1 (102.2 % ± 9.5 % vs 98.3 % ± 10 %, P = 0.037) and PEF (109.5 % ± 14.6 % vs 99.2 % ± 17.5 %, P = 0.009). In contrast, the only statistically significant effects induced by the NF e-cigarette in smokers were reductions in FEV1 (102.2 % ± 9.5 % vs 99.5 ± 7.6 %, P = 0.041) and FEF25 (103.4 % ± 16.4 % vs 94.2 % ± 16.2 %, P =  .014). The present study demonstrated that the specific brand of NF e-cigarette utilized did not induce any majoracute effects. In contrast, several studies have shown that both traditional cigarettes and nicotine-containing e-cigarettes have acute effects on lung function. Our study expands on previous observations on the effects of NF e-cigarettes, but also for the first time describes the changes induced by smoking one traditional cigarette in a group of never smokers. The short-term use of the specific brand of NF e-cigarette assessed in this study had no immediate adverse effects on non-smokers and only small effects on FEV1 and FEF25 in smokers. The long-term health effects of NF e-cigarette use are unknown but worthy of further investigations. Clinicaltrials.gov: NCT02102191.

Primate Lentiviruses Modulate NF-κB Activity by Multiple Mechanisms to Fine-Tune Viral and Cellular Gene Expression

PubMed Central

Heusinger, Elena; Kirchhoff, Frank

2017-01-01

The transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) plays a complex role during the replication of primate lentiviruses. On the one hand, NF-κB is essential for induction of efficient proviral gene expression. On the other hand, this transcription factor contributes to the innate immune response and induces expression of numerous cellular antiviral genes. Recent data suggest that primate lentiviruses cope with this challenge by boosting NF-κB activity early during the replication cycle to initiate Tat-driven viral transcription and suppressing it at later stages to minimize antiviral gene expression. Human and simian immunodeficiency viruses (HIV and SIV, respectively) initially exploit their accessory Nef protein to increase the responsiveness of infected CD4+ T cells to stimulation. Increased NF-κB activity initiates Tat expression and productive replication. These events happen quickly after infection since Nef is rapidly expressed at high levels. Later during infection, Nef proteins of HIV-2 and most SIVs exert a very different effect: by down-modulating the CD3 receptor, an essential factor for T cell receptor (TCR) signaling, they prevent stimulation of CD4+ T cells via antigen-presenting cells and hence suppress further induction of NF-κB and an effective antiviral immune response. Efficient LTR-driven viral transcription is maintained because it is largely independent of NF-κB in the presence of Tat. In contrast, human immunodeficiency virus type 1 (HIV-1) and its simian precursors have lost the CD3 down-modulation function of Nef and use the late viral protein U (Vpu) to inhibit NF-κB activity by suppressing its nuclear translocation. In this review, we discuss how HIV-1 and other primate lentiviruses might balance viral and antiviral gene expression through a tight temporal regulation of NF-κB activity throughout their replication cycle. PMID:28261165

Intake of Fish and Omega-3 (n-3) Fatty Acids: Effect on Humans During Actual and Simulated Weightlessness

NASA Technical Reports Server (NTRS)

Smith, S. M.; Pierson, D. L.; Mehta, S. K.; Zwart, S. R.

2011-01-01

Space flight has many negative effects on human physiology, including bone and muscle loss. Bone and muscle are two systems that are positively affected by dietary intake of fish and n-3 fatty acids. The mechanism is likely to be related to inhibition by n-3 fatty acids of inflammatory cytokines (such as TNF) and thus inhibition of downstream NF-kB activation. We have documented this effect in a 3-dimensional cell culture model, where NF-kB activation in osteoclasts was inhibited by eicosapentaenoic acid, an n-3 fatty acid. We have also indentified that NF-kB activation in peripheral blood mononuclear cells of Space Shuttle crews. We found that after Shuttle flights of 2 wk, expression of the protein p65 (evidence of NF-kB activation) was increased at landing (P less than 0.001). When evaluating the effects of n-3 fatty acid intake on bone breakdown after 60 d of bed rest (a weightlessness analog). We found that after 60 d of bed rest, greater intake of n-3 fatty acids was associated with less N-telopeptide excretion (Pearson r = -0.62, P less than 0.05). We also evaluated the relationship of fish intake and bone loss in astronauts after 4 to 6 mo missions on the International Space Station. Higher consumption of fish during flight was associated with higher bone mineral density (Pearson r = 0.46, P less than 0.05). Together, these findings provide evidence of the cellular mechanism by which n-3 fatty acids can inhibit bone loss, and preliminary human evidence of the potential for n-3 fatty acids to counteract bone loss associated with space flight. This study was supported by the NASA Human Research Program.

Amentoflavone Induces Apoptosis and Inhibits NF-ĸB-modulated Anti-apoptotic Signaling in Glioblastoma Cells

PubMed Central

YEN, TSUNG-HSIEN; HSIEH, CHIA-LING; LIU, TSU-TE; HUANG, CHIH-SHENG; CHEN, YEN-CHUNG; CHUANG, YAO-CHEN; LIN, SONG-SHEI; HSU, FEI-TING

2018-01-01

>The goal of the present study was to investigate anticancer effect of amentoflavone on glioblastoma cells in vitro. Our results demonstrated that amentoflavone not only significantly reduced cell viability, nuclear factor-ĸappa B (NF-ĸB) activation, and protein expression of cellular Fas-associated protein with death domain-like interleukin 1 beta-converting enzyme inhibitory protein (C-FLIP) and myeloid cell leukemia 1 (MCL1), but significantly triggered cell accumulation at the sub-G 1 phase, loss of mitochondrial membrane potential, and expression of active caspase-3 and -8. In order to verify the effect of NF-ĸB inhibitor on expression of anti-apoptotic proteins, we performed western blotting. We found that the of NF-ĸB inhibitor or amentoflavone markedly diminished protein levels of MCL1 and C-FLIP. Taken all together, our findings show that amentoflavone induces intrinsic and extrinsic apoptosis and inhibits NF-ĸB-modulated anti-apoptotic signaling in U-87 MG cells in vitro. PMID:29475910

Hyperforin Suppresses Tumor Growth and NF-κB-mediated Anti-apoptotic and Invasive Potential of Non-small Cell Lung Cancer.

PubMed

Chen, Wei-Ting; Chen, Ying-Kai; Lin, Song-Shei; Hsu, Fei-Ting

2018-04-01

Previous studies have indicated that hyperforin inhibits tumor growth of hepatocellular carcinoma. However, the anticancer effects of hyperforin in non-small cell lung cancer (NSCLC) are ambiguous. The aim of the present study was to investigate the anticancer effect of hyperforin in NSCLC. NSCLC CL1-5-F4 cells were treated with different concentrations of hyperforin or NF-κB inhibitor (QNZ) for different time periods. Change of cell viability, NF-κB activation, apoptotic signaling pathways, expression of anti-apoptotic proteins, and cell invasion were detected using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, NF-κB reporter gene assay, flow cytometry, western blotting, and cell invasion assay. The results demonstrated that hyperforin significantly promotes extrinsic and intrinsic apoptotic pathways, and inhibits cell viability and NF-κB activation. In addition, results also indicated that blockage of NF-κB activation reduces the levels of anti-apoptotic proteins and cell invasion in CL1-5-F4 cells. These results suggested hyperforin induces apoptosis and inhibits NF-κB-modulated anti-apoptotic and invasive potential in NSCLC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Osthole inhibits inflammatory cytokine release through PPARα/γ-mediated mechanisms in LPS-stimulated 3T3-L1 adipocytes.

PubMed

Wang, Xiao-li; Shang, Xiang; Cui, Yan; Zhao, Xi; Zhang, Yan; Xie, Mei-lin

2015-04-01

Peroxisome proliferator-activated receptor (PPAR) α/γ may control inflammatory response by regulating the nuclear factor-kappa B (NF-κB). Osthole may be a dual agonist of PPARα/γ, but whether or not osthole may inhibit inflammatory cytokines in cultured 3T3-L1 adipocytes is unclear. We investigated the action of osthole and its potential mechanisms in lipopolysaccharide (LPS)-stimulated 3T3-L1 adipocytes. The 3T3-L1 adipocytes stimulated with LPS were cultured and treated with different concentrations of osthole. The inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured supernatants were detected by the enzyme-linked immunosorbent assay (ELISA) method, and the protein expressions of PPARα/γ and NF-κB p65 in adipocytes were detected by the Western blot method, respectively. Following treatment of adipocytes with osthole 0.1-1.6 μM, the TNF-α and IL-6 levels in cultured supernatants were decreased, and the NF-κB p65 protein expression in adipocytes was also decreased, while the PPARα/γ protein expressions were increased. After pretreatment of adipocytes with specific inhibitor(s) of PPARα and /or PPARγ, the inhibitory effects of osthole on TNF-α and IL-6 were decreased or almost cancelled, and the effects on NF-κB p65 protein expression also exhibited similar variations. Osthole could inhibit the TNF-α and IL-6 production in LPS-stimulated adipocytes, and its mechanism might be related to reduction of NF-κB expression via activation of PPARα/γ.

Omega-3 polyunsaturated fatty acids alleviate hepatic steatosis-induced inflammation through Sirt1-mediated nuclear translocation of NF-κB p65 subunit in hepatocytes of large yellow croaker (Larmichthys crocea).

PubMed

Wang, Tianjiao; Yang, Bo; Ji, Renlei; Xu, Wei; Mai, Kangsen; Ai, Qinghui

2017-12-01

Hepatic steatosis induced inflammation is becoming increasingly prevalent in farmed fish. This study was conducted to investigate the protective effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) against hepatic steatosis-induced inflammation and its potential molecular mechanisms in hepatocyte of large yellow croaker (Larmichthys crocea). We found that the hepatic steatosis-induced inflammation was relieved by ω-3 PUFAs, meanwhile, the Sirt1 activity and transcript expression was increased by ω-3 PUFAs. The increased Sirt1 activity can decrease the hepatic steatosis-induced inflammation. The protective effects of ω-3 PUFAs against hepatic steatosis-induced inflammation was reversed by the treatment with Sirt1 inhibitor EX-527. The nuclear translocation of nuclear transcription factor kappa-B (NF-κB) p65 was significantly decreased after ω-3 PUFAs treatments compared to the palmitic acid stimulation group. The ω-3 PUFAs induced cytoplasm translocation of NF-κB p65 was reversed by EX-527. Together, ω-3 PUFAs alleviate hepatic steatosis-induced inflammation through Sirt1-mediated nuclear translocation of NF-κB p65 subunit in hepatocytes of large yellow croaker. The present study provides important insight into the mechanisms of the protective effects of ω-3 PUFAs, providing theory bases for alleviating the hepatic steatosis induced inflammation of farmed fish, thereby offering great benefits to the aquaculture industry and fish consumers. Copyright © 2017. Published by Elsevier Ltd.

N-acetyl cysteine inhibits lipopolysaccharide-mediated induction of interleukin-6 synthesis in MC3T3-E1 cells through the NF-kB signaling pathway.

PubMed

Guo, Ling; Zhang, Hui; Li, Wangyang; Zhan, Danting; Wang, Min

2018-06-06

Interleukin-6 (IL-6) is a potent stimulator of osteoclastic activity. Lipopolysaccharide (LPS) has been shown to regulate the expression of potent inflammatory factors, including TNF-α and IL-6. Currently, effective therapeutic treatments for bacteria-caused bone destruction are limited. N-acetyl cysteine (NAC) is an antioxidant small molecule that possibly modulates osteoblastic differentiation. However, whether NAC can affect the LPS-mediated reduction of IL-6 synthesis in MC3T3-E1 cells is still unknown. The aim of this study was to investigate the role of NAC in the LPS -mediated reduction of IL-6 synthesis by MC3T3-E1 cells and to explore the underlying molecular mechanisms. In addition, we aimed to determine the involvement of the NF-kB pathway in any changes in IL-6 expression observed in response to LPS and NAC. MC3T3-E1 cells (ATCC, CRL-2593) were cultured in α-minimum essential medium. Cells were stimulated using NAC or LPS at various concentrations. Cell proliferation was observed at multiple time points using a cell counting kit 8 (CCK-8). IL-6 mRNA expression and protein synthesis were determined using quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay analyses. NF-kB mRNA expression and protein synthesis was determined using qPCR and Western blots analyses. The results demonstrate that LPS induced IL-6 and NF-kB mRNA expression and protein synthesis in the cultured MC3T3-E1 cells. However, these effects were abolished following pre-treatment with NAC. Pretreatment with NAC (1 mmol/l) or BAY11-7082 (10 μmol/l) both significantly inhibited the NF-kB activity induced by LPS. NAC inhibits the LPS-mediated induction of IL-6 synthesis in MC3T3-E1 cells through the NF-kB pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-κB pathway in skeletal muscle.

PubMed

Laure, Lydie; Danièle, Nathalie; Suel, Laurence; Marchand, Sylvie; Aubert, Sophie; Bourg, Nathalie; Roudaut, Carinne; Duguez, Stéphanie; Bartoli, Marc; Richard, Isabelle

2010-10-01

A multiprotein complex encompassing a transcription regulator, cardiac ankyrin repeat protein (CARP), and the calpain 3 protease was identified in the N2A elastic region of the giant sarcomeric protein titin. The present study aimed to investigate the function(s) of this complex in the skeletal muscle. We demonstrate that CARP subcellular localization is controlled by the activity of calpain 3: the higher the calpain 3, the more important the sarcomeric retention of CARP. This regulation would occur through cleavage of the N-terminal end of CARP by the protease. We show that, upon CARP over-expression, the transcription factor nuclear factor NF-κB p65 DNA-binding activity decreases. Taken as a whole, CARP and its regulator calpain 3 appear to occupy a central position in the important cell fate-governing NF-κB pathway. Interestingly, the expression of the atrophying protein MURF1, one of NF-κB main targets, remains unchanged in presence of CARP, suggesting that the pathway encompassing calpain 3/CARP/NF-κB does not play a role in muscle atrophy. With NF-κB also having anti-apoptotic effects, the inability of calpain 3 to lower CARP-driven inhibition of NF-κB could reduce muscle cell survival, hence partly accounting for the dystrophic pattern observed in limb girdle muscular dystrophy 2A, a pathology resulting from the protease deficiency. © 2010 The Authors Journal compilation © 2010 FEBS.

3D morphological characterization of the polyamide active layer of RO and NF membranes using TEM and soft X-ray scattering

NASA Astrophysics Data System (ADS)

Culp, Tyler; Paul, Mou; Roy, Abhishek; Rosenberg, Steve; Behr, Michael; Kumar, Manish; Gomez, Enrique; Penn State Team; Dow Team

Polyamide-based thin-film composite (TFC) membranes used for reverse osmosis (RO) and nanofiltration (NF) separation processes are at the forefront of water desalination and purification technologies due to their high salt rejection, high energy efficiency, and ease of operation. Nevertheless, in spite of the benefits of RO and NF membranes, many open questions about the internal nanostructure of the membrane active layer remain, such as the dispersion and distribution of acid functional groups. We demonstrate that resonant soft X-ray scattering (RSOXS), where the X-ray energy is tuned to absorption edges of the constituent materials, is a powerful tool to examine the microstructure of the polyamide layer. In conjunction with complementary techniques such as transmission electron microscopy (TEM), where tomography is used to obtain a 3D reconstruction of the polyamide active layer, the effect of cross-linking can be quantified in 3D for a systematic series of membranes. This relationship can then be applied to a series of commercially available RO and NF membranes where the effect of polyamide cross-linking on their respective structure and water transport properties can be evaluated. The combination of RSOXS with traditional characterization tools provides a strategy for linking the chemical structure to the morphology and water transport properties of RO and NF membranes.

Jaceosidin, a natural flavone, promotes angiogenesis via activation of VEGFR2/FAK/PI3K/AKT/NF-κB signaling pathways in endothelial cells.

PubMed

Lee, Tae Hoon; Jung, Hana; Park, Keun Hyung; Bang, Myun Ho; Baek, Nam-In; Kim, Jiyoung

2014-10-01

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, plays an important role in physiological and pathological processes such as embryonic development wound healing and revascularization of tissues after exposure to ischemia. We investigated the effects of jaceosidin, a main constituent of medicinal herbs of the genus Artemisia, on angiogenesis and signaling pathways in endothelial cells. Jaceosidin stimulated proliferation, migration and tubulogenesis of ECs as well as ex vivo sprouting from aorta rings, which are phenomena typical of angiogenesis. Jaceosidin activated vascular endothelial growth factor receptor 2 (VEGFR2, FLk-1/KDR) and angiogenic signaling molecules such as focal adhesion kinase, phosphatidylinositol 3-kinase, and its downstream target, the serine-threonine kinase AKTWe also demonstrated that jaceosidin activated the NF-κB-driven expression of a luciferase reporter gene and NF-κB binding to DNA. Jaceosidin-induced proliferation and migration of human umbilical vascular endothelial cells were strongly inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002 and NF-κB inhibitor BAY11-7082, indicating that the PI3K/AKT/NF-κB signaling pathway is involved in jaceosidin-induced angiogenesis. Our results suggest that jaceosidin stimulates angiogenesis by activating the VEGFR2/FAK/PI3K/AKT/NF-κB signaling pathway and that it may be useful in developing angiogenic agents to promote the growth of collateral blood vessels in ischemic tissues. © 2014 by the Society for Experimental Biology and Medicine.

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

PubMed Central

Jiang, Li-Bo; Meng, De-Hua; Lee, Soo-Min; Liu, Shu-Hao; Xu, Qin-Tong; Wang, Yang; Zhang, Jian

2016-01-01

Osteoarthritis is a disease with inflammatory and catabolic imbalance in cartilage. Dihydroartemisinin (DHA), a natural and safe anti-malarial agent, has been reported to inhibit inflammation, but its effects on chondrocytes have yet to be elucidated. We investigated the effects of DHA on catabolism in chondrocytes. Viability of SD rats chondrocytes was analyzed. Autophagy levels were determined via expression of autophagic markers LC3 and ATG5, GFP-LC3 analysis, acridine orange staining, and electron microscopy. ATG5 siRNA induced autophagic inhibition. Catabolic gene and chemokine expression was evaluated using qPCR. The NF-κB inhibitor SM7368 and p65 over-expression were used to analyze the role of NF-κB pathway in autophagic activation. A concentration of 1 μM DHA without cytotoxicity increased LC3-II and ATG5 levels as well as autophagosomal numbers in chondrocytes. DHA inhibited TNF-α-induced expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1, which was reversed by autophagic inhibition. TNF-α-stimulated nuclear translocation and degradation of the p65 and IκBα proteins, respectively, were attenuated in DHA-treated chondrocytes. NF-κB inhibition activated autophagy in TNF-α-treated chondrocytes, but p65 over-expression reduced the autophagic response to DHA. These results indicate that DHA might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition. PMID:27941926

IGF-1 and PDGF-bb Suppress IL-1β-Induced Cartilage Degradation through Down-Regulation of NF-κB Signaling: Involvement of Src/PI-3K/AKT Pathway

PubMed Central

Mobasheri, Ali; Buhrmann, Constanze; Aldinger, Constance; Rad, Jafar Soleimani; Shakibaei, Mehdi

2011-01-01

Objective Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays a key role in the pathogenesis of osteoarthritis (OA). Growth factors (GFs) capable of antagonizing the catabolic actions of cytokines may have therapeutic potential in the treatment of OA. Herein, we investigated the potential synergistic effects of insulin-like growth factor (IGF-1) and platelet-derived growth factor (PDGF-bb) on different mechanisms participating in IL-1β-induced activation of nuclear transcription factor-κB (NF-κB) and apoptosis in chondrocytes. Methods Primary chondrocytes were treated with IL-1β to induce dedifferentiation and co-treated with either IGF-1 or/and PDGF-bb and evaluated by immunoblotting and electron microscopy. Results Pretreatment of chondrocytes with IGF-1 or/and PDGF-bb suppressed IL-1β-induced NF-κB activation via inhibition of IκB-α kinase. Inhibition of IκB-α kinase by GFs led to the suppression of IκB-α phosphorylation and degradation, p65 nuclear translocation and NF-κB-regulated gene products involved in inflammation and cartilage degradation (COX-2, MMPs) and apoptosis (caspase-3). GFs or BMS-345541 (specific inhibitor of the IKK) reversed the IL-1β-induced down-regulation of collagen type II, cartilage specific proteoglycans, β1-integrin, Shc, activated MAPKinase, Sox-9 and up-regulation of active caspase-3. Furthermore, the inhibitory effects of IGF-1 or/and PDGF-bb on IL-1β-induced NF-κB activation were sensitive to inhibitors of Src (PP1), PI-3K (wortmannin) and Akt (SH-5), suggesting that the pathway consisting of non-receptor tyrosine kinase (Src), phosphatidylinositol 3-kinase and protein kinase B must be involved in IL-1β signaling. Conclusion The results presented suggest that IGF-1 and PDGF-bb are potent inhibitors of IL-1β-mediated activation of NF-κB and apoptosis in chondrocytes, may be mediated in part through suppression of Src/PI-3K/AKT pathway, which may contribute to their anti-inflammatory effects. PMID:22194879

Acetyl-11-Keto-β-Boswellic Acid Promotes Osteoblast Differentiation by Inhibiting Tumor Necrosis Factor-α and Nuclear Factor-κB Activity.

PubMed

Bai, Fan; Chen, Xuewu; Yang, Hui; Xu, Hong-Guang

2018-06-20

Tumor necrosis factor (TNF) -α plays a crucial role in rheumatoid arthritis (RA)-related bone loss disease. The main mechanism of action of RA induced bone loss is the significant inhibitory effect of TNF-α on osteoblast differentiation. TNF-α inhibits osteoblast differentiation mainly by activating nuclear factor (NF) -κB signaling pathway. Owing to the crucial role of TNF-α and NF-κB in the inhibition of osteoblast differentiation, they are considered as targets for the development of therapeutic drugs. In the present study, we evaluated the NF-κB inhibitor Boswellic acid (BA) and its derivatives in the regulation of osteoblast differentiation and the molecular mechanism. Based on the cell model of TNF-α induced inhibition of osteoblast differentiation of MC3T3-E1, the regulatory role of BAs was studied. The result of MTT assay indicated that bone morphogenetic protein (BMP) -2, TNF-α, or acetyl-11-keto-β-BA (AKBA) impact no significant effect for cell viability of MC3T3-E1. The results of alkaline phosphatase (ALP activity assay and real-time polymerase chain reaction indicated that AKBA blocked TNF-α-induced inhibition of the expression of osteoblast markers, suggesting that AKBA rescued osteoblast differentiation from TNF-α-induced inhibition. Additionally, AKBA stimulated the BMP-2-induced expression of osteoblast markers, suggesting that AKBA promotes osteoblast differentiation directly. The results of western blotting and luciferase assay indicated that N-κB signaling was activated by TNF-α. The overexpression of NF-κB component p65 in MC3T3-E1 was found to attenuate the positive effect of AKBA in osteoblast differentiation, suggesting that AKBA potentiates osteoblast differentiation by inhibiting NF-κB signaling. Collectively, AKBA promotes osteoblast differentiation by inhibiting TNF-α and NF-κB. Our study revealed a new discovery of AKBA in regulating osteoblast differentiation, and demonstrated that AKBA may be a potential anabolic agent in the treatment of RA-derived bone loss disease.

The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells

PubMed Central

Sasaki, Clarence T.; Toman, Julia; Vageli, Dimitra

2016-01-01

Background Extra-esophageal carcinogenesis has been widely discussed in relation to the chronic effects of laryngopharyngeal reflux and most prominently with pepsin historically central to this discussion. With refluxate known to include gastric (pepsin) and duodenal (bile) fluids, we recently demonstrated the mechanistic role of NF-κB in mediating the preneoplastic effects of acidic-bile. However, the role of pepsin in promoting hypopharyngeal premalignant events remains historically unclear. Here, we investigate the in vitro effect of acidic-pepsin on the NF-κB oncogenic pathway to better define its potential role in hypopharyngeal neoplasia. Methods Human hypopharyngeal primary cells (HHPC) and keratinocytes (HHK) were repetitively exposed to physiologic pepsin concentrations (0.1 mg/ml) at pH 4.0, 5.0 and 7.0. Cellular localization of phospho-NF-κB and bcl-2 was determined using immunofluorescence and western blotting. NF-κB transcriptional activity was tested by luc reporter and qPCR. Analysis of DNA content of pepsin treated HHK and HHPC was performed using Fluorescence-activated-cell sorting assay. To explore a possible dose related effect, pepsin concentration was reduced from 0.1 to 0.05 and 0.01 mg/ml. Results At physiologic concentration, acidic-pepsin (0.1 mg/ml at pH 4.0) is lethal to most normal hypopharyngeal cells. However, in surviving cells, no NF-κB transcriptional activity is noted. Acidic-pepsin fails to activate the NF-κB or bcl-2, TNF-α, EGFR, STAT3, and wnt5α but increases the Tp53 mRNAs, in both HHPC and HHK. Weakly acidic-pepsin (pH 5.0) and neutral-pepsin (pH 7.0) induce mild activation of NF-κB with increase in TNF-α mRNAs, without oncogenic transcriptional activity. Lower concentrations of pepsin at varying pH do not produce NF-κB activity or transcriptional activation of the analyzed genes. Conclusion Our findings in vitro do not support the role of acidic-pepsin in NF-κB related hypopharyngeal carcinogenesis. PMID:27973541

Cs/NF3 adsorption on [001]-oriented GaN nanowire surface: A first principle calculation

NASA Astrophysics Data System (ADS)

Diao, Yu; Liu, Lei; Xia, Sihao; Kong, Yike

2017-11-01

In this study, the adsorption mechanism of Cs/NF3 on the [001]-oriented GaN nanowire surface is investigated by using the density function theory based on first-principles. In the Cs/NF3 co-activation process, the system is inclined to form NF3-in structure. Through the calculation results of adsorption energy, NF3 molecule adsorption tends to take an orientation with F atoms on top and the most favorable adsorption site is BGa-N. The NF3 activation process can further cut down the work function of the Cs-covered nanowire surface only when Cs coverage is 0.75 ML and 1 ML, which can be explained by the double dipole moment theory. With increasing Cs coverage, the valence band and conduction band both shift to lower energy side, contributing to the appearance of a downward band bending region and promoting the escape of surface photoelectrons. After NF3 molecule adsorption, the peak of total density of states near Fermi level increase due to the orbital hybridization between NF3-2s, Cs-5s states and N-2p states, which strengthen the conductivity of the nanowire surface and leads to the metallic properties. All these calculations may direct the Cs/NF3 activation process of GaN nanowire optoelectronic devices.

Effects of ozone on growth, net photosynthesis and yield of two African varieties of Vigna unguiculata.

PubMed

Tetteh, Rashied; Yamaguchi, Masahiro; Wada, Yoshiharu; Funada, Ryo; Izuta, Takeshi

2015-01-01

To assess the effects of O(3)on growth, net photosynthesis and yield of two African varieties of cowpea(Vigna unguiculata L.), Blackeye and Asontem were exposed as potted plants to air that was either filtered to remove O(3) (FA), non-filtered air (NF), non-filtered with added O3 of approximately 50 nL L(-1) (ppb) from 11:00 to 16:00 (NF + O(3)) for 88 days in open-top chambers. The mean O(3) concentration (11:00-16:00) during the exposure period had a range from 16 ppb in the FA treatment to 118 ppb in the NF + O(3) treatment. Net photosynthetic rate and leaf area per plant were significantly reduced by exposure to O(3), reducing the growth of both varieties. Exposure to O(3) significantly reduced the 100-seed weight and number of seeds per pod. As a result, cowpea yield was significantly reduced by long-term exposure to O(3), with no difference in sensitivity between the varieties.

Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.

PubMed

Zhou, Qing; Wang, Hongying; Schwartz, Daniella M; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David T; Zaal, Kristien; Chandrasekharappa, Settara C; P Hanson, Eric; Yu, Zhen; Mullikin, James C; Hasni, Sarfaraz A; Wertz, Ingrid E; Ombrello, Amanda K; Stone, Deborah L; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K; Leavis, Helen L; van Royen-Kerkof, Annet; Sibley, Cailin; Batu, Ezgi D; Gül, Ahmet; Siegel, Richard M; Boehm, Manfred; Milner, Joshua D; Ozen, Seza; Gadina, Massimo; Chae, JaeJin; Laxer, Ronald M; Kastner, Daniel L; Aksentijevich, Ivona

2016-01-01

Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB-mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.

Effects of neurofeedback versus stimulant medication in attention-deficit/hyperactivity disorder: a randomized pilot study.

PubMed

Ogrim, Geir; Hestad, Knut A

2013-09-01

The purpose of this pilot study was to compare the effects of 30 sessions of neurofeedback (NF) with stimulant medication on attention-deficit/hyperactivity disorder (ADHD) patients. Thirty-two medication-naïve ADHD patients, ages 7-16, from a neuropsychiatric clinic, were randomized to NF (n=16) or drug treatment (n=16). Other actions, such as parent management training, information, or support in school were given as needed, with no differences between the groups. All participants were assessed before treatment on two rating scales, each with parent and teacher forms. In addition, quantitative electroencephalogram (QEEG) and event-related potentials (ERPs), which included behavioral data from a go/no go test were administered. NF training took place in the clinic over a period of 7-11 months, and was followed by a repeat of the same assessment tools. The mean time interval between pre- and postassesment was not significantly different in the two groups. The 18 symptoms of ADHD (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)) were used as the primary outcome measure. Analysis of covariance revealed a significant difference between the groups at evaluation in favor of medication, with a large effect size. This picture was confirmed by other outcome measures. The QEEG spectral power in the theta and beta bands did not change in either group. In ERP, the P3 no go component increased significantly in 8 of 12 patients who had a clinically relevant medication effect, but did not increase in the medication nonresponders or the NF group. Our study supports effects for stimulants, but not for NF. Effects of NF may require thorough patient selection, frequent training sessions, a system for excluding nonresponders, and active transfer training. The P3 no go ERP component may be a marker for treatment response.

How sodium arsenite improve amyloid β-induced memory deficit?

PubMed

Nassireslami, Ehsan; Nikbin, Parmida; Amini, Elham; Payandemehr, Borna; Shaerzadeh, Fatemeh; Khodagholi, Fariba; Yazdi, Behnoosh Bonakdar; Kebriaeezadeh, Abbas; Taghizadeh, Ghorban; Sharifzadeh, Mohammad

2016-09-01

Evidence has shown that arsenic exposure, besides its toxic effects results in impairment of learning and memory, but its molecular mechanisms are not fully understood. In the present study, we examined sodium arsenite (1, 5, 10, 100nM) effects on contextual and tone memory of male rats in Pavlovian fear conditioning paradigm alone and in co-administration with β-amyloid. We detected changes in the level of caspase-3, nuclear factor kappa-B (NF-κB), cAMP response element-binding (CREB), heme oxygenase-1 and NF-E2-related factor-2 (Nrf2) by Western blot. Sodium arsenite in high doses induced significant memory impairment 9 and 16days after infusion. By contrast, low doses of sodium arsenite attenuate memory deficit in Aβ injected rats after 16days. Our data revealed that treatment with high concentration of sodium arsenite increased caspase-3 cleavage and NF-κB level, 9days after injection. Whereas, low doses of sodium arsenite cause Nrf2 and HO-1 activation and increased CREB phosphorylation in the hippocampus. These findings suggest the concentration dependent effects of sodium arsenite on contextual and tone memory. Moreover, it seems that the neuroprotective effects of ultra-low concentrations of sodium arsenite on Aβ-induced memory impairment is mediated via an increase Nrf2, HO-1 and CREB phosphorylation levels and decrease caspase-3 and NF-κB amount. Copyright © 2016. Published by Elsevier Inc.

Isolation, structural analysis, and expression characteristics of the maize nuclear factor Y gene families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Zhongbao; Li, Xianglong; Zhang, Chun

NUCLEAR FACTOR-Y (NF-Y) has been shown to play an important role in growth, development, and response to environmental stress. A NF-Y complex, which consists of three subunits, NF-YA, NF-YB, and, NF-YC, binds to CCAAT sequences in a promoter to control the expression of target genes. Although NF-Y proteins have been reported in Arabidopsis and rice, a comprehensive and systematic analysis of ZmNF-Y genes has not yet been performed. To examine the functions of ZmNF-Y genes in this family, we isolated and characterized 50 ZmNF-Y (14 ZmNF-YA, 18 ZmNF-YB, and 18 ZmNF-YC) genes in an analysis of the maize genome. Themore » 50 ZmNF-Y genes were distributed on all 10 maize chromosomes, and 12 paralogs were identified. Multiple alignments showed that maize ZmNF-Y family proteins had conserved regions and relatively variable N-terminal or C-terminal domains. The comparative syntenic map illustrated 40 paralogous NF-Y gene pairs among the 10 maize chromosomes. Microarray data showed that the ZmNF-Y genes had tissue-specific expression patterns in various maize developmental stages and in response to biotic and abiotic stresses. The results suggested that ZmNF-YB2, 4, 8, 10, 13, and 16 and ZmNF-YC6, 8, and 15 were induced, while ZmNF-YA1, 3, 4, 6, 7, 10, 12, and 13, ZmNF-YB15, and ZmNF-YC3 and 9 were suppressed by drought stress. ZmNF-YA3, ZmNF-YA8 and ZmNF-YA12 were upregulated after infection by the three pathogens, while ZmNF-YA1 and ZmNF-YB2 were suppressed. These results indicate that the ZmNF-Ys may have significant roles in the response to abiotic and biotic stresses. - Highlights: • We indicated a total of 50 members of ZmNF-Y gene family in maize genome. • We analyzed gene structure, protein architecture of ZmNF-Y genes. • Evolution pattern and phylogenic relationships were analyzed among 50 ZmNF-Y genes. • Expression pattern of ZmNF-Ys were detected in various maize tissues. • Transcript levels of ZmNF-Ys were measured under various abiotic and biotic stresses.« less

Curcumin Analogue CA15 Exhibits Anticancer Effects on HEp-2 Cells via Targeting NF-κB

PubMed Central

Zhang, Linlin; Chen, Liping; Zhu, Min; Yao, Song; Wang, Jiabing; Wu, Jianzhang; Liang, Guang

2017-01-01

Laryngeal carcinoma remains one of the most common malignancies, and curcumin has been proven to be effective against head and neck cancers in vitro. However, it has not yet been applied in clinical settings due to its low stability. In the current study, we synthesized 34 monocarbonyl analogues of curcumin with stable structures. CA15, which exhibited a stronger inhibited effect on laryngeal cancer cells HEp-2 but a lower toxicity on hepatic cells HL-7702 in MTT assay, was selected for further analysis. The effects of CA15 on cell viability, proliferation, migration, apoptosis, and NF-κB activation were measured using MTT, Transwell migration, flow cytometry, Western blot, and immunofluorescence assays in HEp-2 cells. An NF-κB inhibitor, BMS-345541, as well as curcumin was also tested. Results showed that CA15 induced decreased toxicity towards HL-7702 cells compared to curcumin and BMS-345541. However, similar to BMS-345541 and curcumin, CA15 not only significantly inhibited proliferation and migration and induced caspase-3-dependent apoptosis but also attenuated TNF-α-induced NF-κB activation in HEp-2 cells. These results demonstrated that curcumin analogue CA15 exhibited anticancer effects on laryngeal cancer cells via targeting of NF-κB. PMID:28409156

Curcumin Analogue CA15 Exhibits Anticancer Effects on HEp-2 Cells via Targeting NF-κB.

PubMed

Chen, Jian; Zhang, Linlin; Shu, Yilai; Chen, Liping; Zhu, Min; Yao, Song; Wang, Jiabing; Wu, Jianzhang; Liang, Guang; Wu, Haitao; Li, Wulan

2017-01-01

Laryngeal carcinoma remains one of the most common malignancies, and curcumin has been proven to be effective against head and neck cancers in vitro. However, it has not yet been applied in clinical settings due to its low stability. In the current study, we synthesized 34 monocarbonyl analogues of curcumin with stable structures. CA15, which exhibited a stronger inhibited effect on laryngeal cancer cells HEp-2 but a lower toxicity on hepatic cells HL-7702 in MTT assay, was selected for further analysis. The effects of CA15 on cell viability, proliferation, migration, apoptosis, and NF- κ B activation were measured using MTT, Transwell migration, flow cytometry, Western blot, and immunofluorescence assays in HEp-2 cells. An NF- κ B inhibitor, BMS-345541, as well as curcumin was also tested. Results showed that CA15 induced decreased toxicity towards HL-7702 cells compared to curcumin and BMS-345541. However, similar to BMS-345541 and curcumin, CA15 not only significantly inhibited proliferation and migration and induced caspase-3-dependent apoptosis but also attenuated TNF- α -induced NF- κ B activation in HEp-2 cells. These results demonstrated that curcumin analogue CA15 exhibited anticancer effects on laryngeal cancer cells via targeting of NF- κ B.

Galectin-3 Mediates Tumor Cell-Stroma Interactions by Activating Pancreatic Stellate Cells to Produce Cytokines via Integrin Signaling.

PubMed

Zhao, Wei; Ajani, Jaffer A; Sushovan, Guha; Ochi, Nobuo; Hwang, Rosa; Hafley, Margarete; Johnson, Randy L; Bresalier, Robert S; Logsdon, Craig D; Zhang, Zhiqian; Song, Shumei

2018-04-01

Pancreatic ductal adenocarcinoma (PDAC) is characterized by activated pancreatic stellate cells (PSCs), abundance of extracellular matrix (ECM), and production of cytokines and chemokines. Galectin 3 (GAL3), a β-galactoside-specific lectin, contributes to PDAC development but its effects on the stroma and cytokine production are unclear. The effect of recombinant human GAL3 (rGAL3) on activation of PSCs, production of cytokines, and ECM proteins was determined by proliferation, invasion, cytokine array, and quantitative polymerase chain reaction. We assessed co-cultures of PDAC cells with GAL3 genetic alterations with PSCs. Production of interleukin 8 (IL8) and activities of nuclear factor (NF)-κB were determined by enzyme-linked immunosorbent assay and luciferase reporter analyses. We studied the effects of inhibitors of NF-κB and integrin-linked kinase (ILK) on pathways activated by rGAL3. In analyses of the Gene Expression Omnibus database and our dataset, we observed higher levels of GAL3, IL8, and other cytokines in PDAC than in nontumor tissues. Production of IL8, granulocyte-macrophage colony-stimulating factor, chemokine ligand 1, and C-C motif chemokine ligand 2 increased in PSCs exposed to rGAL3 compared with controls. Culture of PSCs with PDAC cells that express different levels of GAL3 resulted in proliferation and invasion of PSCs that increased with level of GAL3. GAL3 stimulated transcription of IL8 through integrin subunit beta 1 (ITGB1) on PSCs, which activates NF-κB through ILK. Inhibitors of ILK or NF-κB or a neutralizing antibody against ITGB1 blocked transcription and production of IL8 from PSCs induced by rGAL3. The GAL3 inhibitor significantly reduced growth and metastases of orthotopic tumors that formed from PDAC and PSC cells co-implanted in mice. GAL3 activates PSC cells to produce inflammatory cytokines via ITGB1signaling to ILK and activation of NF-κB. Inhibition of this pathway reduced growth and metastases of pancreatic orthotopic tumors in mice. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Performance evaluation of cross-flow membrane system for wastewater reuse from the wood-panels industry.

PubMed

Dizge, Nadir

2014-01-01

The objectives of this investigation were to perform a series of lab-scale membrane separation experiments under various operating conditions to investigate the performance behaviour of nanofiltration membrane (NF 270) for wastewater reuse from the wood-panels industry. The operating condition effects, e.g. cross-flow velocity (CFV), trans membrane pressure (TMP) and temperature, on the permeate flux and contaminant rejection efficiency were investigated. Moreover, three different samples: (1) raw wastewater collected from the wood-panels industry; (2) ultrafiltration pre-treated wastewater (UF-NF); and (3) coagulation/flocculation pre-treated wastewater (CF-NF) were employed in this study. The UF-NF was proposed as a pre-treatment process because it could reduce the chemical oxygen demand (COD) effectively with lower energy consumption than CF-NF. The performance of NF 270 membrane was assessed by measurements of the many parameters (pH, conductivity, total dissolved solids, COD, suspended solids, total nitrogen, nitrite, nitrate, and total phosphate) under various operating conditions. It was noted that the contaminant rejection was affected by changing TMP and CFV. It was concluded that the purified water stream can be recycled into the process for water reuse or safely disposed to the river.

Protective Effect of Zingiber Officinale against CCl4-Induced Liver Fibrosis Is Mediated through Downregulating the TGF-β1/Smad3 and NF-ĸB/IĸB Pathways.

PubMed

Hasan, Iman H; El-Desouky, M A; Hozayen, Walaa G; Abd el Aziz, Ghada M

2016-01-01

No ideal hepatoprotective agents are available in modern medicine to effectively prevent liver disorders. In this study, we aimed at evaluating the potential of Zingiber officinale in the regression of liver fibrosis and its underlining mechanism of action. To induce liver fibrosis, male Wistar rats received CCl4 (2 ml/kg/2 times/week; i.p.), with and without 300 or 600 mg/kg Z. officinale extract daily through oral gavage. To assess the protective effect of Z. officinale, liver function parameters, histopathology, inflammatory markers and gene expression of transforming growth factor-beta 1 (TGF-β1)/Smad3 and nuclear factor-kappa B (NF-ĸB)/IĸB pathways were analyzed. Results demonstrate that Z. officinale extract markedly prevented liver injury as evident by the decreased liver marker enzymes. Concurrent administration of Z. officinale significantly protected against the CCl4-induced inflammation as showed by the decreased pro-inflammatory cytokine levels as well as the downregulation of the NF-ĸB)/IĸB and TGF-β1/Smad3 pathways in CCl4-administered rats. In conclusion, our study provides evidence that the protective effect of Z. officinale against rat liver fibrosis could be explained through its ability to modulate the TGF-β1/Smad3 and NF-ĸB)/IĸB signaling pathways. © 2015 S. Karger AG, Basel.

Increased expression of NF-AT3 and NF-AT4 in the atria correlates with procollagen I carboxyl terminal peptide and TGF-β1 levels in serum of patients with atrial fibrillation.

PubMed

Zhao, Fei; Zhang, ShiJiang; Chen, YiJiang; Gu, WeiDong; Ni, BuQing; Shao, YongFeng; Wu, YanHu; Qin, JianWei

2014-11-25

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Unfortunately, the precise mechanisms and sensitive serum biomarkers of atrial remodeling in AF remain unclear. The aim of this study was to determine whether the expression of the transcription factors NF-AT3 and NF-AT4 correlate with atrial structural remodeling of atrial fibrillation and serum markers for collagen I and III synthesis. Right and left atrial specimens were obtained from 90 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (n = 30), paroxysmal atrial fibrillation (n = 30), and persistent atrial fibrillation (n = 30) groups. NF-AT3, NF-AT4, and collagen I and III mRNA and protein expression in atria were measured. We also tested the levels of the carboxyl-terminal peptide from pro-collagen I, the N-terminal type I procollagen propeptides, the N-terminal type III procollagen propeptides, and TGF-β1 in serum using an enzyme immunosorbent assay. NF-AT3 and NF-AT4 mRNA and protein expression were increased in the AF groups, especially in the left atrium. NF-AT3 and NF-AT4 expression in the right atrium was increased in the persistent atrial fibrillation group compared the sinus rhythm group with similar valvular disease. In patients with AF, the expression levels of nuclear NF-AT3 and NF-AT4 correlated with those of collagens I and III in the atria and with PICP and TGF-β1 in blood. These data support the hypothesis that nuclear NF-AT3 and NF-AT4 participates in atrial structural remodeling, and that PICP and TGF-β1 levels may be sensitive serum biomarkers to estimate atrial structural remodeling with atrial fibrillation.

Therapeutic effect of MG-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of Nrf2 and NF-κB.

PubMed

Wang, Yuehui; Sun, Weixia; Du, Bing; Miao, Xiao; Bai, Yang; Xin, Ying; Tan, Yi; Cui, Wenpeng; Liu, Bin; Cui, Taixing; Epstein, Paul N; Fu, Yaowen; Cai, Lu

2013-02-15

MG-132, a proteasome inhibitor, can upregulate nuclear factor (NF) erythroid 2-related factor 2 (Nrf2)-mediated antioxidative function and downregulate NF-κB-mediated inflammation. The present study investigated whether through the above two mechanisms MG-132 could provide a therapeutic effect on diabetic cardiomyopathy in the OVE26 type 1 diabetic mouse model. OVE26 mice develop hyperglycemia at 2-3 wk after birth and exhibit albuminuria and cardiac dysfunction at 3 mo of age. Therefore, 3-mo-old OVE26 diabetic and age-matched control mice were intraperitoneally treated with MG-132 at 10 μg/kg daily for 3 mo. Before and after MG-132 treatment, cardiac function was measured by echocardiography, and cardiac tissues were then subjected to pathological and biochemical examination. Diabetic mice showed significant cardiac dysfunction, including increased left ventricular systolic diameter and wall thickness and decreased left ventricular ejection fraction with an increase of the heart weight-to-tibia length ratio. Diabetic hearts exhibited structural derangement and remodeling (fibrosis and hypertrophy). In diabetic mice, there was also increased systemic and cardiac oxidative damage and inflammation. All of these pathogenic changes were reversed by MG-132 treatment. MG-132 treatment significantly increased the cardiac expression of Nrf2 and its downstream antioxidant genes with a significant increase of total antioxidant capacity and also significantly decreased the expression of IκB and the nuclear accumulation and DNA-binding activity of NF-κB in the heart. These results suggest that MG-132 has a therapeutic effect on diabetic cardiomyopathy in OVE26 diabetic mice, possibly through the upregulation of Nrf2-dependent antioxidative function and downregulation of NF-κB-mediated inflammation.

Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system.

PubMed

Thomas, Candice M; Yong, Qian Chen; Rosa, Rodolfo M; Seqqat, Rachid; Gopal, Shanthi; Casarini, Dulce E; Jones, W Keith; Gupta, Sudhiranjan; Baker, Kenneth M; Kumar, Rajesh

2014-10-01

Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca(2+) handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca(2+) handling and inhibition of the cardiac renin-angiotensin system.

Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system

PubMed Central

Thomas, Candice M.; Yong, Qian Chen; Rosa, Rodolfo M.; Seqqat, Rachid; Gopal, Shanthi; Casarini, Dulce E.; Jones, W. Keith; Gupta, Sudhiranjan; Baker, Kenneth M.

2014-01-01

Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca2+-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca2+ handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca2+ handling and inhibition of the cardiac renin-angiotensin system. PMID:25085967

High-index faceted Ni3S2 nanosheet arrays as highly active and ultrastable electrocatalysts for water splitting.

PubMed

Feng, Liang-Liang; Yu, Guangtao; Wu, Yuanyuan; Li, Guo-Dong; Li, Hui; Sun, Yuanhui; Asefa, Tewodros; Chen, Wei; Zou, Xiaoxin

2015-11-11

Elaborate design of highly active and stable catalysts from Earth-abundant elements has great potential to produce materials that can replace the noble-metal-based catalysts commonly used in a range of useful (electro)chemical processes. Here we report, for the first time, a synthetic method that leads to in situ growth of {2̅10} high-index faceted Ni3S2 nanosheet arrays on nickel foam (NF). We show that the resulting material, denoted Ni3S2/NF, can serve as a highly active, binder-free, bifunctional electrocatalyst for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). Ni3S2/NF is found to give ∼100% Faradaic yield toward both HER and OER and to show remarkable catalytic stability (for >200 h). Experimental results and theoretical calculations indicate that Ni3S2/NF's excellent catalytic activity is mainly due to the synergistic catalytic effects produced in it by its nanosheet arrays and exposed {2̅10} high-index facets.

Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties

PubMed Central

Olivera, Anlys; Moore, Terry W.; Hu, Fang; Brown, Andrew P.; Sun, Aiming; Liotta, Dennis C.; Snyder, James P.; Yoon, Younghyoun; Shim, Hyunsuk; Marcus, Adam I.; Miller, Andrew H.; Pace, Thaddeus W. W.

2012-01-01

Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogues with enhanced activity on the NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound termed 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analogue whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1–100µM) or vehicle (DMSO 1%) for 1 hour. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1µg/mL). EF31 (IC50 ~5µM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC50~35µM) and curcumin (IC50 >50µM). In addition, EF31 exhibited significantly greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB activity, EF31 (IC50~1.92µM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC50~131µM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analogue for further therapeutic development. PMID:22197802

Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties.

PubMed

Olivera, Anlys; Moore, Terry W; Hu, Fang; Brown, Andrew P; Sun, Aiming; Liotta, Dennis C; Snyder, James P; Yoon, Younghyoun; Shim, Hyunsuk; Marcus, Adam I; Miller, Andrew H; Pace, Thaddeus W W

2012-02-01

Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1-100 μM) or vehicle (DMSO 1%) for 1h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC(50)~5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC(50)~35 μM) and curcumin (IC(50) >50 μM). In addition, EF31 exhibited greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB, EF31 (IC(50)~1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC(50)~131 μM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analog for further therapeutic development. Copyright © 2011 Elsevier B.V. All rights reserved.

Thalidomide suppresses NF-kappa B activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester.

PubMed

Majumdar, Sekhar; Lamothe, Betty; Aggarwal, Bharat B

2002-03-15

Thalidomide ([+]-alpha-phthalimidoglutarimide), a psychoactive drug that readily crosses the blood-brain barrier, has been shown to exhibit anti-inflammatory, antiangiogenic, and immunosuppressive properties through a mechanism that is not fully established. Due to the central role of NF-kappaB in these responses, we postulated that thalidomide mediates its effects through suppression of NF-kappaB activation. We investigated the effects of thalidomide on NF-kappaB activation induced by various inflammatory agents in Jurkat cells. The treatment of these cells with thalidomide suppressed TNF-induced NF-kappaB activation, with optimum effect occurring at 50 microg/ml thalidomide. These effects were not restricted to T cells, as other hematopoietic and epithelial cell types were also inhibited. Thalidomide suppressed H(2)O(2)-induced NF-kappaB activation but had no effect on NF-kappaB activation induced by PMA, LPS, okadaic acid, or ceramide, suggesting selectivity in suppression of NF-kappaB. The suppression of TNF-induced NF-kappaB activation by thalidomide correlated with partial inhibition of TNF-induced degradation of an inhibitory subunit of NF-kappaB (IkappaBalpha), abrogation of IkappaBalpha kinase activation, and inhibition of NF-kappaB-dependent reporter gene expression. Thalidomide abolished the NF-kappaB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-kappaB-inducing kinase, but not that activated by the p65 subunit of NF-kappaB. Overall, our results clearly demonstrate that thalidomide suppresses NF-kappaB activation specifically induced by TNF and H(2)O(2) and that this may contribute to its role in suppression of proliferation, inflammation, angiogenesis, and the immune system.

Multiscale, Converging Defects of Macro-Porosity, Microstructure and Matrix Mineralization Impact Long Bone Fragility in NF1

PubMed Central

Kühnisch, Jirko; Seto, Jong; Lange, Claudia; Schrof, Susanne; Stumpp, Sabine; Kobus, Karolina; Grohmann, Julia; Kossler, Nadine; Varga, Peter; Osswald, Monika; Emmerich, Denise; Tinschert, Sigrid; Thielemann, Falk; Duda, Georg; Seifert, Wenke; el Khassawna, Thaqif; Stevenson, David A.; Elefteriou, Florent; Kornak, Uwe; Raum, Kay; Fratzl, Peter; Mundlos, Stefan; Kolanczyk, Mateusz

2014-01-01

Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro-porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro-porotic bone lesions. PMID:24465906

A method to solubilise protein aggregates for immunoassay quantification which overcomes the neurofilament "hook" effect.

PubMed

Lu, Ching-Hua; Kalmar, Bernadett; Malaspina, Andrea; Greensmith, Linda; Petzold, Axel

2011-02-15

Neurofilament (Nf) aggregates are a common pathological feature of neurodegenerative disorders. Although Nf levels have been investigated as a potential disease biomarker, Nf aggregates may mask Nf epitopes, preventing accurate quantification by immunoassay. Using the SOD1(G93A) mouse model of amyotrophic lateral sclerosis, we developed a method to disrupt Nf aggregates, allowing optimal immunoassay performance. Phosphorylated (NfH(SMI35)) and hyperphosphorylated (NfH(SMI34)) Nf levels in plasma from 120-day SOD1(G93A) mice were quantified using an in-house ELISA modified for use with small volumes. Different pre-analytical methods were tested for their ability to solubilize Nf aggregates and immunoblotting was used for qualitative analysis. A 'hook effect' was observed for serially diluted plasma samples quantified using an ELISA originally developed for CSF samples. Immunoblotting confirmed the existence of high molecular-weight NfH aggregates in plasma and the resolving effect of timed urea on these aggregates. Thermostatic (pre-thawing) and chemical (calcium chelators, urea) pre-analytical processing of samples had variable success in disrupting NfH aggregates. Timed urea-calcium chelator incubation yielded the most consistent plasma NfH levels. A one hour sample pre-incubation with 0.5M urea in Barbitone-EDTA buffer at room temperature resolved the "hook effect" without compromising the ELISA. In SOD1(G93A) mice, median levels of NfH(SMI34) were over 10-fold and NfH(SMI35) levels 5-fold greater than controls. NfH aggregates can be solubilised and the "hook effect" abolished by a one-hour sample pre-incubation in a urea-calcium chelator-enriched buffer. This method is applicable for quantification of NfH phosphoforms in experimental and disease settings where Nf aggregate formation occurs. © 2010 Elsevier B.V. All rights reserved.

Epstein-Barr virus EBNA2 directs doxorubicin resistance of B cell lymphoma through CCL3 and CCL4-mediated activation of NF-κB and Btk.

PubMed

Kim, Joo Hyun; Kim, Won Seog; Hong, Jung Yong; Ryu, Kung Ju; Kim, Seok Jin; Park, Chaehwa

2017-01-17

Epstein-Barr virus (EBV)-encoded nuclear antigen, EBNA2, expressed in EBV-infected B lymphocytes is critical for lymphoblastoid cell growth. Microarray profiling and cytokine array screening revealed that EBNA2 is associated with upregulation of the chemokines CCL3 and CCL4 in lymphoma cells. Depletion or inactivation of CCL3 or CCL4 sensitized DLBCL cells to doxorubicin. Our results indicate that EBV influences cell survival via an autocrine mechanism whereby EBNA2 increases CCL3 and CCL4, which in turn activate the Btk and NF-κB pathways, contributing to doxorubicin resistance of B lymphoma cells. Western blot data further confirmed that CCL3 and CCL4 direct activation of Btk and NF-κB. Based on these findings, we propose that a pathway involving EBNA2/Btk/NF-κB/CCL3/CCL4 plays a key role in doxorubicin resistance, and therefore, inhibition of specific components of this pathway may sensitize lymphoma cells to doxorubicin. Evaluation of the relationship between CCL3 expression and EBV infection revealed high CCL3 levels in EBV-positive patients. Our data collectively suggest that doxorubicin treatment for EBNA2-positive DLBCL cells may be effectively complemented with a NF-κB or Btk inhibitor. Moreover, evaluation of the CCL3 and CCL4 levels may be helpful for selecting DLBCL patients likely to benefit from doxorubicin treatment in combination with the velcade or ibrutinib.

Therapeutic effects of silibinin on LPS-induced acute lung injury by inhibiting NLRP3 and NF-κB signaling pathways.

PubMed

Tian, Lin; Li, Weimin; Wang, Tan

2017-07-01

Silibinin, a natural product extracted from Silybum marianum (milk thistle), has been reported to have anti-inflammatory effect. The aim of this study was to explore the therapeutic effects and potential mechanisms of silibinin on lipopolysaccharide (LPS)-stimulated inflammatory responses in acute lung injury (ALI). Male BALB/c mice were conditioned with silibinin 1 h after intranasal instillation of LPS. After 12 h, the myeloperoxidase (MPO) level in lung tissues, the wet/dry (W/D) ratio, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), and histopathological examination of lung were detected. Our results showed that silibinin inhibited LPS-induced histopathological changes and MPO activity, as well as the wet/dry (W/D) ratio in the lung tissues. Furthermore, silibinin significantly inhibited LPS-induced inflammatory cytokines production in the BALF. In addition, silibinin suppressed LPS-induced NF-κB activation and the expression of NLRP3 inflammasome. These results indicate that silibinin exerts its anti-inflammatory effect by inhibiting NF-κB and NLRP3 signaling pathways. Copyright © 2017. Published by Elsevier Ltd.

Chikusetsu saponin IVa ameliorates high fat diet-induced inflammation in adipose tissue of mice through inhibition of NLRP3 inflammasome activation and NF-κB signaling

PubMed Central

Yuan, Chengfu; Liu, Chaoqi; Wang, Ting; He, Yumin; Zhou, Zhiyong; Dun, Yaoyan; Zhao, Haixia; Ren, Dongming; Wang, Junjie; Zhang, Changcheng; Yuan, Ding

2017-01-01

Chronic metabolic inflammation in adipose tissue plays an important role in the development of obesity-associated diseases. Our previous study indicated that total saponins of Panax japonicus (SPJ) rhizoma and Chikusetsu saponin V, one main component of SPJ, could exert the anti-oxidative and anti-inflammatory effects. The present study aimed to investigate the in vivo and Ex vivo anti-inflammatory activities of another main component of SPJ, namely Chikusetsu saponin IVa (CS). CS could significantly inhibited HFD-induced lipid homeostasis, and inhibited inflammation in adipose tissue, as reflected by the decreased mRNA expression levels of inflammation-related genes and secretion of the chemokines/cytokines, inhibited the accumulation of adipose tissue macrophages (ATMs) and shifted their polarization from M1 to M2, suppressed HFD-induced expression of NLRP3 inflammasome component genes and decreased IL-1β and Caspase-1 production in mice. Moreover, CS treatment also inhibited the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs). Meanwhile, CS treatment inhibited an NLRP3-induced ASC pyroptosome formation and lipopolysaccharide (LPS)-induced pyroptosis. Furthermore, CS treatment suppressed HFD-induced NF-κB signaling in vivo and LPS-induced NF-κB activation as reflected by the fact that their phosphorylated forms and the ratios of pNF-κB/NF-κB, pIKK/IKK, and pIκB/IκB were all decreased in EAT from HFD-fed mice treated with CS as compared with those of HFD mice. Taking together, this study has revealed that CS effectively inhibits HFD-induced inflammation in adipose tissue of mice through inhibiting both NLRP3 inflammasome activation and NF-κB signaling. Thus, CS can serve as a potential therapeutic drug in the prevention and treatment of inflammation-associated diseases. PMID:28415686

Chikusetsu saponin IVa ameliorates high fat diet-induced inflammation in adipose tissue of mice through inhibition of NLRP3 inflammasome activation and NF-κB signaling.

PubMed

Yuan, Chengfu; Liu, Chaoqi; Wang, Ting; He, Yumin; Zhou, Zhiyong; Dun, Yaoyan; Zhao, Haixia; Ren, Dongming; Wang, Junjie; Zhang, Changcheng; Yuan, Ding

2017-05-09

Chronic metabolic inflammation in adipose tissue plays an important role in the development of obesity-associated diseases. Our previous study indicated that total saponins of Panax japonicus (SPJ) rhizoma and Chikusetsu saponin V, one main component of SPJ, could exert the anti-oxidative and anti-inflammatory effects. The present study aimed to investigate the in vivo and Ex vivo anti-inflammatory activities of another main component of SPJ, namely Chikusetsu saponin IVa (CS). CS could significantly inhibited HFD-induced lipid homeostasis, and inhibited inflammation in adipose tissue, as reflected by the decreased mRNA expression levels of inflammation-related genes and secretion of the chemokines/cytokines, inhibited the accumulation of adipose tissue macrophages (ATMs) and shifted their polarization from M1 to M2, suppressed HFD-induced expression of NLRP3 inflammasome component genes and decreased IL-1β and Caspase-1 production in mice. Moreover, CS treatment also inhibited the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs). Meanwhile, CS treatment inhibited an NLRP3-induced ASC pyroptosome formation and lipopolysaccharide (LPS)-induced pyroptosis. Furthermore, CS treatment suppressed HFD-induced NF-κB signaling in vivo and LPS-induced NF-κB activation as reflected by the fact that their phosphorylated forms and the ratios of pNF-κB/NF-κB, pIKK/IKK, and pIκB/IκB were all decreased in EAT from HFD-fed mice treated with CS as compared with those of HFD mice. Taking together, this study has revealed that CS effectively inhibits HFD-induced inflammation in adipose tissue of mice through inhibiting both NLRP3 inflammasome activation and NF-κB signaling. Thus, CS can serve as a potential therapeutic drug in the prevention and treatment of inflammation-associated diseases.

Response of female Ceratitis capitata (Diptera: Tephritidae) to a spinosad bait and polymer matrix mixture with extended residual effect in Hawaii.

PubMed

Piñero, Jaime C; Souder, Steven K; Gomez, Luis E; Mau, Ronald F L; Vargas, Roger I

2011-12-01

The effectiveness of foliar applications of protein baits against pestiferous fruit flies (Tephritidae) can be adversely affected by a rapid loss of attractive volatile compounds and by rainfall due to the high water solubility of the baits. In a large coffee, Coffea arabica L., plantation in Hawaii with high and low populations of Mediterranean fruit fly, Ceratitis capitata (Wiedemann) (Diptera: Tephritidae), the relative attractiveness of GF-120 NF Naturalyte Fruit Fly Bait as either a 40% (vol:vol) spray solution (= GF-120 NF) or as a formulated proprietary amorphous polymer matrix (= GF-120 APM) was compared. The GF-120 APM formulations contained either, 25, 50, or 75% of GF-120 NF (wt:wt). All baits were tested in association with visually attractive yellow bait stations as a way of standardizing the evaluations. With both high and low C. capitata populations, significantly more females were attracted to the fresh sprayed GF-120 NF than to any of the three fresh GF-120 APM formulations. The attractiveness of GF-120 sprayed decreased significantly after 1 wk, whereas 1-wk-old GF-120 APM formulations were as attractive as similar fresh formulations. GF-120 APM 75% aged for 3 wk outperformed similarly-aged sprayed GF-120 NF with comparatively high C. capitata populations. With low populations, both GF-120 APM 75% and GF-120 APM 50% aged for 2 wk outperformed the similarly aged sprayed GF-120 NF. Combined findings indicate that APM mixed with either 50 or 75% GF-120 applied to bait stations can be attractive to female C. capitata for up to 3 wk longer than the standard sprayed GF-120 NF.

A reduced graphene oxide nanofiltration membrane intercalated by well-dispersed carbon nanotubes for drinking water purification

NASA Astrophysics Data System (ADS)

Chen, Xianfu; Qiu, Minghui; Ding, Hao; Fu, Kaiyun; Fan, Yiqun

2016-03-01

In this study, we report a promising rGO-CNT hybrid nanofiltration (NF) membrane that was fabricated by loading reduced graphene oxide that was intercalated with carbon nanotubes (rGO-CNTs) onto an anodic aluminum oxide (AAO) microfiltration membrane via a facile vacuum-assisted filtration process. To create this NF membrane, the CNTs were first dispersed using block copolymers (BCPs); the effects of the types and contents of BCPs used on the dispersion of CNTs have been investigated. The as-prepared rGO-CNT hybrid NF membranes were then used for drinking water purification to retain the nanoparticles, dyes, proteins, organophosphates, sugars, and particularly humic acid. Experimentally, it is shown that the rGO-CNT hybrid NF membranes have high retention efficiency, good permeability and good anti-fouling properties. The retention was above 97.3% even for methyl orange (327 Da); for other objects, the retention was above 99%. The membrane's permeability was found to be as high as 20-30 L m-2 h-1 bar-1. Based on these results, we can conclude that (i) the use of BCPs as a surfactant can enhance steric repulsion and thus disperse CNTs effectively; (ii) placing well-dispersed 1D CNTs within 2D graphene sheets allows an uniform network to form, which can provide many mass transfer channels through the continuous 3D nanostructure, resulting in the high permeability and separation performance of the rGO-CNT hybrid NF membranes.In this study, we report a promising rGO-CNT hybrid nanofiltration (NF) membrane that was fabricated by loading reduced graphene oxide that was intercalated with carbon nanotubes (rGO-CNTs) onto an anodic aluminum oxide (AAO) microfiltration membrane via a facile vacuum-assisted filtration process. To create this NF membrane, the CNTs were first dispersed using block copolymers (BCPs); the effects of the types and contents of BCPs used on the dispersion of CNTs have been investigated. The as-prepared rGO-CNT hybrid NF membranes were then used for drinking water purification to retain the nanoparticles, dyes, proteins, organophosphates, sugars, and particularly humic acid. Experimentally, it is shown that the rGO-CNT hybrid NF membranes have high retention efficiency, good permeability and good anti-fouling properties. The retention was above 97.3% even for methyl orange (327 Da); for other objects, the retention was above 99%. The membrane's permeability was found to be as high as 20-30 L m-2 h-1 bar-1. Based on these results, we can conclude that (i) the use of BCPs as a surfactant can enhance steric repulsion and thus disperse CNTs effectively; (ii) placing well-dispersed 1D CNTs within 2D graphene sheets allows an uniform network to form, which can provide many mass transfer channels through the continuous 3D nanostructure, resulting in the high permeability and separation performance of the rGO-CNT hybrid NF membranes. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08697c

Up-regulation of OLR1 expression by TBC1D3 through activation of TNFα/NF-κB pathway promotes the migration of human breast cancer cells.

PubMed

Wang, Bei; Zhao, Huzi; Zhao, Lei; Zhang, Yongchen; Wan, Qing; Shen, Yong; Bu, Xiaodong; Wan, Meiling; Shen, Chuanlu

2017-11-01

Metastatic spread of cancer cells is the most life-threatening aspect of breast cancer and involves multiple steps including cell migration. We recently found that the TBC1D3 oncogene promotes the migration of breast cancer cells, and its interaction with CaM enhances the effects of TBC1D3. However, little is known regarding the mechanism by which TBC1D3 induces the migration of cancer cells. Here, we demonstrated that TBC1D3 stimulated the expression of oxidized low density lipoprotein receptor 1 (OLR1), a stimulator of cell migration, in breast cancer cells at the transcriptional level. Depletion of OLR1 by siRNAs or down-regulation of OLR1 expression using pomalidomide, a TNFα inhibitor, significantly decreased TBC1D3-induced migration of these cells. Notably, TBC1D3 overexpression activated NF-κB, a major effector of TNFα signaling, while inhibition of TNFα signaling suppressed the effects of TBC1D3. Consistent with this, NF-κB inhibition using its specific inhibitor caffeic acid phenethyl ester decreased both TBC1D3-induced OLR1 expression and cell migration, suggesting a critical role for TNFα/NF-κB signaling in TBC1D3-induced migration of breast cancer cells. Mechanistically, TBC1D3 induced activation of this signaling pathway on multiple levels, including by increasing the release of TNFα, elevating the transcription of TNFR1, TRAF1, TRAF5 and TRAF6, and decreasing the degradation of TNFR1. In summary, these studies identify the TBC1D3 oncogene as a novel regulator of TNFα/NF-κB signaling that mediates this oncogene-induced migration of human breast cancer cells by up-regulating OLR1. Copyright © 2017 Elsevier B.V. All rights reserved.

Double-edged swords as cancer therapeutics: novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway.

PubMed

Zhuang, Chunlin; Miao, Zhenyuan; Wu, Yuelin; Guo, Zizhao; Li, Jin; Yao, Jianzhong; Xing, Chengguo; Sheng, Chunquan; Zhang, Wannian

2014-02-13

Simultaneous inactivation of p53 and hyperactivation of nuclear factor-κB (NF-κB) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-κB. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-κB pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-κB pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-κB activation through inhibition of IκBα phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKKα/β. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-κB pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).

Combination of quercetin, cinnamaldehyde and hirudin protects rat dorsal root ganglion neurons against high glucose-induced injury through Nrf-2/HO-1 activation and NF-κB inhibition.

PubMed

Shi, Yue; Liang, Xiao-Chun; Zhang, Hong; Sun, Qing; Wu, Qun-Li; Qu, Ling

2017-09-01

To examine the effects of the combination of quercetin (Q), cinnamaldehyde (C) and hirudin (H), a Chinese medicine formula on high glucose (HG)-induced apoptosis of cultured dorsal root ganglion (DRG) neurons. DRG neurons exposed to HG (45 mmol/L) for 24 h were employed as an in vitro model of diabetic neuropathy. Cell viability, reactive oxygen species (ROS) level and apoptosis were determined. The expression of nuclear factor of Kappa B (NF-κB), inhibitory kappa Bα(IκBα), phosphorylated IκBα and Nf-E2 related factor 2 (Nrf2) were examined using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay. The expression of hemeoxygenase-1 (HO-1), interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and caspase-3 were also examined by RT-PCR and Western blot assay. HG treatment markedly increased DRG neuron apoptosis via increasing intracellular ROS level and activating the NF-κB signaling pathway (P<0.05). Co-treatment with Q, C, H and their combination decreased HG-induced caspase-3 activation and apoptosis (P<0.05 or P<0.01). The expressions of NF-κB, IL-6 and TNF-α were down-regulated, and Nrf2/HO-1 expression was up-regulated (P<0.05 or P<0.01). QCH has better effect in scavenging ROS, activating Nrf-2/HO-1, and down-regulating the NF-κB pathway than other treatment group. DRG neurons' apoptosis was increased in diabetic conditions, which was reduced by QCH formula treatment. The possible reason could be activating Nrf-2/HO-1 pathway, scavenging ROS, and inhibition of NF-κB activation. The effect of QCH combination was better than each monomer or the combination of the two monomers.

TELMISARATAN PROVIDES BETTER RENAL PROTECTION THAN VALSARTAN IN A RAT MODEL OF METABOLIC SYNDROME

PubMed Central

Khan, Abdul Hye; Imig, John D.

2013-01-01

BACKGROUND Angiotension receptor blockers (ARB), telmisartan and valsartan were compared for renal protection in spontaneously hypertensive rats (SHR) fed high fat diet. We hypothesized that in cardiometabolic syndrome, telmisartan an ARB with PPAR-γ activity will offer better renal protection. METHODS SHR were fed either normal (SHR-NF, 7% fat) or high fat (SHR-HF, 36% fat) diet and treated with an ARB for 10 weeks. RESULTS Blood pressure was similar between SHR-NF (190±3 mmHg) and SHR-HF (192±4 mmHg) at the end of the 10 week period. Telmisartan and valsartan decreased blood pressure to similar extents in SHR-NF and SHR-HF groups. Body weight was significantly higher in SHR-HF (368±5g) compared to SHR-NF (328±7g). Telmisartan but not valsartan significantly reduced the body weight gain in SHR-HF. Telmisartan was also more effective than valsartan in improving glycemic and lipid status in SHR-HF. Monocyte chemoattractant protein-1 (MCP-1), an inflammatory marker, was higher in SHR-HF (24±2 ng/d) compared to SHR-NF (14±5 ng/d). Telmisartan reduced MCP-1 excretion in both SHR-HF and SHR-NF to a greater extent than valsartan. An indicator of renal injury, urinary albumin excretion increased to 85±8 mg/d in SHR-HF compared to 54±9 mg/d in SHR-NF. Telmisartan (23±5 mg/d) was more effective than valsartan (45±3 mg/d) in lowering urinary albumin excretion in SHR-HF. Moreover, telmisartan reduced glomerular damage to a greater extent than valsartan in the SHR-HF. CONCLUSIONS Collectively, our data demonstrate that telmisartan was more effective than valsartan in reducing body weight gain, renal inflammation, and renal injury in a rat model of cardiometabolic syndrome. PMID:21415842

NF-κB Regulates Caspase-4 Expression and Sensitizes Neuroblastoma Cells to Fas-Induced Apoptosis

PubMed Central

Yang, Hai-Jie; Wang, Mian; Wang, Lei; Cheng, Bin-Feng; Lin, Xiao-Yu; Feng, Zhi-Wei

2015-01-01

Found in neurons and neuroblastoma cells, Fas-induced apoptosis and accompanied activation of NF-κB signaling were thought to be associated with neurodegenerative diseases. However, the detailed functions of NF-κB activation in Fas killing and the effect of NF-κB activation on its downstream events remain unclear. Here, we demonstrated that agonistic Fas antibody induces cell death in a dose-dependent way and NF-κB signaling is activated as well, in neuroblastoma cells SH-EP1. Unexpectedly, NF-κB activation was shown to be pro-apoptotic, as suggested by the reduction of Fas-induced cell death with either a dominant negative form of IκBα (DN-IκBα) or an IκB kinase-specific inhibitor. To our interest, when analyzing downstream events of NF-κB signaling, we found that DN-IκBα only suppressed the expression of caspase-4, but not other caspases. Vice versa, enhancement of NF-κB activity by p65 (RelA) overexpression increased the expression of caspase-4 at both mRNA and protein levels. More directly, results from dual luciferase reporter assay demonstrated the regulation of caspase-4 promoter activity by NF-κB. When caspase-4 activity was blocked by its dominant negative (DN) form, Fas-induced cell death was substantially reduced. Consistently, the cleavage of PARP and caspase-3 induced by Fas was also reduced. In contrast, the cleavage of caspase-8 remained unaffected in caspase-4 DN cells, although caspase-8 inhibitor could rescue Fas-induced cell death. Collectively, these data suggest that caspase-4 activity is required for Fas-induced cell apoptosis and caspase-4 may act upstream of PARP and caspase-3 and downstream of caspase-8. Overall, we demonstrate that NF-κB can mediate Fas-induced apoptosis through caspase-4 protease, indicating that caspase-4 is a new mediator of NF-κB pro-apoptotic pathway in neuroblastoma cells. PMID:25695505

Randomized clinical trial of laparoscopic anterior 180° partial versus 360° Nissen fundoplication: 5-year results.

PubMed

Cao, Z; Cai, W; Qin, M; Zhao, H; Yue, P; Li, Y

2012-02-01

Anterior partial fundoplication (AF) has been popularized by a lower risk of mechanical side effects. The question then emerges whether anterior partial wrap has a similar antireflux effect with Nissen fundoplication (NF). We therefore conducted a randomized study to compare the long-term outcome of anterior fundoplication with NF. One hundred patients who enrolled in the trial from May 2003 to March 2005 were randomized to laparoscopic AF or laparoscopic NF. Endoscopy, pH monitoring, manometry, a detailed questionnaire, and a visual analog symptom score were completed preoperative at 6, 12, 24, and 60 months after surgical procedures. The postoperative adverse effects such as dysphagia and flatulence were compared between the two groups. Revision surgery or maintenance proton pump inhibitor therapy was defined as failure. Fifty procedures were performed in each group. The outcome at 5 years follow-up was determined for 96 patients (96%; 49 patients in the AF group and 47 in the NF group). Three patients (3%) died of unrelated causes during follow-up, and one patient changed address. Both fundoplications were found to provide good control of reflux-related symptoms in most of the patients. For 96 patients followed up more than 5 years, gastroesophageal reflux symptoms were well controlled in 81 patients (84.38%); the mean DeMeester scores in the AF group decreased from 106.89 ± 14.12 to 12.67 ± 3.14 and in the NF group from 109.51 ± 17.98 to 10.81 ± 2.65, and the esophagitis was ameliorated visibly. Moreover, there were significantly fewer patients in the AF group who complained of flatulence. Compared with NF, anterior 180° partial fundoplication is an effective treatment of gastroesophageal reflux and associates with fewer postoperative adverse effects. © 2011 Copyright the Authors. Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

PubMed Central

Habineza Ndikuyeze, Georges; Gaurnier-Hausser, Anita; Patel, Reema; Baldwin, Albert S.; May, Michael J.; Flood, Patrick; Krick, Erika; Propert, Kathleen J.; Mason, Nicola J.

2014-01-01

Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL. PMID:24798348

NF-κB Is the Transcription Factor for FGF-2 That Causes Endothelial Mesenchymal Transformation in Cornea

PubMed Central

Lee, Jeong Goo

2012-01-01

Purpose. To determine the role of nuclear factor-κB (NF-κB) during FGF-2–mediated endothelial mesenchymal transformation (EMT) in response to interleukin (IL)-1β stimulation in corneal endothelial cells (CECs). Methods. Expression and/or activation of IL-1 receptor–associated protein kinase (IRAK), TNF receptor–associated factor 6 (TRAF6), phosphatidylinositol 3-kinase (PI 3-kinase), IκB kinase (IKK), IκB, NF-κB, and FGF-2 were analyzed by immunoblot analysis. Cell proliferation was measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. NF-κB activity was measured by NF-κB ELISA kit, while binding of NF-κB to the promoter region of FGF-2 gene was determined by chromatin immunoprecipitation. Results. Brief stimulation of CECs with IL-1β upregulated expression of IRAK and TRAF6 and activated PI 3-kinase; expression of IRAK and TRAF6 reached maximum within 60 minutes, after which the expression disappeared, while PI 3-kinase activity was observed up to 4 hours after IL-1β stimulation. Use of specific inhibitor to PI 3-kinase or IRAK demonstrated that IRAK activates PI 3-kinase, the signaling of which phosphorylates IKKα/β and degrades IκB, subsequently leading to activation of NF-κB. The induction of FGF-2 by IL-1β was completely blocked by inhibitors to NF-κB activation (sulfasalazine) or PI 3-kinase (LY294002), and both inhibitors greatly blocked cell proliferation of CECs. Chromatin immunoprecipitation further demonstrated that NF-κB is the transcription factor of FGF-2 as NF-κB binds the putative NF-κB binding site of the FGF-2 promoter. Conclusions. These data suggest that IL-1β signaling combines the canonical pathway and the PI 3-kinase signaling to upregulate FGF-2 production through NF-κB, which plays a key role as a transcription factor of FGF-2 gene. PMID:22323467

Baryon interactions from lattice QCD with physical quark masses - Nuclear forces and ΞΞ forces -

NASA Astrophysics Data System (ADS)

Doi, Takumi; Iritani, Takumi; Aoki, Sinya; Gongyo, Shinya; Hatsuda, Tetsuo; Ikeda, Yoichi; Inoue, Takashi; Ishii, Noriyoshi; Miyamoto, Takaya; Nemura, Hidekatsu; Sasaki, Kenji

2018-03-01

We present the latest lattice QCD results for baryon interactions obtained at nearly physical quark masses. Nf = 2 + 1 nonperturbatively O(a)-improved Wilson quark action with stout smearing and Iwasaki gauge action are employed on the lattice of (96a)4 ≃(8.1fm)4 with a-1 ≃2.3 GeV, where mπ ≃146 MeV and mK ≃525 MeV. In this report, we study the two-nucleon systems and two-Ξ systems in 1S0 channel and 3S1-3D1 coupled channel, and extract central and tensor interactions by the HAL QCD method. We also present the results for the NΩ interaction in 5S2 channel which is relevant to the NΩ pair-momentum correlation in heavy-ion collision experiments.

A Bio-Guided Fractionation to Assess the Inhibitory Activity of Calendula officinalis L. on the NF-κB Driven Transcription in Human Gastric Epithelial Cells

PubMed Central

Colombo, Elisa; Sangiovanni, Enrico; D'Ambrosio, Michele; Bosisio, Enrica; Ciocarlan, Alexandru; Fumagalli, Marco; Guerriero, Antonio; Harghel, Petru; Dell'Agli, Mario

2015-01-01

Calendula officinalis L. has been largely known for its topical anti-inflammatory properties; however, there are no experimental evidences about its antiphlogistic effect at the gastric level. To investigate whether marigold might exert an activity against gastric inflammation, a CH2Cl2 extract obtained from C. officinalis flowers was evaluated in vitro on the NF-κB pathway. The lipophilic extract demonstrated a significant inhibitory effect on the NF-κB driven transcription. The identification of active compounds was conducted by a bio-guided fractionation of the extract that afforded 16 fractions. Fraction J exhibited a concentration-dependent inhibitory activity on the NF-κB driven transcription and significantly contributed to the antiphlogistic effect showed by CH2Cl2 extract. The main components of fraction J were loliolide and the fucoside acetates of β-eudesmol and viridiflorol. HPLC analysis of fractions D and E led to the identification and isolation of triterpene esters that showed a concentration-dependent inhibition of the NF-κB driven transcription, with faradiol-3-myristate and the corresponding aglycone being the most active compounds. The present study provides some experimental evidences that Calendula officinalis L. may exert an anti-inflammatory activity on the gastric district by the inhibition of the NF-κB system, identifying the compounds responsible, at least in part, for the observed effect. PMID:26491463

NF45/ILF2 tissue expression, promoter analysis, and interleukin-2 transactivating function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao Guohua; Shi Lingfang; Qiu Daoming

2005-05-01

NF45/ILF2 associates with NF90/ILF3 in the nucleus and regulates IL-2 gene transcription at the antigen receptor response element (ARRE)/NF-AT DNA target sequence (P.N. Kao, L. Chen, G. Brock, J. Ng, A.J. Smith, B. Corthesy, J. Biol. Chem. 269 (1994) 20691-20699). NF45 is widely expressed in normal tissues, especially testis, brain, and kidney, with a predominantly nuclear distribution. NF45 mRNA expression is increased in lymphoma and leukemia cell lines. The human and murine NF45 proteins differ only by substitution of valine by isoleucine at amino acid 142. Fluorescence in situ hybridization localized the human NF45 gene to chromosome 1q21.3, and mousemore » NF45 gene to chromosome 3F1. Promoter analysis of 2.5 kB of the murine NF45 gene reveals that significant activation is conferred by factors, possible including NF-Y, that bind to the CCAAT-box sequence. The function of human NF45 in regulating IL-2 gene expression was characterized in Jurkat T-cells stably transfected with plasmids directing expression of NF45 cDNA in sense or antisense orientations. NF45 sense expression increased IL-2 luciferase reporter gene activity 120-fold, and IL-2 protein expression 2-fold compared to control cells. NF45 is a highly conserved, regulated transcriptional activator, and one target gene is IL-2.« less

BNN-20, a synthetic microneurotrophin, strongly protects dopaminergic neurons in the "weaver" mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor.

PubMed

Botsakis, Konstantinos; Mourtzi, Theodora; Panagiotakopoulou, Vasiliki; Vreka, Malamati; Stathopoulos, Georgios T; Pediaditakis, Iosif; Charalampopoulos, Ioannis; Gravanis, Achilleas; Delis, Foteini; Antoniou, Katerina; Zisimopoulos, Dimitrios; Georgiou, Christos D; Panagopoulos, Nikolaos T; Matsokis, Nikolaos; Angelatou, Fevronia

2017-07-15

Neurotrophic factors are among the most promising treatments aiming at slowing or stopping and even reversing Parkinson's disease (PD). However, in most cases, they cannot readily cross the human blood-brain-barrier (BBB). Herein, we propose as a therapeutic for PD the small molecule 17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20), a synthetic analogue of DHEA, which crosses the BBB and is deprived of endocrine side-effects. Using the "weaver" mouse, a genetic model of PD, which exhibits progressive dopaminergic neurodegeneration in the Substantia Nigra (SN), we have shown that long-term administration (P1-P21) of BNN-20 almost fully protected the dopaminergic neurons and their terminals, via i) a strong anti-apoptotic effect, probably mediated through the Tropomyosin receptor kinase B (TrkB) neurotrophin receptor's PI3K-Akt-NF-κB signaling pathway, ii) by exerting an efficient antioxidant effect, iii) by inducing significant anti-inflammatory activity and iv) by restoring Brain-Derived Neurotrophic Factor (BDNF) levels. By intercrossing "weaver" with NGL mice (dual GFP/luciferase-NF-κΒ reporter mice, NF-κΒ.GFP.Luc), we obtained Weaver/NGL mice that express the NF-κB reporter in all somatic cells. Acute BNN-20 administration to Weaver/NGL mice induced a strong NF-κB-dependent transcriptional response in the brain as detected by bioluminescence imaging, which was abolished by co-administration of the TrkB inhibitor ANA-12. This indicates that BNN-20 exerts its beneficial action (at least in part) through the TrkB-PI3K-Akt-NF-κB signaling pathway. These results could be of clinical relevance, as they suggest BNN-20 as an important neuroprotective agent acting through the TrkB neurotrophin receptor pathway, mimicking the action of the endogenous neurotrophin BDNF. Thus BNN-20 could be proposed for treatment of PD. Copyright © 2017. Published by Elsevier Ltd.

Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced NF-κB activation and caspase inhibition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Changjiang; Key Lab of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020; Yang, Jixin

2014-06-15

Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxicity, endocrine disruption and reproductive abnormalities. In order to verify the hypothesis that the PI3K/Akt and MAPK pathways play important roles in hepatotoxicity induced by PCBs, Sprague–Dawley (SD) rats were dosed with PCB153 intraperitoneally at 0, 4, 16 and 32 mg/kg for five consecutive days; BRL cells (rat liver cell line) were treated with PCB153 (0, 1, 5, and 10 μM) for 24 h. Results indicated that the PI3K/Akt and ERK pathways were activated in vivo and in vitro after exposuremore » to PCB153, and protein levels of phospho-Akt and phospho-ERK were significantly increased. Nuclear factor-κB (NF-κB) activation and caspase-3, -8 and -9 inhibition caused by PCB153 were also observed. Inhibiting the ERK pathway significantly attenuated PCB153-induced NF-κB activation, whereas inhibiting the PI3K/Akt pathway hardly influenced phospho-NF-κB level. However, inhibiting the PI3K/Akt pathway significantly elevated caspase-3, -8 and -9 activities, while the ERK pathway only synergistically regulated caspase-9. Proliferating cell nuclear antigen (PCNA), a reliable indicator of cell proliferation, was also induced. Moreover, PCB153 led to hepatocellular hypertrophy and elevated liver weight. Taken together, PCB153 leads to aberrant proliferation and apoptosis of hepatocytes through NF-κB activation and caspase inhibition, and coactivated PI3K/Akt and ERK pathways play critical roles in PCB153-induced hepatotoxicity. - Highlights: • PCB153 led to hepatotoxicity through NF-κB activation and caspase inhibition. • The PI3K/Akt and ERK pathways were coactivated in vivo and in vitro by PCB153. • The ERK pathway regulated levels of phospho-NF-κB and caspase-9. • The PI3K/Akt pathway regulated levels of caspase-3, -8 and -9.« less

S100A8/MYD88/NF-қB: a novel pathway involved in cardiomyocyte hypertrophy driven by thyroid hormone.

PubMed

Takano, Ana Paula Cremasco; Munhoz, Carolina Demarchi; Moriscot, Anselmo Sigari; Gupta, Sudhiranjan; Barreto-Chaves, Maria Luiza Morais

2017-06-01

Recent studies have evidenced the involvement of inflammation-related pathways to the development of cardiac hypertrophy and other consequences on the cardiovascular system, including the calcium-binding protein S100A8. However, this has never been investigated in the thyroid hormone (TH)-prompted cardiac hypertrophy. Thus, we aimed to test whether S100A8 and related signaling molecules, myeloid differentiation factor-88 (MyD88) and nuclear factor kappa B (NF-қB), could be associated with the cardiomyocyte hypertrophy induced by TH. Our results demonstrate that the S100A8/MyD88/NF-қB signaling pathway is activated in cardiomyocytes following TH stimulation. The knockdown of S100A8 and MyD88 indicates the contribution of those molecules to cardiomyocyte hypertrophy in response to TH, as evaluated by cell surface area, leucine incorporation assay, and gene expression. Furthermore, S100A8 and MyD88 are crucial mediators of NF-қB activation, which is also involved in the hypertrophic growth of TH-treated cardiomyocytes. Supporting the in vitro data, the contribution of NF-қB for TH-induced cardiac hypertrophy is confirmed in vivo, by using transgenic mice with cardiomyocyte-specific suppression of NF-қB. These data identify a novel pathway regulated by TH that mediates cardiomyocyte hypertrophy. However, the potential role of this new pathway in short and long-term cardiac effects of TH remains to be further investigated. Inflammation-related signaling is activated by T3 in cardiomyocytes. S100A8 and MyD88 have a crucial role in cardiomyocyte hypertrophy by T3. S100A8 and MyD88 mediate NF-қB activation by T3. NF-қB contributes to T3-induced cardiac hypertrophy in vitro and in vivo.

Salt-Inducible Kinase 1 (SIK1) is Induced by Alcohol and Suppresses Microglia Inflammation via NF-κB Signaling.

PubMed

Zhang, Yu; Gao, Weida; Yang, Kongbin; Tao, Haiquan; Yang, Haicheng

2018-06-19

Alcohol consumption has been shown to cause neuroinflammation and increase a variety of immune-related signaling processes. Microglia are a crucial part of alcohol-induced neuroinflammation and undergo apoptosis. Even though the importance of these inflammatory processes in the effects of alcohol-related neurodegeneration have been established, the mechanism of alcohol-induced microglia apoptosis is unknown. In prior research, we discovered that alcohol increases expression of salt-inducible kinase 1 (SIK1) in rodent brain tissue. In this study, we sought to determine what role SIK1 expression plays in alcohol-induced neuroinflammation as well as whether and by what mechanism it regulates microglia apoptosis. Adult C57BL/6 mice were divided into four groups and for 3 weeks treated with either 0%, 5%, 10%, or 15% alcohol during 3 hour periods. The mice were sacrificed and their brains excised for analysis. Additionally, primary microglia were isolated from neonatal mice. SIK1 expression in alcohol-treated brain tissue and microglia was analyzed via RT-PCR and western blotting. TUNEL staining, caspase-3, and caspase-9 activity assays were performed to evaluate microglial apoptosis. Cell fluorescence staining and NF-κB luciferase activity assays were used to evaluate the effects of SIK1 expression on the NF-κB signaling pathway. SIK1 expression was increased in the brains of mice that consumed alcohol, and this effect was seen in mouse primary microglia. SIK1 knockdown in microglia increased alcohol-induced apoptosis in these cells. Furthermore, SIK1 reduced NF-κB signaling pathway factors, and SIK1 knockdown in microglia promoted alcohol-induced NF-κB activity. TUNEL staining, caspase-3, and caspase-9 activity assays consistently revealed that alcohol-induced microglial apoptosis was inhibited by depletion of p65. Finally, we determined that NF-κB signaling is required for alcohol-induced, SIK1-mediated apoptosis in microglia. This study establishes for the first time not only that SIK1 is crucial to regulating alcohol-induced microglial apoptosis, but also that the NF-κB signaling pathway is required for its activity. Overall, our results help elucidate mechanisms of alcohol-induced neuroinflammation. © 2018 The Author(s). Published by S. Karger AG, Basel.

Loose nanofiltration membrane for dye/salt separation through interfacial polymerization with in-situ generated TiO2 nanoparticles

NASA Astrophysics Data System (ADS)

Zhang, Qi; Fan, Lin; Yang, Zhen; Zhang, Runnan; Liu, Ya-nan; He, Mingrui; Su, Yanlei; Jiang, Zhongyi

2017-07-01

In this study, a high flux nanofiltration (NF) membrane with hybrid polymer-nanoparticle active layer was fabricated by chemical crosslinking of piperazine (PIP) and 1, 3, 5-benzene tricarbonyl trichloride (TMC). An in-situ generated method was applied to deposit titanium dioxide (TiO2) nanoparticles uniformly on the membrane surface, leading to the enhancement of the surface hydrophilicity, roughness and relative surface area of the polyamide (PA) layer. The morphology of the modified membrane was investigated by scanning electron microscopy (SEM) and Atomic force microscopy (AFM), also energy dispersive X-ray microanalysis (EDX) was used to analyze the distribution of Ti element. Chemical structure was observed by Fourier transmission infrared attenuated total reflectance (FTIR-ATR) spectroscopy. Remarkably, the optimal water flux of the loose NF membrane was 65.0 Lm-2 h-1 bar-1 nearly 5 times as much as the pure PA membrane flux. The rejections of the loose NF membranes for dyes were almost all greater than 95.0%, while the rejection for sodium sulfate (Na2SO4) was only about 17.0%, which indicated that the modified membrane had an impressive potential application for dye desalination and purification.

1, 25(OH){sub 2}D{sub 3}-induced interaction of vitamin D receptor with p50 subunit of NF-κB suppresses the interaction between KLF5 and p50, contributing to inhibition of LPS-induced macrophage proliferation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Dong; School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063000; Zhang, Ruo-nan

KLF5 and nuclear factor κB (NF-κB) regulate cell proliferation and inflammation. Vitamin D signaling through vitamin D receptor (VDR) exerts anti-proliferative and anti-inflammatory actions. However, an actual relationship between KLF5, NF-κB and VDR in the inflammation and proliferation of macrophages is still unclear. Here, we showed that LPS and proinflammatory cytokines stimulate KLF5 gene expression in macrophages, and that 1, 25(OH){sub 2}D{sub 3} suppresses LPS-induced KLF5 expression and cell proliferation via upregulation of VDR expression. Mechanistic studies suggested that KLF5 interacts with p50 subunit of NF-κB to cooperatively induce the expressions of positive cell cycle regulators cyclin B1 and Cdk1/Cdc2more » in LPS-treated macrophages. Further studies revealed that 1, 25(OH){sub 2}D{sub 3}-induced interaction of VDR with p50 decreases LPS-induced interaction of KLF5 with p50. Collectively, we identify a novel regulatory pathway in which 1, 25(OH){sub 2}D{sub 3} induces VDR expression and promotes VDR interaction with p50 subunit of NF-κB, which in turn attenuates the association of KLF5 with p50 subunit of NF-κB and thus exerts anti-inflammatory and anti-proliferative effects on macrophages. - Highlights: • 1, 25(OH){sub 2}D{sub 3} suppresses LPS-induced KLF5 expression via upregulation of VDR expression. • KLF5 interacts with NF-κB-p50 to cooperatively induce the expressions of positive cell cycle regulators cyclin B1 and Cdk1/Cdc2 in LPS-treated macrophages. • 1,25(OH){sub 2}D{sub 3} induces interaction of VDR with p50.« less

Psidium guajava 'Paluma' (the guava plant) as a new bio-indicator of ozone in the tropics.

PubMed

Furlan, C M; Moraes, R M; Bulbovas, P; Domingos, M; Salatino, A; Sanz, M J

2007-06-01

Psidium guajava 'Paluma' saplings were exposed to carbon filtered air (CF), ambient non-filtered air (NF), and ambient non-filtered air+40ppb ozone (NF+O(3)) 8h per day during two months. The AOT40 values at the end of the experiment were 48, 910 and 12 895ppbh(-1), respectively for the three treatments. After 5 days of exposure (AOT40=1497ppbh(-1)), interveinal red stippling appeared in plants in the NF+O(3) chamber. In the NF chamber, symptoms were observed only after 40 days of exposure (AOT40=880ppbh(-1)). After 60 days, injured leaves per plant corresponded to 86% in NF+O(3) and 25% in the NF treatment, and the average leaf area injured was 45% in NF+O(3) and 5% in the NF treatment. The extent of leaf area injured (leaf injury index) was explained mainly by the accumulated exposure of ozone (r(2)=0.91; p<0.05).

Semen Brassicae ameliorates hepatic fibrosis by regulating transforming growth factor-β1/Smad, nuclear factor-κB, and AKT signaling pathways in rats.

PubMed

Cao, Si; Zheng, Baoping; Chen, Tao; Chang, Xinfeng; Yin, Bao; Huang, Zhihua; Shuai, Ping; Han, Limin

2018-01-01

There is no effective treatment for liver fibrosis, which is a common phase during the progression of many chronic liver diseases to cirrhosis. Previous studies found that Semen Brassicae therapy can effectively improve the clinical symptoms of patients with asthma, allergic rhinitis, and chronic lung diseases; however, its effects on liver fibrosis in rats and its possible mechanisms of action remain unclear. Rats were injected intraperitoneally with 4% thioacetamide aqueous solution (5 mL·kg -1 ) at a dose of 200 mg·kg -1 twice a week for 8 consecutive weeks to establish the liver fibrosis model and were then treated with different concentrations of Semen Brassicae extract. After Semen Brassicae treatment, the morphology of the liver tissue was analyzed using hematoxylin and eosin and Masson's trichrome staining, and liver index and liver fibrosis grade were calculated. Thereafter, the levels of collagen-I, collagen-III, α-SMA, transforming growth factor (TGF)-β1, p-Smad 2/3, Smad 2/3, Smad4, NF-κB-p65, p-NF-κB-p65, IL-1β, IL-6, AKT, and p-AKT were determined using Western blotting. Compared with the untreated model group, the Semen Brassicae-treated group showed significantly decreased liver function indices; expression levels of collagen-I, collagen-III, and α-SMA; and hepatic fibrosis. Further studies also showed that the expression of TGF-β1, Smad4, p-Smad 2/3/Smad 2/3, p-NF-κB-p65/NF-κB-p65, IL-1β, IL-6, and p-AKT/AKT significantly decreased after the treatment. These results indicate that Semen Brassicae exhibits an anti-hepatic fibrosis effect, and the underlying mechanism of action may be related to the regulation of TGF-β1/Smad, NF-κB, and AKT signaling pathways and the reduction of extracellular matrix deposition.

Tetramethylpyrazine attenuates TNF-α-induced iNOS expression in human endothelial cells: Involvement of Syk-mediated activation of PI3K-IKK-IκB signaling pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Zhen; Li, Zhiliang; Chen, Song

2013-08-15

Endothelial cells produce nitric oxide (NO) by activation of constitutive nitric oxide synthase (NOS) and transcription of inducible NO synthase (iNOS). We explored the effect of tetramethylpyrazine (TMP), a compound derived from chuanxiong, on tumor necrosis factor (TNF)-α-induced iNOS in human umbilical vein endothelial cells (HUVECs) and explored the signal pathways involved by using RT-PCR and Western blot. TMP suppressed TNF-α-induced expression of iNOS by inhibiting IκB kinase (IKK) phosphorylation, IκB degradation and nuclear factor κB (NF-κB) nuclear translocation, which were required for NO gene transcription. Exposure to wortmannin abrogated IKK/IκB/NF-κB-mediated iNOS expression, suggesting activation of such a signal pathwaymore » might be phosphoinositide-3-kinase (PI3K) dependent. Spleen tyrosine kinase (Syk) inhibitor piceatannol significantly inhibited NO production. Furthermore, piceatannol obviously suppressed TNF-α-induced IκB phosphorylation and the downstream NF-κB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/IKK/IκB-mediated signaling. TMP significantly inhibited TNF-α-induced phosphorylation of Syk and PI3K. Our data indicate that TMP might repress iNOS expression, at least in part, through its inhibitory effect of Syk-mediated PI3K phosphorylation in TNF-α-stimulated HUVECs. -- Highlights: •TMP suppressed TNF-α-induced expression of iNOS by inhibiting IKK/IκB/NF-κB pathway. •PI3K inhibitor wortmannin abrogated IKK/IκB/NF-κB-mediated iNOS expression. •Syk inhibitor piceatannol repressed PI3K/IKK/IκB mediated NO production. •Syk is an upstream regulator in the activation of PI3K/IKK/IκB-mediated signaling. •TMP might repress iNOS expression through Syk-mediated PI3K pathway.« less

Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Daqing; Wang, Jing; Yang, Niandi

Matrine has been demonstrated to attenuate allergic airway inflammation. Elevated suppressor of cytokine signaling 3 (SOCS3) was correlated with the severity of asthma. The aim of this study was to investigate the effect of matrine on SOCS3 expression in airway inflammation. In this study, we found that matrine significantly inhibited OVA-induced AHR, inflammatory cell infiltration, goblet cell differentiation, and mucous production in a dose-dependent manner in mice. Matrine also abrogated the level of interleukin (IL)-4 and IL-13, but enhanced interferon (IFN)-γ expression, both in BALF and in lung homogenates. Furthermore, matrine impeded TNF-α-induced the expression of IL-6 and adhesion moleculesmore » in airway epithelial cells (BEAS-2B and MLE-12). Additionally, we found that matrine inhibited SOCS3 expression, both in asthmatic mice and TNF-α-stimulated epithelial cells via suppression of the NF-κB signaling pathway by using pcDNA3.1-SOCS3 plasmid, SOCS3 siRNA, or nuclear factor kappa-B (NF-κB) inhibitor PDTC. Conclusions: Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice. - Highlights: • Matrine attenuates asthmatic symptoms and regulates Th1/Th2 balance in vivo. • Matrine suppresses inflammation responses in vitro. • Matrine decreases SOCS3 expression both in vivo and in vitro. • Matrine inhibits SOCS3 expression by suppressing NF-κB signaling.« less

SQL/NF Translator for the Triton Nested Relational Database System

DTIC Science & Technology

1990-12-01

18as., Ohio .. 9~~ ~~ 1 4- AFIT/GCE/ENG/90D-05 SQL/Nk1 TRANSLATOR FOR THE TRITON NESTED RELATIONAL DATABASE SYSTEM THESIS Craig William Schnepf Captain...FOR THE TRITON NESTED RELATIONAL DATABASE SYSTEM THESIS Presented to the Faculty of the School of Engineering of the Air Force Institute of Technnlogy... systems . The SQL/NF query language used for the nested relationil model is an extension of the popular relational model query language SQL. The query

Chronic chlorpyrifos exposure elicits diet-specific effects on metabolism and the gut microbiome in rats.

PubMed

Fang, Bing; Li, Jin Wang; Zhang, Ming; Ren, Fa Zheng; Pang, Guo Fang

2018-01-01

Chlorpyrifos is a commonly-used pesticide which was reported to interfere with hormone signaling and metabolism, however, little is known about its effect on gut microbiota. In this study, adult male rats fed a normal (NF) or high fat (HF) diet were exposed to 0.3 or 3.0 mg chlorpyrifos/kg bodyweight/day or vehicle alone for 9 weeks. Effects on bodyweight, serum levels of glucose, lipid, cytokines, and gut microbiome community structure were measured. The effects of chlorpyrifos on metabolism were dose- and diet-dependent, with NF-fed rats administered the low dose showing the largest metabolic changes. NF-fed rats exposed to chlorpyrifos exhibited a pro-obesity phenotype compared with their controls, whereas there was no difference in pro-obesity phenotype between HF-fed groups. Chlorpyrifos exposure significantly reduced serum insulin, C-peptide, and amylin concentrations in NF- and HF-fed rats, leaving serum glucose and lipid profiles unaffected. Chlorpyrifos exposure also significantly altered gut microbiota composition, including the abundance of opportunistic pathogens, short chain fatty acid-producing bacteria and other bacteria previously associated with obese and diabetic phenotypes. The abundance of bacteria associated with neurotoxicity and islet injury was also significantly increased by chlorpyrifos. Our results suggest risk assessments for chlorpyrifos exposure should consider other effects in addition to neurotoxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tuition. . .and the Open Door

ERIC Educational Resources Information Center

Lombardi, John

1972-01-01

The financial crisis currently being experienced in community colleges is forcing the imposition of fees and tuition and thereby changing the basic philosophy of community colleges as open door" institutions. (NF)

Analysis of esophageal cancer cell lines exposed to X-ray based on radiosensitivity influence by tumor necrosis factor-α.

PubMed

Wang, Buhai; Ge, Yizhi; Gu, Xiang

2016-10-06

Assess the effects of tumor necrosis factor-α (TNF-α) in enhancing the radiosensitivity of esophageal cancer cell line in vitro. Three esophageal cancer cell line cells were exposed to X-ray with or without TNF-α treatment. MTT assay was used to evaluate the cell growth curve, and flow cytometry was performed to assess the cell apoptosis. The radiosensitizing effects of TNF-α were detected by cell colony formation assay. Western blotting was applied to observe the expression of NF-κB and caspase-3 protein in the exposed cells. Our results indicated that cellular inhibition rate increased over time, the strongest is combined group (P < 0.05). Western blotting showed that the decline expression of NF-κB protein was stated between only rhTNF-α and only X-ray radiation group and the maximum degree was manifested in combined group. Caspase-3 protein content expression just works opposite. Three kinds of cells in the NF-κB protein were similar without rhTNF-α. Then SEG1 NF-κB protein content was reduced more than other two kinds. We concluded that the cells treated with TNF-α showed significantly suppressed cell proliferation, increasing the cell apoptosis, and caspase-3 protein expression after X-ray exposure. TNF-α can enhance the radiosensitivity of esophageal cancer to enhancing the effect of the former.

Concurrent suppression of NF-κB, p38 MAPK and reactive oxygen species formation underlies the effect of a novel compound isolated from Curcuma comosa Roxb. in LPS-activated microglia.

PubMed

Jiamvoraphong, Nittaya; Jantaratnotai, Nattinee; Sanvarinda, Pantip; Tuchinda, Patoomratana; Piyachaturawat, Pawinee; Thampithak, Anusorn; Sanvarinda, Pimtip

2017-07-01

We investigated the molecular mechanisms underlying the effect of (3S)-1-(3,4-dihydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol, also known as compound 092, isolated from Curcuma comosa Roxb on the production of pro-inflammatory mediators and oxidative stress in lipopolysaccharide (LPS)-activated highly aggressive proliferating immortalized (HAPI) microglial cell lines. Nitric oxide (NO) production was determined using the Griess reaction, and reverse transcription polymerase chain reaction was used to measure the expression of inducible nitric oxide synthase (iNOS) mRNA. Western blotting was used to determine the levels of pro-inflammatory mediators and their related upstream proteins. Compound 092 suppressed NO production and iNOS expression in LPS-stimulated HAPI cells. These effects originated from the ability of compound 092 to attenuate the activation of nuclear factor (NF)-κB as determined by the reduction in p-NF-κB and p-IκB kinase (IKK) protein levels. Compound 092 also significantly lowered LPS-activated intracellular reactive oxygen species production and p38 mitogen-activated protein kinase (MAPK) activation. Compound 092 suppresses microglial activation through attenuation of p38 MAPK and NF-κB activation. Compound 092 thus holds the potential to treat neurodegenerative disorders associated with neuroinflammation and oxidative stress. © 2017 Royal Pharmaceutical Society.

Sulfasalazine inhibits inflammation and fibrogenesis in pancreas via NF-κB signaling pathway in rats with oxidative stress-induced pancreatic injury.

PubMed

Wang, Ya-Ru; Tian, Fei-Long; Yan, Ming-Xian; Fan, Jin-Hua; Wang, Li-Yun; Kuang, Rong-Guang; Li, Yan-Qing

2016-01-01

Pathogenesis and effective therapeutics of chronic pancreatic inflammation and fibrosis remain uncertain. To investigate the effects of sulfasalazine (SF) on pancreatic inflammation and fibrogenesis. Chronic pancreatic injury in rats was induced by diethyldithiocarbamate (DDC) and interfered by SF through intraperitoneal injection. The rats were divided into five groups: group N, normal control group, rats were treated with dilated water only; group DS1, rats received SF (10 mg/kg) 2 hours before DDC treatment; group DS2, rats were treated with DDC and then SF (100 mg/kg, twice a week); group DS3, rats were treated with DDC, then SF (100 mg/kg, thrice a week); and group DDC, rats were treated with DDC only. Pancreatic inflammation and fibrosis were determined by hematoxylin and eosin staining and Sirius red staining. The genes and proteins related to NF-κB pathway and fibrogenesis including NF-κB/p65, TNF-α, ICAM-1, α-SMA, and Con 1 were detected by immunohistochemical staining, reverse transcription polymerase chain reaction, and Western blotting. Rats in the DDC and DS1 groups showed the highest histological scores after DDC treatment, but the scores of DS2 and DS3 groups decreased significantly when compared with the DDC group. Sirius red staining showed collagen formation clearly in DDC and DS1 rats rather than in DS2 and DS3 rats. NF-κB/p65, ICAM-1, and α-SMA were strongly expressed in DDC and DS1 rats, while DS2 and DS3 rats showed mild to moderate expression by immunohistochemistry. Reverse transcription polymerase chain reaction showed increased levels of NF-κB/p65, ICAM-1, TNF-α, α-SMA, and Con 1 mRNA in DDC and DS1 rats in comparison to normal controls. The mRNA levels of these molecules in DS2 and DS3 rats were significantly lower than those in DS1 and DDC rats. Western blotting demonstrated that the NF-κB/p65, ICAM-1, and α-SMA expressions in pancreatic tissues of the rats of the DDC group were more clear than those of the normal control, DS2, and DS3 rats. SF inhibits pancreatic inflammation and fibrogenesis via NF-κB signaling pathway.

Mn porphyrin-based SOD mimic, MnTnHex-2-PyP(5+), and non-SOD mimic, MnTBAP(3-), suppressed rat spinal cord ischemia/reperfusion injury via NF-κB pathways.

PubMed

Celic, T; Španjol, J; Bobinac, M; Tovmasyan, A; Vukelic, I; Reboucas, J S; Batinic-Haberle, I; Bobinac, D

2014-12-01

Herein we have demonstrated that both superoxide dismutase (SOD) mimic, cationic Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTnHex-2-PyP(5+)), and non-SOD mimic, anionic Mn(III) meso-tetrakis(4-carboxylatophenyl)porphyrin (MnTBAP(3-)), protect against oxidative stress caused by spinal cord ischemia/reperfusion via suppression of nuclear factor kappa B (NF-κB) pro-inflammatory pathways. Earlier reports showed that Mn(III) N-alkylpyridylporphyrins were able to prevent the DNA binding of NF-κB in an aqueous system, whereas MnTBAP(3-) was not. Here, for the first time, in a complex in vivo system-animal model of spinal cord injury-a similar impact of MnTBAP(3-), at a dose identical to that of MnTnHex-2-PyP(5+), was demonstrated in NF-κB downregulation. Rats were treated subcutaneously at 1.5 mg/kg starting at 30 min before ischemia/reperfusion, and then every 12 h afterward for either 48 h or 7 days. The anti-inflammatory effects of both Mn porphyrins (MnPs) were demonstrated in the spinal cord tissue at both 48 h and 7 days. The downregulation of NF-κB, a major pro-inflammatory signaling protein regulating astrocyte activation, was detected and found to correlate well with the suppression of astrogliosis (as glial fibrillary acidic protein) by both MnPs. The markers of oxidative stress, lipid peroxidation and protein carbonyl formation, were significantly reduced by MnPs. The favorable impact of both MnPs on motor neurons (Tarlov score and inclined plane test) was assessed. No major changes in glutathione peroxidase- and SOD-like activities were demonstrated, which implies that none of the MnPs acted as SOD mimic. Increasing amount of data on the reactivity of MnTBAP(3-) with reactive nitrogen species (RNS) (.NO/HNO/ONOO(-)) suggests that RNS/MnTBAP(3-)-driven modification of NF-κB protein cysteines may be involved in its therapeutic effects. This differs from the therapeutic efficacy of MnTnHex-2-PyP(5+) which presumably occurs via reactive oxygen species and relates to NF-κB thiol oxidation; the role of RNS cannot be excluded.

Necrotizing Fasciitis and The Diabetic Foot.

PubMed

Iacopi, Elisabetta; Coppelli, Alberto; Goretti, Chiara; Piaggesi, Alberto

2015-12-01

Necrotizing fasciitis (NF) represents a rapidly progressive, life-threatening infection involving skin, soft tissue, and deep fascia. An early diagnosis is crucial to treat NF effectively. The disease is generally due to an external trauma that occurs in predisposed patients: the most important risk factor is represented by diabetes mellitus. NF is classified into 3 different subtypes according to bacterial strains responsible: type 1 associated to polymicrobial infection, type 2 NF, generally associated to Streptococcus species, often associated to Staphylococcus aureus and, eventually, Type 3, due to Gram-negative strains, such as Clostridium difficile or Vibrio. NF is usually characterized by the presence of the classic triad of symptoms: local pain, swelling, and erythema. In daily clinical practice immune-compromised or neuropathic diabetic patients present with atypical symptomatology. This explains the high percentage of misdiagnosed cases in the emergency department and, consequently, the worse outcome presented by these patients. Prompt aggressive surgical debridement and antibiotic systemic therapy are the cornerstone of its treatment. These must be associated with an accurate systemic management, consisting in nutritional support, glycemic compensation, and hemodynamic stabilization. Innovative methods, such as negative pressure therapy, once the acute conditions have resolved, can help fasten the surgical wound closure. Prompt management can improve prognosis of patients affected from NF reducing limb loss and saving lives. © The Author(s) 2015.

Genomic organization of the neurofibromatosis 1 gene (NF1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Y.; O`Connell, P.; Huntsman Breidenbach, H.

Neurofibromatosis 1 maps to chromosome band 17q11.2, and the NF1 locus has been partially characterized. Even though the full-length NF1 cDNA has been sequenced, the complete genomic structure of the NF1 gene has not been elucidated. The 5{prime} end of NF1 is embedded in a CpG island containing a NotI restriction site, and the remainder of the gene lies in the adjacent 350-kb NotI fragment. In our efforts to develop a comprehensive screen for NF1 mutations, we have isolated genomic DNA clones that together harbor the entire NF1 cDNA sequence. We have identified all intron-exon boundaries of the coding regionmore » and established that it is composed of 59 exons. Furthermore, we have defined the 3{prime}-untranslated region (3{prime}-UTR) of the NF1 gene; it spans approximately 3.5 kb of genomic DNA sequence and is continuous with the stop codon. Oligonucleotide primer pairs synthesized from exon-flanking DNA sequences were used in the polymerase chain reaction with cloned, chromosome 17-specific genomic DNA as template to amplify NF1 exons 1 through 27b and the exon containing the 3{prime}-UTR separately. This information should be useful for implementing a comprehensive NF1 mutation screen using genomic DNA as template. 41 refs., 3 figs., 2 tabs.« less

NZ suppresses TLR4/NF-κB signalings and NLRP3 inflammasome activation in LPS-induced RAW264.7 macrophages.

PubMed

Xiang, Pengjun; Chen, Tong; Mou, Yi; Wu, Hui; Xie, Peng; Lu, Guo; Gong, Xiaojian; Hu, Qinghua; Zhang, Yihua; Ji, Hui

2015-10-01

The purpose of the present study was to evaluate the potential therapeutic effects of NZ on lipopolysaccharide (LPS)-induced RAW264.7 cells and explore its underlying mechanisms. The effect of NZ on NO generation in LPS-activated macrophage was measured by Griess assay. The concentrations of TNF-α, IL-18, IL-1β were analyzed with ELISA kits. The LPS-induced production of reactive oxygen species (ROS) was determined by flow cytometry. The protein expressions of TLR4, NF-κB and NLRP3 signaling pathway were investigated with Western blot analysis. It was shown that NZ significantly reduced the production of NO and the generation of pro-inflammatory cytokines in LPS-induced RAW264.7 cells. In addition, NZ markedly inhibited the up-regulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and the activation of nuclear factor kappa B (NF-κB) in LPS-stimulated RAW 264.7 macrophages. Of note, NZ suppressed the expression of the inflammasome component such as NOD-like receptor 3(NLRP3), apoptosis-associated speck-like protein containing CARD(ASC), as well as the levels of cytokines including Interleukin-18(IL-18) and Interleukin-1β(IL-1β). These results indicated that NZ inhibited the generations of NO and pro-inflammatory cytokines by suppressing TLR4/MyD88/NF-κB pathway, suggesting that NZ could be an effective candidate for ameliorating LPS-induced inflammatory responses.

Eupatilin inhibits T-cell activation by modulation of intracellular calcium flux and NF-kappaB and NF-AT activity.

PubMed

Kim, Young-Dae; Choi, Suck-Chei; Oh, Tae-Young; Chun, Jang-Soo; Jun, Chang-Duk

2009-09-01

Eupatilin, one of the pharmacologically active ingredients of Artemisia princeps, exhibits a potent anti-ulcer activity, but its effects on T-cell immunity have not been investigated. Here, we show that eupatilin has a profound inhibitory effect on IL-2 production in Jurkat T cells as well as in human peripheral blood leukocytes. Eupatilin neither influenced clustering of CD3 and LFA-1 to the immunological synapse nor inhibited conjugate formation between T cells and B cells in the presence or absence of superantigen (SEE). Eupatilin also failed to inhibit T-cell receptor (TCR) internalization, thereby, suggesting that eupatilin does not interfere with TCR-mediated signals on the membrane proximal region. In unstimulated T cells, eupatilin significantly induced apoptotic cell death, as evidenced by an increased population of annexin V(+)/PI(+) cells and cleavage of caspase-3 and PARP. To our surprise, however, once cells were activated, eupatilin had little effect on apoptosis, and instead slightly protected cells from activation-induced cell death, suggesting that apoptosis also is not a mechanism for eupatilin-induced T-cell suppression. On the contrary, eupatilin dramatically inhibited I-kappaBalpha degradation and NF-AT dephosphorylation and, consequently, inhibited NF-kappaB and NF-AT promoter activities in PMA/A23187-stimulated T cells. Interestingly, intracellular calcium flux was significantly perturbed in cells pre-treated with eupatilin, suggesting that calcium-dependent cascades might be targets for eupatilin action. Collectively, our results provide evidence for dual regulatory functions of eupatilin: (1) a pro-apoptotic effect on resting T cells and (2) an immunosuppressive effect on activated T cells, presumably through modulation of Ca(2+) flux. (c) 2009 Wiley-Liss, Inc.

Increased p50/p50 NF-κB Activation in Human Papillomavirus Type 6- or Type 11-Induced Laryngeal Papilloma Tissue

PubMed Central

Vancurova, Ivana; Wu, Rong; Miskolci, Veronika; Sun, Shishinn

2002-01-01

We have observed elevated NF-κB DNA-binding activity in nuclear extracts from human papillomavirus type 6- and 11-infected laryngeal papilloma tissues. The predominant DNA-binding species is the p50/p50 homodimer. The elevated NF-κB activity could be correlated with a reduced level of cytoplasmic IκBβ and could be associated with the overexpression of p21CIP1/WAF1 in papilloma cells. Increased NF-κB activity and cytoplasmic accumulation of p21CIP1/WAF1 might counteract death-promoting effects elicited by overexpressed PTEN and reduced activation of Akt and STAT3 previously noted in these tissues. PMID:11773428

Oleanane-triterpenoids from Panax stipuleanatus inhibit NF-κB

PubMed Central

Liang, Chun; Ding, Yan; Song, Seok Bean; Kim, Jeong Ah; Cuong, Nguyen Manh; Ma, Jin Yeul; Kim, Young Ho

2013-01-01

In continuation of our research to find biological components from Panax stipuleanatus, four oleanane-type triterpenes (12 to 15) were isolated successively. Fifteen oleanane-type saponins (1 to 15) were evaluated for nuclear factor (NF)-κB activity using a luciferase reporter gene assay in HepG2 cells. Compounds 6 to 11 inhibited NF-κB, with IC50 values between 3.1 to 18.9 μM. The effects on inducible nitric oxide synthase and cyclooxygenase-2 by compounds 8, 10, and 11 were also examined using reverse transcription-polymerase chain reaction. Three compounds (8, 10, and 11) inhibited NF-κB activity by reducing the concentration of inflammatory factors in HepG2 cells. PMID:23717159

The 11S Proteasome Subunit PSME3 Is a Positive Feedforward Regulator of NF-κB and Important for Host Defense against Bacterial Pathogens.

PubMed

Sun, Jinxia; Luan, Yi; Xiang, Dong; Tan, Xiao; Chen, Hui; Deng, Qi; Zhang, Jiaojiao; Chen, Minghui; Huang, Hongjun; Wang, Weichao; Niu, Tingting; Li, Wenjie; Peng, Hu; Li, Shuangxi; Li, Lei; Tang, Wenwen; Li, Xiaotao; Wu, Dianqing; Wang, Ping

2016-02-02

The NF-κB pathway plays important roles in immune responses. Although its regulation has been extensively studied, here, we report an unknown feedforward mechanism for the regulation of this pathway by Toll-like receptor (TLR) ligands in macrophages. During bacterial infections, TLR ligands upregulate the expression of the 11S proteasome subunit PSME3 via NF-κB-mediated transcription in macrophages. PSME3, in turn, enhances the transcriptional activity of NF-κB by directly binding to and destabilizing KLF2, a negative regulator of NF-κB transcriptional activity. Consistent with this positive role of PSME3 in NF-κB regulation and importance of the NF-κB pathway in host defense against bacterial infections, the lack of PSME3 in hematopoietic cells renders the hosts more susceptible to bacterial infections, accompanied by increased bacterial burdens in host tissues. Thus, this study identifies a substrate for PSME3 and elucidates a proteolysis-dependent, but ubiquitin-independent, mechanism for NF-κB regulation that is important for host defense and innate immunity. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Astaxanthin inhibits NF-κB and Wnt/β-catenin signaling pathways via inactivation of Erk/MAPK and PI3K/Akt to induce intrinsic apoptosis in a hamster model of oral cancer.

PubMed

Kavitha, K; Kowshik, J; Kishore, T Kranthi Kiran; Baba, Abdul Basit; Nagini, S

2013-10-01

The oncogenic transcription factors NF-κB and β-catenin, constitutively activated by upstream serine/threonine kinases control several cellular processes implicated in malignant transformation including apoptosis evasion. The aim of this study was to investigate the chemopreventive effects of astaxanthin, an antioxidant carotenoid, in the hamster buccal pouch (HBP) carcinogenesis model based on its ability to modulate NF-κB and Wnt signaling pathways and induce apoptosis. We determined the effect of dietary supplementation of astaxanthin on the oncogenic signaling pathways - NF-κB and Wnt/β-catenin, their upstream activator kinases - Erk/MAPK and PI-3K/Akt, and the downstream event - apoptosis evasion by real-time quantitative RT-PCR, western blot, and immunohistochemical analyses. We found that astaxanthin inhibits NF-κB and Wnt signaling by downregulating the key regulatory enzymes IKKβ and GSK-3β. Analysis of gene expression and docking interactions revealed that inhibition of these pathways may be mediated via inactivation of the upstream signaling kinases Erk/Akt by astaxanthin. Astaxanthin also induced caspase-mediated mitochondrial apoptosis by downregulating the expression of antiapoptotic Bcl-2, p-Bad, and survivin and upregulating proapoptotic Bax and Bad, accompanied by efflux of Smac/Diablo and cytochrome-c into the cytosol, and induced cleavage of poly (ADP-ribose) polymerase (PARP). The results provide compelling evidence that astaxanthin exerts chemopreventive effects by concurrently inhibiting phosphorylation of transcription factors and signaling kinases and inducing intrinsic apoptosis. Astaxanthin targets key molecules in oncogenic signaling pathways and induces apoptosis and is a promising candidate agent for cancer prevention and therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

4-Hydroxy-17-methylincisterol from Agaricus blazei Decreased Cytokine Production and Cell Proliferation in Human Peripheral Blood Mononuclear Cells via Inhibition of NF-AT and NF-κB Activation

PubMed Central

Tsai, Wei-Jern; Yang, Shih-Chien; Huang, Yu-Ling; Chen, Chien-Chih; Chuang, Kai-An; Kuo, Yuh-Chi

2013-01-01

Agaricus blazei Murill is an edible and medicinal mushroom. In the previous study, we have proved that extracts of A. blazei inhibit human peripheral blood mononuclear cell (PBMC) proliferation activated with phytohemagglutinin (PHA). Currently, we purified 4-hydroxy-17-methylincisterol (4-HM; C21H33O3) from A. blazei investigated its regulatory effects on cytokine productions and cell proliferation of PBMC induced by PHA. The results indicated that 4-HM suppressed, in activated PBMC, the production and mRNA expression of interleukin-2 (IL-2), IL-4, tumor necrosis factor-α, and interferon-γ in a concentration-dependent manner. This inhibition was not related to cell viability. While 4-HM did not affect ERK phosphorylation and its downstream c-fos gene expression in PBMC induced by PHA, it decreased both NF-AT and NF-κB activation. The upstream signaling of NF-AT and NF-κB, intracellular calcium concentrations ([Ca2+]i), and protein kinase C theta (PKC θ) activation in PHA-treated PBMC were reduced by 4-HM. The data demonstrated that the suppressant effects of 4-HM on cell proliferation in PBMC activated by PHA appeared to be mediated, at least in part, through inhibition of Ca2+ mobilization and PKC θ activation, NF-AT and NF-κB activation, and cytokine transcripts and productions of PBMC. We suggested that A. blazei contained a potential immunomodulator 4-HM. PMID:23533483

Systemic delivery of NEMO binding domain/IKKγ inhibitory peptide to young mdx mice improves dystrophic skeletal muscle histopathology.

PubMed

Reay, Daniel P; Yang, Michele; Watchko, Jon F; Daood, Molly; O'Day, Terrence L; Rehman, Khaleel K; Guttridge, Denis C; Robbins, Paul D; Clemens, Paula R

2011-09-01

The activation of nuclear factor κB (NF-κB) contributes to muscle degeneration that results from dystrophin deficiency in human Duchenne muscular dystrophy (DMD) and in the mdx mouse. In dystrophic muscle, NF-κB participates in inflammation and failure of muscle regeneration. Peptides containing the NF-κB Essential Modulator (NEMO) binding domain (NBD) disrupt the IκB kinase complex, thus blocking NF-κB activation. The NBD peptide, which is linked to a protein transduction domain to achieve in vivo peptide delivery to muscle tissue, was systemically delivered to mdx mice for 4 or 7 weeks to study NF-κB activation, histological changes in hind limb and diaphragm muscle and ex vivo function of diaphragm muscle. Decreased NF-κB activation, decreased necrosis and increased regeneration were observed in hind limb and diaphragm muscle in mdx mice treated systemically with NBD peptide, as compared to control mdx mice. NBD peptide treatment resulted in improved generation of specific force and greater resistance to lengthening activations in diaphragm muscle ex vivo. Together these data support the potential of NBD peptides for the treatment of DMD by modulating dystrophic pathways in muscle that are downstream of dystrophin deficiency. Published by Elsevier Inc.

Functional Genomic Characterization of Virulence Factors from Necrotizing Fasciitis-Causing Strains of Aeromonas hydrophila

PubMed Central

Grim, Christopher J.; Kozlova, Elena V.; Ponnusamy, Duraisamy; Fitts, Eric C.; Sha, Jian; Kirtley, Michelle L.; van Lier, Christina J.; Tiner, Bethany L.; Erova, Tatiana E.; Joseph, Sandeep J.; Read, Timothy D.; Shak, Joshua R.; Joseph, Sam W.; Singletary, Ed; Felland, Tracy; Baze, Wallace B.; Horneman, Amy J.

2014-01-01

The genomes of 10 Aeromonas isolates identified and designated Aeromonas hydrophila WI, Riv3, and NF1 to NF4; A. dhakensis SSU; A. jandaei Riv2; and A. caviae NM22 and NM33 were sequenced and annotated. Isolates NF1 to NF4 were from a patient with necrotizing fasciitis (NF). Two environmental isolates (Riv2 and -3) were from the river water from which the NF patient acquired the infection. While isolates NF2 to NF4 were clonal, NF1 was genetically distinct. Outside the conserved core genomes of these 10 isolates, several unique genomic features were identified. The most virulent strains possessed one of the following four virulence factors or a combination of them: cytotoxic enterotoxin, exotoxin A, and type 3 and 6 secretion system effectors AexU and Hcp. In a septicemic-mouse model, SSU, NF1, and Riv2 were the most virulent, while NF2 was moderately virulent. These data correlated with high motility and biofilm formation by the former three isolates. Conversely, in a mouse model of intramuscular infection, NF2 was much more virulent than NF1. Isolates NF2, SSU, and Riv2 disseminated in high numbers from the muscular tissue to the visceral organs of mice, while NF1 reached the liver and spleen in relatively lower numbers on the basis of colony counting and tracking of bioluminescent strains in real time by in vivo imaging. Histopathologically, degeneration of myofibers with significant infiltration of polymorphonuclear cells due to the highly virulent strains was noted. Functional genomic analysis provided data that allowed us to correlate the highly infectious nature of Aeromonas pathotypes belonging to several different species with virulence signatures and their potential ability to cause NF. PMID:24795370

Mid-aortic syndrome with renovascular hypertension and multisystem involvement in a girl with familiar neurofibromatosis von Recklinghausen type 1.

PubMed

Petrak, Borivoj; Bendova, Sarka; Seeman, Tomas; Klein, Tibor; Lisy, Jiri; Zatrapa, Tomas; Marikova, Tana

2007-12-01

Neurofibromatosis von Recklinghausen type 1 (NF1) is an autosomal dominant neurocutaneous disorder affecting one in 3 000-4 000 individuals. Mid-aortic syndrome (MAS) is a rare condition characterized by segmental narrowing of abdominal aorta and stenosis of its major branches - mainly renal arteries, including manifestation of renovascular hypertension. MAS can be caused by different diseases, including NF1. A 9 years old girl with primary diagnosis of NF1 combined with renovascular hypertension due to MAS, suffered of bilateral optic and chiasm glioma, pubertas praecox, speech disorder, light mental retardation and scoliosis. We have found a mutation in exone 34 of the NF1 gene (17q11.2). Her father has been also diagnosed with NF1 and hypertension developed at early age. He has the same mutation in exone 34 of NF1 gene. The girl is currently treated with conservative antihypertensive medication with positive effect. Bilateral optic and chiasm glioma are asymptomatic at the time and they had been without progress over period of time. Any vascular surgery, neurosurgical and oncological therapy are not indicated at the present time. This article is a summary of clinical findings in patient with NF1 due to NF1 gene mutation in exone 34. It confirms the importance of complex multidisciplinar approach to examination and taking care of NF1 patients and their families.

Study of Cs/NF3 adsorption on GaN (0 0 1) surface

NASA Astrophysics Data System (ADS)

Diao, Yu; Liu, Lei; Xia, Sihao; Kong, Yike

2017-03-01

To investigate the optoelectronics properties of Cs/NF3 adsorption on GaN (0 0 1) photocathode surface, different adsorption models of Cs-only, Cs/O, Cs/NF3 adsorption on GaN clean surface were established, respectively. Atomic structures, work function, adsorption energy, E-Mulliken charge distribution, density of states and optical properties of all these adsorption systems were calculated using first principles. Compared with Cs/O co-adsorption, Cs/NF3 co-adsorption show better stability and more decline of work function, which is more beneficial for photoemission efficiency. Besides, surface band structures of Cs/NF3 co-adsorption system exhibit metal properties, implying good conductivity. Meanwhile, near valence band minimum of Cs/NF3 co-adsorption system, more acceptor levels emerges to form a p-type emission surface, which is conductive to the escape of photoelectrons. In addition, imaginary part of dielectric function curve and absorption curve of Cs/NF3 co-adsorption system both move towards lower energy side. This work can direct the optimization of activation process of NEA GaN photocathode.

Anti-nociceptive effect of dexmedetomidine in a rat model of monoarthritis via suppression of the TLR4/NF-κB p65 pathway

PubMed Central

Ji, Dong; Zhou, Yalan; Li, Shuangshuang; Li, Dai; Chen, Hui; Xiong, Yuanchang; Zhang, Yuqiu; Xu, Hua

2017-01-01

As a therapeutic target for neuropathic pain, the anti-nociceptive effects of α 2-adrenoceptors (α2AR) have attracted attention. Dexmedetomidine (DEX), a potent and highly selective α2AR agonist, has exhibited significant analgesic effects in neuropathic pain, but the underlying mechanism has remained elusive. The present study investigated the effect of DEX on Toll-like receptor (TLR)4 and nuclear factor (NF)-κB p65 expression, as well as the production of pro-inflammatory cytokines. The rat monoarthritis (MA) model was induced by intra-articular injection of complete Freund's adjuvant (CFA) at the ankle joint. After induction of MA, the rats were intrathecally treated with normal saline or DEX (2.5 µg) for 3 consecutive days. The concentration of interleukin-1β and −6 as well as tumor necrosis factor-α was examined by ELISA. The expression levels of TLR4 and NF-κB p65 were determined by western blot analysis and immunohistochemistry. The results indicated that the pro-inflammatory cytokines TLR4 and NF-κB p65 were significantly upregulated in MA rats. DEX treatment markedly reduced mechanical and thermal hyperalgesia, suppressed MA-induced elevation of the pro-inflammatory cytokines and inhibited the TLR4/NF-κB p65 pathway, while these effects were blocked by pre-treatment with the selective α2AR antagonist BRL44408 (15 µg) at 30 min prior to CFA injection. These results suggested that DEX has an anti-nociceptive effect via suppressing the TLR4/NF-κB p65 pathway. PMID:29201195

A new concept in polymeric thin-film composite nanofiltration membranes with antibacterial properties.

PubMed

Mollahosseini, Arash; Rahimpour, Ahmad

2013-01-01

A new, thin film, biofouling resistant, nanofiltration (NF) membrane was fabricated with two key characteristics, viz. a low rate of silver (Ag) release and long-lasting antibacterial properties. In the new approach, nanoparticles were embedded completely in a polymeric thin-film layer. A comparison was made between the new thin-film composite (TFC), NF membrane and thin-film nanocomposite (TFN), and antibacterial NF membranes. Both types of NF membrane were fabricated by interfacial polymerization on a polysulphone sublayer using m-phenylenediamine and trimesoyl chloride as an amine monomer and an acid chloride monomer, respectively. Energy dispersive X-ray (EDX) microanalysis demonstrated the presence of Ag nanoparticles. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to study the cross-sectional and surface morphological properties of the NF membranes. Permeability and salt rejection were tested using a dead-end filtration cell. Ag leaching from the membranes was measured using inductively coupled mass spectrometry (ICP-MS). Morphological studies showed that the TFC NF membranes had better thin-film formation (a more compact structure and a smoother surface) than TFN NF membranes. Performance experiments on TFC NF membranes revealed that permeability was good, without sacrificing salt rejection. The antibacterial properties of the fabricated membranes were tested using the disk diffusion method and viable plate counts. The antibiofouling properties of the membranes were examined by measuring the quantity of bacterial cells released from the biofilm formed (as a function of the amount of biofilm present). A more sensitive surface was observed compared to that of a typical antibacterial NF membrane. The Ag leaching rates were low, which will likely result in long-lasting antibacterial and biofouling resistant properties.

Strategies of NF-κB signaling modulation by ectromelia virus in BALB/3T3 murine fibroblasts.

PubMed

Struzik, Justyna; Szulc-Dąbrowska, Lidia; Winnicka, Anna; Niemiałtowski, Marek

2015-10-01

Nuclear factor κB (NF-κB) is a pleiotropic transcription factor that regulates the expression of immune response genes. NF-κB signaling can be disrupted by pathogens that prevent host immune response. In this work, we examined the influence of ectromelia (mousepox) virus (ECTV) on NF-κB signaling in murine BALB/3T3 fibroblasts. Activation of NF-κB via tumor necrosis factor (TNF) receptor 1 (TNFR1) in these cells induces proinflammatory cytokine secretion. We show that ECTV does not recruit NF-κB to viral factories or induce NF-κB nuclear translocation in BALB/3T3 cells. Additionally, ECTV counteracts TNF-α-induced p65 NF-κB nuclear translocation during the course of infection. Inhibition of TNF-α-induced p65 nuclear translocation was also observed in neighboring cells that underwent fusion with ECTV-infected cells. ECTV inhibits the key step of NF-κB activation, i.e. Ser32 phosphorylation and degradation of inhibitor κBα (IκBα) induced by TNF-α. We also observed that ECTV prevents TNF-α-induced Ser536 of p65 phosphorylation in BALB/3T3 cells. Studying TNFR1 signaling provides information about regulation of inflammatory response and cell survival. Unraveling poxviral immunomodulatory strategies may be helpful in drug target identification as well as in vaccine development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rig-I regulates NF-κB activity through binding to Nf-κb1 3′-UTR mRNA

PubMed Central

Zhang, Hong-Xin; Liu, Zi-Xing; Sun, Yue-Ping; Lu, Shun-Yuan; Liu, Xue-Song; Huang, Qiu-Hua; Xie, Yin-Yin; Dang, Su-Ying; Zheng, Guang-Yong; Li, Yi-Xue; Kuang, Ying; Fei, Jian; Chen, Zhu; Wang, Zhu-Gang

2013-01-01

Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-κb1. Rig-I is required for NF-κB activity via regulating Nf-κb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3′-UTR of Nf-κb1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3′-UTR fragments can be recognized by Rig-I. The 3′-UTR binding with Rig-I plays a critical role in normal translation of Nf-κb1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-κb1 and 3′-UTR–mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-κB signaling and is involved in multiple biological processes in addition to host antivirus immunity. PMID:23553835

A hybrid method for quantifying China's nitrogen footprint during urbanisation from 1990 to 2009.

PubMed

Cui, Shenghui; Shi, Yalan; Malik, Arunima; Lenzen, Manfred; Gao, Bing; Huang, Wei

2016-12-01

In this study, we devise a national nitrogen footprint method to evaluate the life cycle nitrogen flows through the national economy of China from 1990 to 2009. To this end, we build a hybrid method based on two well-established techniques, namely material flow analysis (MFA) and input-output analysis (IOA). This integration allows for the evaluation of the effects of international trade and interdependencies among economic sectors. Our results suggest that China's nitrogen footprint (NF) has increased from 30.3Teragrams (Tg) in 1990 to 54.0Tg in 2009, whereas the NF per capita has increased from 25.9 to 39.5kgN/yr. Relationship between the world NF per capita and human development index (HDI) appears to show an inverted U curve, whilst China shows an increase both in NF per capita and HDI. We find that an increase in China's NF is largely associated with high levels of urbanisation. Although the energy NF (E_NF) has increased more drastically than the food NF (F_NF), the latter still dominates China's total NNF, with proportions of 91% in 1990 and 82% in 2009. Taking international trade into account, our results demonstrate that China was a net exporter of F_NF, whilst a net importer of E_NF over this time period. There are many measures considered to reduce China's nitrogen footprint, including improvements in N use efficiency of food systems, transformation of meat-based diets and optimisation of China's economic structure. Copyright © 2016 Elsevier Ltd. All rights reserved.

Stabilisation of p53 enhances reovirus-induced apoptosis and virus spread through p53-dependent NF-κB activation.

PubMed

Pan, D; Pan, L-Z; Hill, R; Marcato, P; Shmulevitz, M; Vassilev, L T; Lee, P W K

2011-09-27

Naturally oncolytic reovirus preferentially kills cancer cells, making it a promising cancer therapeutic. Mutations in tumour suppressor p53 are prevalent in cancers, yet the role of p53 in reovirus oncolysis is relatively unexplored. Human cancer cell lines were exposed to Nutlin-3a, reovirus or a combination of the two and cells were processed for reovirus titration, western blot, real-time PCR and apoptosis assay using Annexin V and 7-AAD staining. Confocal microscopy was used to determine translocation of the NF-κB p65 subunit. We show that despite similar reovirus replication in p53(+/+) and p53(-/-) cells, stabilisation of p53 by Nutlin-3a significantly enhanced reovirus-induced apoptosis and hence virus release and dissemination while having no direct effect on virus replication. Enhanced apoptosis by Nutlin-3a was not observed in p53(-/-) or p53 knockdown cells; however, increased expression of Bax and p21 are required. Moreover, elevated NF-κB activation in reovirus-infected cells following Nutlin-3a treatment was necessary for enhanced reovirus-induced apoptosis, as synergistic cytotoxicity was overcome by specific NF-κB inhibitors. Nutlin-3a treatment enhances reovirus-induced apoptosis and virus spread through p53-dependent NF-κB activation, and combination of reovirus and Nutlin-3a might represent an improved therapy against cancers harbouring wild-type p53.

Overexpression of BAG3 Attenuates Hypoxia-Induced Cardiomyocyte Apoptosis by Inducing Autophagy.

PubMed

Zhang, Jiankai; He, Zhangyou; Xiao, Wenjian; Na, Qingqing; Wu, Tianxiu; Su, Kaixin; Cui, Xiaojun

2016-01-01

Hypoxia is a well-known factor in the promotion of apoptosis, which contributes to the development of numerous cardiac diseases, such as heart failure and myocardial infarction. Inhibiting apoptosis is an important therapeutic strategy for the treatment of related heart diseases caused by ischemia/hypoxic injury. Previous studies have demonstrated that BAG3 plays an important role in cardiomyocyte apoptosis and survival. However, the role of BAG3 in hypoxia-induced cardiomyocyte apoptosis remains to be clarified. Here, we demonstrate that BAG3 is induced by hypoxia stimuli in cultured cardiomyocytes. BAG3 expression level was measured in H9c2 cells treated with hypoxia for 48 h. Cell proliferation and apoptosis were tested using MTT assay and Annexin V FITC-PI staining assay, respectively. The mRNA or protein expression level of BAG3, LC3-I, LC3-II, Atg5, NF-x03BA;B p65 and phosphorylated NF-x03BA;B p65 were assessed by qRT-PCR and western blot assay, respectively. Resluts: Overexpression of BAG3 inhibited cell apoptosis and promoted proliferation in hypoxia-injured H9c2 cells. Furthermore, autophagy and NF-x03BA;B were activated by BAG3 overexpression, and the NF-x03BA;B inhibitor PDTC could inhibit the activation of autophagy induced by BAG3 overexpression. In addition, the autophagy inhibitor 3-MA partly impeded the inhibitory effect of BAG3 on hypoxia-induced cardiomyocyte apoptosis. these results suggested that overexpression of BAG3 promoted cell proliferation and inhibited apoptosis by activating autophagy though the NF-x03BA;B signaling pathway in hypoxia-injured cardiomyocytes. © 2016 The Author(s) Published by S. Karger AG, Basel.

Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-κB signaling pathway with distinct mechanisms

PubMed Central

Peng, Yan-min; Zheng, Jian-bin; Zhou, Yu-bo; Li, Jia

2013-01-01

Aim: Curcumin has shown promising anticancer activity, which relies on its inhibition on NF-κB pathway. In this study, we characterized the pharmacological profile of a novel curcumin analog P1 and elucidate the related mechanisms. Methods: HEK293/NF-κB cells, stably transfected with an NF-κB-responsive luciferase reporter plasmid, were generated for high-throughput screen (HTS). Eight cancer cell lines, including PC3, COLO 205, HeLa cells etc. were tested. Cell viability was assessed using the sulforhodamine B (SRB) assays. Cell apoptosis was evaluated using FACS, immunocytochemistry, and Western blotting. H2-DCFDA and MitoSOX Red were used to detect cellular and mitochondrial reactive oxygen species (ROS). The mitochondrial function was evaluated using mitochondrial oxygen consumption assay. Results: P1, a tropinone curcumin, was found in HTS targeting the NF-κB pathway. Its IC50 value in inhibition of TNF-α-induced NF-κB activation was 0.8 μmol/L, whereas its IC50 values in inhibiting the growth of A549 and HeLa cells were 1.24 and 0.69 μmol/L, respectively, which was 20- to 30-fold more potent than curcumin. The inhibition of P1 on the NF-κB pathway was further addressed in HeLa cells. The compound up to 10 μmol/L did not affect the binding of NF-κB to DNA, but markedly inhibited NF-κB nuclear translocation, IκB degradation and IκB kinase phosphorylation. The compound (1 and 3 μmol/L) concentration-dependently induced ROS generation, whereas curcumin up to 20 μmol/L had no effect. P1-induced ROS generation was mainly localized in mitochondria, and reversed by NAC. Moreover, the compound significantly enhanced TNF-α-induced apoptosis. Conclusion: P1 is a novel curcumin analog with potent anticancer activities, which exerts a distinct inhibition on the NF-κB pathway. PMID:23603982

Oil mixes omega 9, 6 and 3, enriched with seaweed, promoted reduction of thermal burned modulating NF-kB and Ki-67.

PubMed

Campelo, Ana Paula Bomfim Soares; Campelo, Márcio Wilker Soares; Brito, Gerly Anne de Castro; Jamacaru, Francisco Vagnaldo Fechine; Leitão, Renata Ferreira de Carvalho; Vasconcelos, Paulo Roberto Leitão de

2015-06-01

To examine the effects of the oil mixes (ω-9, ω-6 and ω-3) in rats subjected to thermal burn. It was also aimed to assess whether the sources of ω3 would interfere with the effect of such mixes on the thermal injury. Thirty-six rats distributed into five groups: burned + water, burned + isolipid mix, burned + oil mix 1 (ALA), burned + oil mix 2 (ALA + EPA + DHA of fish) and burned + oil mix 3 (ALA + DHA from seaweed). The thermal injury was involving total thickness of skin. After the burns animals received the oil mixes for seven days. The lesions were evaluated by immunohistochemistry. Animals receiving mix 3 showed a smaller extension of the thermal injury as compared to those that were supplemented with other oils mixes. Expression of Ki-67 in the receiving Mix 3 increased as compared to all the other groups. Animals supplemented with mix 3 were able to inhibit NF-κB in injured tissue. Rats received oil mix in which the source of ω3 (ALA+DHA of seaweed) showed inhibition of NF-κB, increase in cell proliferation, and reduction the extension of thermal lesion.

Investigations on GSK-3β/NF-kB signaling in stress and stress adaptive behavior in electric foot shock subjected mice.

PubMed

Bali, Anjana; Jaggi, Amteshwar Singh

2016-04-01

The present study was designed to explore the role of GSK-3β and NF-kB signaling in electric foot shock-induced stress and stress adaptation. Mice were subjected to foot shocks of 0.5mA intensity and 1s duration of 1h to produce acute stress. Animals were exposed to the same stressor for 5 days to induce stress adaptation. The behavioral alterations were assessed using the actophotometer, hole board, open field and social interaction tests. The serum corticosterone levels were assessed as a marker of the HPA axis. The levels of total GSK-3β, p-GSK-3β-S9 and p-NF-kB were determined in the hippocampus, frontal cortex and amygdala. Acute electric foot shock stress produced behavioral and biochemical changes; decreased the levels of p-GSK-3β-S9, produced no change in total GSK-3β levels and increased p-NF-kB levels in the brain. However, repeated exposure of foot shock stress restored the behavioral and biochemical changes along with normalization of p-GSK-3β-S9 and p-NF-kB levels. Administration of AR-A01, a selective GSK-3β inhibitor, or diethyldithiocarbamic acid (DDTC), a selective NF-kB inhibitor, diminished acute stress-induced behavioral and biochemical changes. Furthermore, AR-A014418 normalized acute stress-induced alterations in p-GSK-3β-S9 and p-NF-kB levels, however, DDTC selectively restored NF-kB levels without any change in p-GSK-3β-S9 levels. It probably suggests that NF-kB is a downstream mediator of the GSK-3 signaling cascade. It may conclude that acute stress associated decrease in p-GSK-3β-S9 and increase in p-NF-kB levels in the brain contribute in the development of behavioral and biochemical alterations and normalization of GSK-3β/NF-kB signaling may contribute in stress adaptive behavior in response to repeated electric foot shock-subjected mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of cranberry components on human aggressive periodontitis gingival fibroblasts.

PubMed

Tipton, D A; Babu, J P; Dabbous, M Kh

2013-08-01

Aggressive periodontitis (AgP) causes rapid periodontal breakdown involving AgP gingival fibroblast production of cytokines [i.e. interleukin (IL)-6, a bone metabolism regulator], and matrix metalloproteinase (MMP)-3. Lipopolysaccharide upregulates fibroblast IL-6 and MMP-3, via transcription factors (i.e. NF-κB). Cranberry (Vaccinium macrocarpon) inhibits lipopolysaccharide-stimulated macrophage and normal gingival fibroblast activities, but little is known of its effects on AgP fibroblasts. Objectives of this study are to use AgP fibroblasts, to determine cytotoxicity of cranberry components or periodontopathogen (Fusobacterium nucleatum, Porphyromonas gingivalis) lipopolysaccharide ± cranberry components, and effects of cranberry components on lipopolysaccharide-stimulated NF-κB activation and IL-6 and MMP-3 production. AgP fibroblasts were incubated ≤ 6 d with high molecular weight non-dialyzable material (NDM) (derived from cranberry juice (1-500 μg/mL) or lipopolysaccharide (1 μg/mL) ± NDM. Membrane damage and viability were assessed by enzyme activity released into cell supernatants and activity of a mitochondrial enzyme, respectively. Secreted IL-6 and MMP-3 were measured by ELISA. NF-κB p65 was measured via binding to an oligonucleotide containing the NF-κB consensus site. Data were analyzed using analysis of variance and Scheffe's F procedure for post hoc comparisons. Short-term exposure to NDM, or lipopolysaccharide ± NDM caused no membrane damage. NDM (≤ 100 μg/mL) or lipopolysaccharide ± NDM had no effect on viability ≤ 7 d exposure. NDM (50 μg/mL) inhibited lipopolysaccharide-stimulated p65 (P ≤ 0.003) and constitutive or lipopolysaccharide-stimulated MMP-3 (P ≤ 0.02). NDM increased AgP fibroblast constitutive or lipopolysaccharide-stimulated IL-6 (P ≤ 0.0001), but inhibited normal human gingival fibroblast IL-6 (P ≤ 0.01). Lack of toxicity of low NDM concentrations, and its inhibition of NF-κB and MMP-3, suggest that cranberry components may regulate AgP fibroblast inflammatory responses. Distinct effects of NDM on AgP and gingival fibroblast production of IL-6 (which can have both positive and negative effects on bone metabolism) may reflect phenotypic differences in IL-6 regulation in the two cell types. © 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sodium tanshinone IIA silate inhibits oxygen-glucose deprivation/recovery-induced cardiomyocyte apoptosis via suppression of the NF-κB/TNF-α pathway

PubMed Central

Wu, Wen-Yu; Wang, Wen-Yi; Ma, Yan-Ling; Yan, Hong; Wang, Xin-Bo; Qin, Yin-Lin; Su, Mei; Chen, Tao; Wang, Yi-Ping

2013-01-01

Background and Purpose Inhibition of apoptosis may attenuate the irreversible injury associated with reperfusion. In the current study, we focused on the cytoprotective effects and the underlying mechanism of sodium tanshinone IIA silate (STS) against damage induced by oxygen-glucose deprivation/recovery (OGD/R). in H9c2 cardiomyocytes and the underlying mechanisms. Experimental Approach We used a model of cardiac ischaemia/reperfusion, OGD/R in H9c2 cardiomyocytes, to assess the cardioprotective effects of STS. Apoptosis of cells was measured with Hoechst 33342-based fluorescence microscopy, and annexin V-FITC-based flow cytometry. Caspase-3 and caspase-8 activities and mitochondrial membrane potential were also measured using commercial kits. TNF-α in the cell culture supernatant fractions were measured with sandwich elisa, and protein levels assayed using Western blot. Key Results STS inhibited OGD/R-induced apoptosis by suppressing JNK-mediated activation of NF-κB, TNF-α expression, activation of caspase-3 and caspase-8 and the Bax/Bcl-2 ratio. Additionally, positive feedback between NF-κB and TNF-α and amplification of TNF-α were inhibited, suggesting that STS plays a protective role against apoptosis in cardiomyocytes, even upon activation of pro-inflammatory cytokines. Interestingly, the cytoprotective effects of STS on OGD/R-induced apoptosis and promotion of cell survival were attenuated after inhibition of PI3K. Conclusion and Implications The inhibitory effects of STS on TNF-α and positive feedback signalling of the NF-κB/TNF-α pathways may play important roles in myocardial protection against ischaemia/reperfusion. These protective effects of STS are mediated by suppressing JNK activity through activation of the PI3K-Akt pathway. PMID:23517194

Isobutyrylshikonin inhibits lipopolysaccharide-induced nitric oxide and prostaglandin E2 production in BV2 microglial cells by suppressing the PI3K/Akt-mediated nuclear transcription factor-κB pathway.

PubMed

Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Lee, Kyoung-Tae; Kang, Chang-Hee; Dilshara, Matharage Gayani; Lee, Hak-Ju; Choi, Yung Hyun; Choi, Il-Whan; Kim, Gi-Young

2014-12-01

Microglia are important macrophages to defend against pathogens in the central nervous system (CNS); however, persistent or acute inflammation of microglia lead to CNS disorders via neuronal cell death. Therefore, we theorized that a good strategy for the treatment of CNS disorders would be to target inflammatory mediators from microglia in disease. Consequently, we investigated whether isobutyrylshikonin (IBS) attenuates the production of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Treatment with IBS inhibited the secretion of NO and prostaglandin E2 (as well as the expression of their key regulatory genes), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2). Isobutyrylshikonin also suppressed LPS-induced DNA-binding activity of nuclear transcription factor-κB (NF-κB), by inhibiting the nuclear translocation of p50 and p65 in addition to blocking the phosphorylation and degradation of IκBα. Pretreatment with pyrrolidine dithiocarbamate, a specific NF-κB inhibitor, showed the down-regulation of LPS-induced iNOS and COX-2 messenger RNA by suppressing NF-κB activity. This indirectly suggests that IBS-mediated NF-κB inhibition is the main signaling pathway involved in the inhibition of iNOS and COX-2 expression. In addition, IBS attenuated LPS-induced phosphorylation of PI3K and Akt, which are upstream molecules of NF-κB, in LPS-stimulated BV2 microglial cells. The functional aspects of the PI3K/Akt signaling pathway were analyzed with LY294002, which is a specific PI3K/Akt inhibitor that attenuated LPS-induced iNOS and COX-2 expression by suppressing NF-κB activity. These data suggest that an IBS-mediated anti-inflammatory effect may be involved in suppressing the PI3K/Akt-mediated NF-κB signaling pathway. Copyright © 2014 Elsevier Inc. All rights reserved.

Dietary L-glutamine supplementation modulates microbial community and activates innate immunity in the mouse intestine.

PubMed

Ren, Wenkai; Duan, Jielin; Yin, Jie; Liu, Gang; Cao, Zhong; Xiong, Xia; Chen, Shuai; Li, Tiejun; Yin, Yulong; Hou, Yongqing; Wu, Guoyao

2014-10-01

This study was conducted to determine effects of dietary supplementation with 1 % L-glutamine for 14 days on the abundance of intestinal bacteria and the activation of intestinal innate immunity in mice. The measured variables included (1) the abundance of Bacteroidetes, Firmicutes, Lactobacillus, Streptococcus and Bifidobacterium in the lumen of the small intestine; (2) the expression of toll-like receptors (TLRs), pro-inflammatory cytokines, and antibacterial substances secreted by Paneth cells and goblet cells in the jejunum, ileum and colon; and (3) the activation of TLR4-nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), and phosphoinositide-3-kinases (PI3K)/PI3K-protein kinase B (Akt) signaling pathways in the jejunum and ileum. In the jejunum, glutamine supplementation decreased the abundance of Firmicutes, while increased mRNA levels for antibacterial substances in association with the activation of NF-κB and PI3K-Akt pathways. In the ileum, glutamine supplementation induced a shift in the Firmicutes:Bacteroidetes ratio in favor of Bacteroidetes, and enhanced mRNA levels for Tlr4, pro-inflammatory cytokines, and antibacterial substances participating in NF-κB and JNK signaling pathways. These results indicate that the effects of glutamine on the intestine vary with its segments and compartments. Collectively, dietary glutamine supplementation of mice beneficially alters intestinal bacterial community and activates the innate immunity in the small intestine through NF-κB, MAPK and PI3K-Akt signaling pathways.

27 CFR 21.68 - Formula No. 38-F.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) Six pounds of either boric acid, N.F., or Polysorbate 80, N.F.; 11/3 pounds of thymol, N.F.; 11/3... of any two or more denaturing materials listed under Formula No. 38-B, plus sufficient boric acid, N..., U.S.P., 2.6 fluid ounces of hydrochloric acid, N.F., and a total of 3 pounds of any two or more of...

27 CFR 21.68 - Formula No. 38-F.

Code of Federal Regulations, 2013 CFR

2013-04-01

...) Six pounds of either boric acid, N.F., or Polysorbate 80, N.F.; 11/3 pounds of thymol, N.F.; 11/3... of any two or more denaturing materials listed under Formula No. 38-B, plus sufficient boric acid, N..., U.S.P., 2.6 fluid ounces of hydrochloric acid, N.F., and a total of 3 pounds of any two or more of...

27 CFR 21.68 - Formula No. 38-F.

Code of Federal Regulations, 2012 CFR

2012-04-01

...) Six pounds of either boric acid, N.F., or Polysorbate 80, N.F.; 11/3 pounds of thymol, N.F.; 11/3... of any two or more denaturing materials listed under Formula No. 38-B, plus sufficient boric acid, N..., U.S.P., 2.6 fluid ounces of hydrochloric acid, N.F., and a total of 3 pounds of any two or more of...

27 CFR 21.68 - Formula No. 38-F.

Code of Federal Regulations, 2010 CFR

2010-04-01

...) Six pounds of either boric acid, N.F., or Polysorbate 80, N.F.; 11/3 pounds of thymol, N.F.; 11/3... of any two or more denaturing materials listed under Formula No. 38-B, plus sufficient boric acid, N..., U.S.P., 2.6 fluid ounces of hydrochloric acid, N.F., and a total of 3 pounds of any two or more of...

27 CFR 21.68 - Formula No. 38-F.

Code of Federal Regulations, 2011 CFR

2011-04-01

...) Six pounds of either boric acid, N.F., or Polysorbate 80, N.F.; 11/3 pounds of thymol, N.F.; 11/3... of any two or more denaturing materials listed under Formula No. 38-B, plus sufficient boric acid, N..., U.S.P., 2.6 fluid ounces of hydrochloric acid, N.F., and a total of 3 pounds of any two or more of...

Biomimetic Engineering of Nanofibrous Gelatin Scaffolds with Noncollagenous Proteins for Enhanced Bone Regeneration

PubMed Central

Sun, Yao; Jiang, Yong; Liu, Qilin; Gao, Tian; Feng, Jian Q.; Dechow, Paul; D'Souza, Rena N.; Qin, Chunlin

2013-01-01

Biomimetic approaches are widely used in scaffolding designs to enhance tissue regeneration. In this study, we integrated noncollagenous proteins (NCPs) from bone extracellular matrix (ECM) with three-dimensional nanofibrous gelatin (NF-Gelatin) scaffolds to form an artificial matrix (NF-Gelatin-NCPs) mimicking both the nano-structured architecture and chemical composition of natural bone ECM. Through a chemical coupling process, the NCPs were evenly distributed over all the surfaces (inner and outer) of the NF-gelatin-NCPs. The in vitro study showed that the number of osteoblasts (MC3T3-E1) on the NF-Gelatin-NCPs was significantly higher than that on the NF-Gelatin after being cultured for 14 days. Both the alkaline phosphatase (ALP) activity and the expression of osteogenic genes (OPN, BSP, DMP1, CON, and Runx2) were significantly higher in the NF-Gelatin-NCPs than in the NF-Gelatin at 3 weeks. Von Kossa staining, backscattered scanning electron microscopy, and microcomputed tomography all revealed a higher amount of mineral deposition in the NF-Gelatin-NCPs than in the NF-Gelatin after in vitro culturing for 3 weeks. The in vivo calvarial defect study indicated that the NF-Gelatin-NCPs recruited more host cells to the defect and regenerated a higher amount of bone than the controls after implantation for 6 weeks. Immunohistochemical staining also showed high-level mineralization of the bone matrix in the NF-Gelatin-NCPs. Taken together, both the in vitro and in vivo results confirmed that the incorporation of NCPs onto the surfaces of the NF-Gelatin scaffold significantly enhanced osteogenesis and mineralization. Biomimetic engineering of the surfaces of the NF-Gelatin scaffold with NCPs, therefore, is a promising strategy to enhance bone regeneration. PMID:23469769

Development of a practical NF1 genetic testing method through the pilot analysis of five Japanese families with neurofibromatosis type 1.

PubMed

Okumura, Akiko; Ozaki, Mamoru; Niida, Yo

2015-08-01

Mutation analysis of NF1, the responsible gene for neurofibromatosis type 1 (NF1), is still difficult due to its large size, lack of mutational hotspots, the presence of many pseudogenes, and its wide spectrum of mutations. To develop a simple and inexpensive NF1 genetic testing for clinical use, we analyzed five Japanese families with NF1 as a pilot study. Our original method, CEL endonuclease mediated heteroduplex incision with polyacrylamide gel electrophoresis and silver staining (CHIPS) was optimized for NF1 mutation screening, and reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the effect of transcription. Also, we employed DNA microarray analysis to evaluate the break points of the large deletion. A new nonsense mutation, p.Gln209(∗), was detected in family 1 and the splicing donor site mutation, c.2850+1G>T, was detected in family 2. In family 3, c.4402A>G was detected in exon 34 and the p.Ser1468Gly missense mutation was predicted. However mRNA analysis revealed that this substitution created an aberrant splicing acceptor site, thereby causing the p.Phe1457(∗) nonsense mutation. In the other two families, type-1 and unique NF1 microdeletions were detected by DNA microarray analysis. Our results show that the combination of CHIPS and RT-PCR effectively screen and characterize NF1 point mutations, and both DNA and RNA level analysis are required to understand the nature of the NF1 mutation. Our results also suggest the possibility of a higher incidence and unique profile of NF1 large deletions in the Japanese population as compared to previous studies performed in Europe. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Regulatory Role of the NF-kB Pathway in Lymphangiogenesis and Breast Cancer Metastasis

DTIC Science & Technology

2010-10-01

Task 3. To determine the effect of anti -inflammatory treatment on VEGFR-3 expression, tumor lymphangiogenesis, lymphatic metastasis, and spread to...breast carcinoma line MDA-MB-231 into the MFP of CB-17 SCID mice and treat them with NF-κB targeting anti -inflammatory drugs, PDTC and dexamethasone...model of human breast cancer is significantly enhanced by concurrent anti -VEGF-A therapy. Neoplasia. 2008 Jun;10(6):613-23. Awards/Presentations

[Clinical and neurophysiological data of neurofeedback therapy in children with ADHD].

PubMed

Kubik, Alicja; Kubik, Paweł; Stanios, Martyna; Kraj, Bogusława

2016-01-01

ADHD occurs in 3% of school-age children (and in 70% of them in adulthood) and represents an important medical and social problem. It is characterized by attention deficits, hyperactivity and impulsiveness. Neurofeedback therapy (EEG biofeedback, NF) is carried out based on the analysis of EEG. To investigate the effect of NF therapy on clinical status and parameters of the EEG in ADHD. In the years 2007-2014, 287 children (191 boys), aged 6-17 years were included into the study. Some children with ADHD had other coexisting disorders like: tics, dyslexia, emotional or behavior disorders. Visual analysis of EEG was made and 7 selected parameters of bioelectrical activity were assessed. EEG tracing before and after NF therapy were compared. NF therapy lasted from 9 months to 3 years (mean 1.5 years). 60-240 NF training sessions were performed with the use of NF device, video-games and 16-channel Elmiko devices. Statistical analysis of the results was made. Children with ADHD additionally presented low self-esteem, anxiety and sleep disorders. The baseline theta/beta ratio in children with ADHD and ADHD with cooccurring dyslexia was >4.0 and in children with ADHD and coexisting tics 3.0-3.8, with coexisting behavioral disorders 3.7-4.0 and emotional disorders 3.3-3.7. After therapy, this ratio decreased significantly in all groups, but most significantly in ADHD and ADHD with dyslexia group. In the group with dyslexia theta and alpha activity in the left fronto-temporo-parietal region (the speech centers) has been increased. In children with ADHD and behavior disorders right-sided paroxysmal changes in the form of slow and sharp waves in the temporo-centro-parietal regions were found. In emotionally disturbed children increased fast beta activity in the right hemisphere (anxiety, fear) was observed. Initially NF therapy reduced hyperactivity and impulsivity of children, subsequently improvement of attention was observed and eventually reduction of emotional and behavior disturbances was noticed. Noticeable improvement in the self-esteem was observed as well. The therapy had a positive impact on the spatial organization of EEG in each group. It proved to be particularly useful in children with ADHD and dyslexia. Neurofeedback therapy is a valuable tool with beneficial impact on children with ADHD and accompanying disorders. Characteristics of brain bioelectric activity provides a reliable basis to establish individual EEG bio-feedback protocols of therapy in children and monitor the effectiveness of treatment. In the last 4 years the number of children with ADHD and cooccurring tics who applied for neurofeedback therapy has increased significantly.

MicroRNA-22 and microRNA-140 suppress NF-{kappa}B activity by regulating the expression of NF-{kappa}B coactivators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takata, Akemi; Otsuka, Motoyuki, E-mail: otsukamo-tky@umin.ac.jp; Kojima, Kentaro

2011-08-12

Highlights: {yields} miRNAs were screened for their ability to regulate NF-{kappa}B activity. {yields} miRNA-22 and miRNA-140-3p suppress NF-{kappa}B activity by regulating coactivators. {yields} miRNA-22 targets nuclear receptor coactivator 1 (NCOA1). {yields} miRNA-140-3p targets nuclear receptor-interacting protein 1 (NRIP1). -- Abstract: Nuclear factor {kappa}B (NF-{kappa}B) is a transcription factor that regulates a set of genes that are critical to many biological phenomena, including liver tumorigenesis. To identify microRNAs (miRNAs) that regulate NF-{kappa}B activity in the liver, we screened 60 miRNAs expressed in hepatocytes for their ability to modulate NF-{kappa}B activity. We found that miRNA-22 and miRNA-140-3p significantly suppressed NF-{kappa}B activity bymore » regulating the expression of nuclear receptor coactivator 1 (NCOA1) and nuclear receptor-interacting protein 1 (NRIP1), both of which are NF-{kappa}B coactivators. Our results provide new information about the roles of miRNAs in the regulation of NF-{kappa}B activity.« less

Enhanced hydrogen production in microbial electrolysis cell with 3D self-assembly nickel foam-graphene cathode.

PubMed

Cai, Weiwei; Liu, Wenzong; Han, Jinglong; Wang, Aijie

2016-06-15

In comparison to precious metal catalyst especially Platinum (Pt), nickel foam (NF) owned cheap cost and unique three-dimensional (3D) structure, however, it was scarcely applied as cathode material in microbial electrolysis cell (MEC) as the intrinsic laggard electrochemical activity for hydrogen recovery. In this study, a self-assembly 3D nickel foam-graphene (NF-G) cathode was fabricated by facile hydrothermal approach for hydrogen evolution in MECs. Electrochemical analysis (linear scan voltammetry and electrochemical impedance spectroscopy) revealed the improved electrochemical activity and effective mass diffusion after coating with graphene. NF-G as cathode in MEC showed a significant enhancement in hydrogen production rate compared with nickel foam at a variety of biases. Noticeably, NF-G showed a comparable averaged hydrogen production rate (1.31 ± 0.07 mL H2 mL(-1) reactor d(-1)) to Platinum/carbon (Pt/C) (1.32 ± 0.07 mL H2 mL(-1) reactor d(-1)) at 0.8 V. Profitable energy recovery could be achieved by NF-G cathode at higher applied voltage, which performed the best hydrogen yield of 3.27 ± 0.16 mol H2 mol(-1) acetate at 0.8 V and highest energy efficiency of 185.92 ± 6.48% at 0.6 V. Copyright © 2016 Elsevier B.V. All rights reserved.

The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes.

PubMed

Watchorn, Tammy M; Dowidar, Nabil; Dejong, Cornelis H C; Waddell, Ian D; Garden, O James; Ross, James A

2005-10-01

A novel proteoglycan, proteolysis inducing factor (PIF), is capable of inducing muscle proteolysis during the process of cancer cachexia, and of inducing an acute phase response in human hepatocytes. We investigated whether PIF is able to activate pro-inflammatory pathways in human Kupffer cells, the resident macrophages of the liver, and in monocytes, resulting in the production of pro-inflammatory cytokines. Normal liver tissue was obtained from patients undergoing partial hepatectomy and Kupffer cells were isolated. Monocytes were isolated from peripheral blood. Following exposure to native PIF, pro-inflammatory cytokine production from Kupffer cells and monocytes was measured and the NF-kappaB and STAT3 transcriptional pathways were investigated using electrophoretic mobility shift assays. We demonstrate that PIF is able to activate the transcription factor NF-kappaB and NF-kappaB-inducible genes in human Kupffer cells, and in monocytes, resulting in the production of pro-inflammatory cytokines such as TNF-alpha, IL-8 and IL-6. PIF enhances the expression of the cell surface molecules LFA-1 and CD14 on macrophages. PIF also activates the transcription factor STAT3 in Kupffer cells. The pro-inflammatory effects of PIF, mediated via NF-kappaB and STAT3, are important in macrophage behaviour and may contribute to the inflammatory pro-cachectic process in the liver.

NF-κB is involved in the LPS-mediated proliferation and apoptosis of MAC-T epithelial cells as part of the subacute ruminal acidosis response in cows.

PubMed

Fan, Wen-Jie; Li, He-Ping; Zhu, He-Shui; Sui, Shi-Ping; Chen, Pei-Ge; Deng, Yue; Sui, Tong-Ming; Wang, Yue-Ying

2016-11-01

To determine the effect of NF-κB on cell proliferation and apoptosis, we investigate the expression of inflammation and apoptosis-related factors in the bovine mammary epithelial cell line, MAC-T. MAC-T cells were cultured in vitro and MTT and LDH assays used to determine the effects of lipopolysaccharide (LPS) on proliferation and cytotoxicity respectively. RT-PCR and western blotting were used to evaluate the effect of LPS and NF-κB inhibition [pyrrolidine dithiocarbamate (PDTC) treatment] on the expression of inflammation and apoptosis-related factors. LPS significantly inhibited MAC-T cell proliferation in a dose- and time-dependent manner. Furthermore, LPS promoted apoptosis while the NF-кB inhibitor PDTC attenuated this effect. After LPS treatment, the NF-кB signaling pathway was activated, and the expression of inflammation and apoptosis-related factors increased. When PDTC blocked NF-кB signaling, the expression of inflammation and apoptosis-related factors were decreased in MAC-T cells. LPS activates the TLR4/NF-κB signaling pathway, inhibits proliferation and promotes apoptosis in MAC-T cells. NF-кB inhibition attenuates MAC-T cell apoptosis and TLR4/NF-κB signaling pathway. NF-кB inhibitor alleviating MAC-T cell apoptosis is presumably modulated by NF-кB.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, M.; Soppet, W.K.; Rink, D.L.

This report provides an update on the evaluation of thermal-aging induced degradation of tensile properties of advanced ferritic-martensitic steels. The report is the first deliverable (level 3) in FY11 (M3A11AN04030103), under the Work Package A-11AN040301, 'Advanced Alloy Testing' performed by Argonne National Laboratory, as part of Advanced Structural Materials Program for the Advanced Reactor Concepts. This work package supports the advanced structural materials development by providing tensile data on aged alloys and a mechanistic model, validated by experiments, with a predictive capability on long-term performance. The scope of work is to evaluate the effect of thermal aging on the tensilemore » properties of advanced alloys such as ferritic-martensitic steels, mod.9Cr-1Mo, NF616, and advanced austenitic stainless steel, HT-UPS. The aging experiments have been conducted over a temperature of 550-750 C for various time periods to simulate the microstructural changes in the alloys as a function of time at temperature. In addition, a mechanistic model based on thermodynamics and kinetics has been used to address the changes in microstructure of the alloys as a function of time and temperature, which is developed in the companion work package at ANL. The focus of this project is advanced alloy testing and understanding the effects of long-term thermal aging on the tensile properties. Advanced materials examined in this project include ferritic-martensitic steels mod.9Cr-1Mo and NF616, and austenitic steel, HT-UPS. The report summarizes the tensile testing results of thermally-aged mod.9Cr-1Mo, NF616 H1 and NF616 H2 ferritic-martensitic steels. NF616 H1 and NF616 H2 experienced different thermal-mechanical treatments before thermal aging experiments. NF616 H1 was normalized and tempered, and NF616 H2 was normalized and tempered and cold-rolled. By examining these two heats, we evaluated the effects of thermal-mechanical treatments on material microstructures and associated mechanical properties during long-term aging at elevated temperatures. Thermal aging experiments at different temperatures and periods of time have been completed: 550 C for up to 5000 h, 600 C for up to 7500 h, and 650 C for more than 10,000 h. Tensile properties were measured on thermally aged specimens and aging effect on tensile behavior was assessed. Effects of thermal aging on deformation and failure mechanisms were investigated by using in-situ straining technique with simultaneous synchrotron XRD measurements.« less

Overexpression of StNF-YB3.1 reduces photosynthetic capacity and tuber production, and promotes ABA-mediated stomatal closure in potato (Solanum tuberosum L.).

PubMed

Xuanyuan, Guochao; Lu, Congming; Zhang, Ruofang; Jiang, Jiming

2017-08-01

Nuclear factor Y (NF-Y) is one of the most ubiquitous transcription factors (TFs), comprising NF-YA, NF-YB and NF-YC subunits, and has been identified and reported in various aspects of development for plants and animals. In this work, StNF-YB3.1, a putative potato NF-YB subunit encoding gene, was isolated from Solanum tuberosum by rapid amplification of cDNA ends (RACE). Overexpression of StNF-YB3.1 in potato (cv. Atlantic) resulted in accelerated onset of flowering, and significant increase in leaf chlorophyll content in field trials. However, transgenic potato plants overexpressing StNF-YB3.1 (OEYB3.1) showed significant decreases in photosynthetic rate and stomatal conductance both at tuber initiation and bulking stages. OEYB3.1 lines were associated with significantly fewer tuber numbers and yield reduction. Guard cell size and stomatal density were not changed in OEYB3.1 plants, whereas ABA-mediated stomatal closure was accelerated compared to that of wild type plants because of the up-regulation of genes for ABA signaling, such as StCPK10-like, StSnRK2.6/OST1-like, StSnRK2.7-like and StSLAC1-like. We speculate that the acceleration of stomatal closure was a possible reason for the significantly decreased stomatal conductance and photosynthetic rate. Copyright © 2017 Elsevier B.V. All rights reserved.

Flavocoxid counteracts muscle necrosis and improves functional properties in mdx mice: a comparison study with methylprednisolone.

PubMed

Messina, Sonia; Bitto, Alessandra; Aguennouz, M'hammed; Mazzeo, Anna; Migliorato, Alba; Polito, Francesca; Irrera, Natasha; Altavilla, Domenica; Vita, Gian Luca; Russo, Massimo; Naro, Antonino; De Pasquale, Maria Grazia; Rizzuto, Emanuele; Musarò, Antonio; Squadrito, Francesco; Vita, Giuseppe

2009-12-01

Muscle degeneration in dystrophic muscle is exacerbated by the endogenous inflammatory response and increased oxidative stress. A key role is played by nuclear factor(NF)-kappaB. We showed that NF-kappaB inhibition through compounds with also antioxidant properties has beneficial effects in mdx mice, the murine model of Duchenne muscular dystrophy (DMD), but these drugs are not available for clinical studies. We evaluated whether flavocoxid, a mixed flavonoid extract with anti-inflammatory, antioxidant and NF-kappaB inhibiting properties, has beneficial effects in mdx mice in comparison with methylprednisolone, the gold standard treatment for DMD patients. Five-week-old mdx mice were treated for 5 weeks with flavocoxid, methylprednisolone or vehicle. The evaluation of in vivo and ex vivo functional properties and morphological parameters was performed. Serum samples were assayed for oxidative stress markers, creatine-kinase (CK) and leukotriene B-4. Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), tumor necrosis factor-alpha, p-38, JNK1 expression was evaluated in muscle by western blot analysis. NF-kappaB binding activity was investigated by electrophoresis mobility shift assay. The administration of flavocoxid: (1) ameliorated functional properties in vivo and ex vivo; (2) reduced CK; (3) reduced the expression of oxidative stress markers and of inflammatory mediators; (4) inhibited NF-kappaB and mitogen-activated protein kinases (MAPKs) signal pathways; (5) reduced muscle necrosis and enhanced regeneration. Our results highlight the detrimental effects of oxidative stress and NF-kappaB, MAPKs and COX/5-LOX pathways in the dystrophic process and show that flavocoxid is more effective in mdx mice than methylprednisolone.

Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis.

PubMed

Louvrier, Camille; Pasmant, Eric; Briand-Suleau, Audrey; Cohen, Joëlle; Nitschké, Patrick; Nectoux, Juliette; Orhant, Lucie; Zordan, Cécile; Goizet, Cyril; Goutagny, Stéphane; Lallemand, Dominique; Vidaud, Michel; Vidaud, Dominique; Kalamarides, Michel; Parfait, Béatrice

2018-06-18

Clinical overlap between neurofibromatosis type 2 (NF2), schwannomatosis, and meningiomatosis can make clinical diagnosis difficult. Hence, molecular investigation of germline and tumor tissues may improve the diagnosis. We present the targeted next-generation sequencing (NGS) of NF2, SMARCB1, LZTR1, SMARCE1, and SUFU tumor suppressor genes, using an amplicon-based approach. We analyzed blood DNA from a cohort of 196 patients, including patients with NF2 (N = 79), schwannomatosis (N = 40), meningiomatosis (N = 12), and no clearly established diagnosis (N = 65). Matched tumor DNA was analyzed when available. Forty-seven NF2-/SMARCB1-negative schwannomatosis patients and 27 NF2-negative meningiomatosis patients were also evaluated. A NF2 variant was found in 41/79 (52%) NF2 patients. SMARCB1 or LZTR1 variants were identified in 5/40 (12.5%) and 13/40 (∼32%) patients in the schwannomatosis cohort. Potentially pathogenic variants were found in 12/65 (18.5%) patients with no clearly established diagnosis. A LZTR1 variant was identified in 16/47 (34%) NF2/SMARCB1-negative schwannomatosis patients. A SMARCE1 variant was found in 3/39 (∼8%) meningiomatosis patients. No SUFU variant was found in the cohort. NGS was an effective and sensitive method to detect mutant alleles in blood or tumor DNA of mosaic NF2 patients. Interestingly, we identified a 4-hit mechanism resulting in the complete NF2 loss-of-function combined with SMARCB1 and LZTR1 haploinsufficiency in two-thirds of tumors from NF2 patients. Simultaneous investigation of NF2, SMARCB1, LZTR1, and SMARCE1 is a key element in the differential diagnosis of NF2, schwannomatosis, and meningiomatosis. The targeted NGS strategy is suitable for the identification of NF2 mosaicism in blood and for the investigation of tumors from these patients.

Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p38.

PubMed

Jang, Se-Eun; Ryu, Kwon-Ryeol; Park, Sung-Hwan; Chung, Suna; Teruya, Yuto; Han, Myung Joo; Woo, Je-Tae; Kim, Dong-Hyun

2013-11-01

Nobiletin and tangeretin are polymethoxy flavonoids that are abundantly present in the pericarp of Citrus unshiu (family Rutaceae) and the fruit of Citrus depressa (family Rutaceae). They exhibit various biological activities, including anti-inflammatory and anti-asthmatic effects. To evaluate the anti-allergic effects of nobiletin and tangeretin, we measured their inhibitory effects in histamine- or compound 48/80-induced scratching behavioral mice. Nobiletin and tangeretin potently inhibited scratching behavior, as well as histamine-induced vascular permeability. Furthermore, they inhibited the expression of the allergic cytokines, IL-4 and TNF-α as well as the activation of their transcription factors NF-κB, AP-1 and p38 in histamine-stimulated skin tissues. They also inhibited the expression of IL-4 and TNF-α and the activation of NF-κB and c-jun in PMA-stimulated RBL-2H3 cells. Furthermore, nobiletin and tangeretin inhibited protein kinase C (PKC) activity and the IgE-induced degranulation of RBL-2H3 cells. These agents showed potent anti-histamine effect through the Magnus test when guinea pig ileum was used. Based on these results, nobiletin and tangeretin may ameliorate scratching behavioral reactions by inhibiting the action of histamine as well as the activation of the transcription factors NF-κB and AP-1 via PKC. © 2013.

The Anti-Atherosclerotic Effect of Naringin Is Associated with Reduced Expressions of Cell Adhesion Molecules and Chemokines through NF-κB Pathway.

PubMed

Hsueh, Tun-Pin; Sheen, Jer-Ming; Pang, Jong-Hwei S; Bi, Kuo-Wei; Huang, Chao-Chun; Wu, Hsiao-Ting; Huang, Sheng-Teng

2016-02-05

Naringin has been reported to have an anti-atherosclerosis effect but the underlying mechanism is not fully understood. The aim of this study is to investigate the impact of naringin on the TNF-α-induced expressions of cell adhesion molecules, chemokines and NF-κB signaling pathway in human umbilical vein endothelial cells (HUVECs). The experiments revealed that naringin, at concentrations without cytotoxicity, dose-dependently inhibited the adhesion of THP-1 monocytes to the TNF-α-stimulated HUVECs. The TNF-α-induced expressions of cell adhesion molecules, including VCAM-1, ICAM-1 and E-selectin, at both the mRNA and protein levels, were significantly suppressed by naringin in a dose dependent manner. In addition, the TNF-α-induced mRNA and protein levels of chemokines, including fractalkine/CX3CL1, MCP-1 and RANTES, were also reduced by naringin. Naringin significantly inhibited TNF-α-induced nuclear translocation of NF-κB, which resulted from the inhibited phosphorylation of IKKα/β, IκB-α and NF-κB. Altogether, we proposed that naringin modulated TNF-α-induced expressions of cell adhesion molecules and chemokines through the inhibition of TNF-α-induced activation of IKK/NF-κB signaling pathway to exert the anti-atherosclerotic effect.

Anti-inflammatory effects of vinpocetine on the functional expression of nuclear factor-kappa B and tumor necrosis factor-alpha in a rat model of cerebral ischemia-reperfusion injury.

PubMed

Wang, Hongxin; Zhang, Kan; Zhao, Lan; Tang, Jiangwei; Gao, Luyan; Wei, Zhongping

2014-04-30

The restoration of blood flow to the brain after ischemic stroke prevents further, extensive damage but can result in reperfusion injury. The inflammation response is one of many factors involved in cerebral ischemia-reperfusion injury. This study investigated the use of vinpocetine, a drug used to treat cognitive impairment, to explore its effects on inflammation in a rat model of cerebral ischemia-reperfusion. Wistar rats were randomly assigned to a control group, (n=40) a cerebral ischemia-reperfusion group (n=52) and a vinpocetine cerebral ischemia-reperfusion group (n=52). A model of middle cerebral artery occlusion was induced for 2h followed by reperfusion and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining 6h, 24h, 3 days, and 7 days after reperfusion. The dry-wet weight method was used to measure brain water content and evaluate the extent of brain edema. Immunohistochemistry and in-situ hybridization were used to detect the expression of NF-κB and TNF-α. The NF-κB levels in ischemic brain tissue increased 6h after reperfusion and the TNF-α levels increased at 24h, both reached their peaks at day 3 then decreased gradually, but remained above the controls at day 7. Vinpocetine decreased the levels of NF-κB and TNF-α 24h and 3 days after reperfusion. NF-κB and TNF-α is associated with changes in brain edema and infarct volume. Vinpocetine decreases the expression of NF-κB and TNF-α and inhibits the inflammatory response after cerebral ischemia-reperfusion. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Matrine displayed antiviral activity in porcine alveolar macrophages co-infected by porcine reproductive and respiratory syndrome virus and porcine circovirus type 2

PubMed Central

Sun, Na; Sun, Panpan; Lv, Haipeng; Sun, Yaogui; Guo, Jianhua; Wang, Zhirui; Luo, Tiantian; Wang, Shaoyu; Li, Hongquan

2016-01-01

The co-infection of porcine reproductive respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) is quite common in clinical settings and no effective treatment to the co-infection is available. In this study, we established the porcine alveolar macrophages (PAM) cells model co-infected with PRRSV/PCV2 with modification in vitro, and investigated the antiviral activity of Matrine on this cell model and further evaluated the effect of Matrine on virus-induced TLR3,4/NF-κB/TNF-α pathway. The results demonstrated PAM cells inoculated with PRRSV followed by PCV2 2 h later enhanced PRRSV and PCV2 replications. Matrine treatment suppressed both PRRSV and PCV2 infection at 12 h post infection. Furthermore, PRRSV/PCV2 co- infection induced IκBα degradation and phosphorylation as well as the translocation of NF-κB from the cytoplasm to the nucleus indicating that PRRSV/PCV2 co-infection induced NF-κB activation. Matrine treatment significantly down-regulated the expression of TLR3, TLR4 and TNF-α although it, to some extent, suppressed p-IκBα expression, suggesting that TLR3,4/NF-κB/TNF-α pathway play an important role of Matrine in combating PRRSV/PCV2 co-infection. It is concluded that Matrine possesses activity against PRRSV/PCV2 co-infection in vitro and suppression of the TLR3,4/NF-κB/TNF-α pathway as an important underlying molecular mechanism. These findings warrant Matrine to be further explored for its antiviral activity in clinical settings. PMID:27080155

Compressive force induces osteoclast differentiation via prostaglandin E(2) production in MC3T3-E1 cells.

PubMed

Sanuki, Rina; Shionome, Chieko; Kuwabara, Akiko; Mitsui, Narihiro; Koyama, Yuki; Suzuki, Naoto; Zhang, Fan; Shimizu, Noriyoshi; Maeno, Masao

2010-04-01

In orthodontic tooth movement, prostaglandin E(2) (PGE(2)) released from osteoblasts can alter the normal process of bone remodeling. We previously showed that compressive force (CF) controls bone formation by stimulating the production of PGE(2) and Ep2 and/or Ep4 receptors in osteoblasts. The present study was undertaken to examine the effect of CF on the production of PGE(2), cyclooxygenase-2 (COX-2), macrophage colony-stimulating factor (M-CSF), receptor activator of NF-kappaB ligand (RANKL), and osteoprotegerin (OPG) using osteoblastic MC3T3-E1 cells and to examine the indirect effect of CF on osteoclast differentiation using RAW264.7 cells as osteoclast precursors. MC3T3-E1 cells were cultured with or without continuous CF (1.0 or 3.0 g/cm(2)) for 24 hr, and PGE(2) production was determined using ELISA. The expression of COX-2, M-CSF, RANKL, and OPG genes and proteins was determined using real-time PCR and ELISA, respectively. Osteoclast differentiation was estimated using tartrate-resistant acid phosphatase (TRAP) staining of RAW 264.7 cells cultured for 10 days with conditioned medium from CF-treated MC3T3-E1 cells and soluble RANKL. As CF increased, PGE(2) production and the expression of COX-2, M-CSF, and RANKL increased, whereas OPG expression decreased. The number of TRAP-positive cells increased as CF increased. Celecoxib, a specific inhibitor of COX-2, blocked the stimulatory effect of CF on TRAP staining and the production of PGE(2), M-CSF, RANKL, and OPG. These results suggest that CF induces osteoclast differentiation by increasing M-CSF production and decreasing OPG production via PGE(2) in osteoblasts.

A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry.

PubMed

Zucchi, Elisabetta; Lu, Ching-Hua; Cho, Yunju; Chang, Rakwoo; Adiutori, Rocco; Zubiri, Irene; Ceroni, Mauro; Cereda, Cristina; Pansarasa, Orietta; Greensmith, Linda; Malaspina, Andrea; Petzold, Axel

2018-06-30

Neurofilament proteins (Nf) are a biomarker of disease progression in amyotrophic lateral sclerosis (ALS). This study investigated whether there are major differences in expression from in vivo measurements of neurofilament isoforms, from the light chain, NfL (68 kDa), compared to larger proteins, the medium chain (NfM, 150 kDa) and the heavy (NfH, 200-210 kDa) chains in ALS patients and healthy controls. New immunological methods were combined with Nf subunit stoichiometry calculations and Monte-Carlo simulations of a coarse-grained Nf brush model. Based on a physiological Nf subunit stoichiometry of 7:3:2 (NfL:NfM:NfH) we found an "adaptive" Nf subunit stoichiometry of 24:2.4:1.6 in ALS. Adaptive Nf stoichiometry preserved NfL gyration radius in the Nf brush model. The energy and time requirements for Nf translation were 56±27k ATP (5.6 hours) in control subjects compared to 123±102k (12.3 h) in ALS with "adaptive" Nf stoichiometry (not significant) and increased significantly to 355±330k (35.5 h) with "luxury" Nf subunit stoichiometry (p<0.0001 for each comparison). Longitudinal disease progression related energy consumption was highest with a "luxury" Nf stoichiometry. Therefore, an energy and time saving option for motor neurons is to shift protein expression from larger to smaller (cheaper) subunits, at little or no costs on a protein structural level, to compensate for increased energy demands. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Valsartan attenuates bleomycin-induced pulmonary fibrosis by inhibition of NF-κB expression and regulation of Th1/Th2 cytokines.

PubMed

Mojiri-Forushani, Hoda; Hemmati, Ali Asghar; Khodadadi, Ali; Rashno, Mohammad

2018-06-01

Pulmonary fibrosis (PF) is a chronic respiratory system disease. The role of inflammation and angiotensin in the development and progression of PF has previously been demonstrated. Alternation in antifibrotic/profibrotic mediators and NF-κB activation have important roles in PF development. NF-κB, a nuclear factor, induces the transcription of inflammatory and pro-inflammatory cytokines. The aim of this study was to evaluate the effect of valsartan as an angiotensin receptor blocker on IL-4, INF-γ, and NF-κB expression in the treatment of PF. Rats were divided into five groups: groups I (bleomycin) and II (control) received a single injection of bleomycin (7.5 IU/kg) or vehicle, respectively. Groups III-V received valsartan (20, 40, and 80 mg/kg, respectively) orally a week before and for 3 weeks after the bleomycin injection. Serum levels of IL-4 and INF- γ were then measured. Relative NF-κB expression was investigated by real-time PCR. Histopathological examination showed the anti-inflammation effect of valsartan. Bleomycin significantly increased IL-4 serum level and decreased that of INF-γ in the serum. Valsartan could restore their levels to normal. Valsartan raised the decreased ratio of INF-γ/IL-4. Exposure to bleomycin elevated NF-κB expression; and valsartan decreased the increased gene expression. Valsartan as an angiotensin receptor antagonist presumably by blocking angiotensin receptor causes to ameliorated PF, which was at least partly due to antifibrotic/profibrotic cytokine regulation and reduced NF-κB expression. Valsartan showed a significant protective effect against bleomycin-induced PF.

CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP.

PubMed

Rojas, Julio C; Bang, Jee; Lobach, Iryna V; Tsai, Richard M; Rabinovici, Gil D; Miller, Bruce L; Boxer, Adam L

2018-01-23

To determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP). We compared the ability of baseline CSF β-amyloid 1-42 , tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients. Higher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS ( p = 0.004, false discovery rate-corrected) and SEADL ( p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS ( p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL ( p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau ( p = 0.003) or NfL ( p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively). Both CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease. Copyright © 2017 American Academy of Neurology.

Intake of Fish and Omega-3 (N-3) Fatty Acid: Effect on Humans during Actual and Simulated Weightlessness

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Mehta, Satish K.; Pierson, Duane L.; Zwart, Sara R.

2009-01-01

Space flight has many negative effects on human physiology, including bone and muscle loss. These are some of the systems on which intakes of fish and n-3 fatty acids have positive effects. These effects are likely to occur through inhibition of inflammatory cytokines (such as TNFalpha) and thus inhibition of downstream NF-KB activation. We documented this effect in a 3D cell culture model, where NF-KB activation in osteoclasts was inhibited by eicosapentaenoic acid, an n-3 fatty acid. We have extended these studies and report here (a) NF-KB expression in peripheral blood mononuclear cells of Space Shuttle crews on 2-wk missions, (b) the effects of n-3 fatty acid intake after 60 d of bed rest (a weightlessness analog), and (c) the effects of fish intake in astronauts after 4 to 6 mo on the International Space Station. After Shuttle flights of 2 wk, NFKB p65 expression at landing was increased (P less than 0.001). After 60 d of bed rest, higher intake of n-3 fatty acids was associated with less N-telopeptide excretion (Pearson r = -0.62, P less than 0.05). Higher consumption of fish during flight was associated with higher bone mineral density (Pearson r = -0.46, P less than 0.05). Together with our earlier findings, these data provide mechanistic cellular and preliminary human evidence of the potential for n-3 fatty acids to counteract bone loss associated with spaceflight. This study was supported by the NASA Human Research Program.

A herbal formula comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos inhibits the production of inflammatory mediators and the IRAK-1/TAK1 and TBK1/IRF3 pathways in RAW 264.7 and THP-1 cells.

PubMed

Cheng, Brian Chi Yan; Yu, Hua; Su, Tao; Fu, Xiu-Qiong; Guo, Hui; Li, Ting; Cao, Hui-Hui; Tse, Anfernee Kai-Wing; Kwan, Hiu-Yee; Yu, Zhi-Ling

2015-11-04

As documented in the Chinese Materia Medica Grand Dictionary (), a herbal formula (RL) consisting of Rosae Multiflorae Fructus (multiflora rose hips) and Lonicerae Japonicae Flos (Japanese honeysuckle flowers) has traditionally been used in treating inflammatory disorders. RL was previously reported to inhibit the expression of various inflammatory mediators regulated by NF-κB and MAPKs that are components of the TLR4 signalling pathways. This study aims to provide further justification for clinical application of RL in treating inflammatory disorders by further delineating the involvement of the TLR4 signalling cascades in the effects of RL on inflammatory mediators. RL consisting of Rosae Multiflorae Fructus and Lonicerae Japonicae Flos (in 5:3 ratio) was extracted using absolute ethanol. We investigated the effect of RL on the production of cytokines and chemokines that are regulated by three key transcription factors of the TLR4 signalling pathways AP-1, NF-κB and IRF3 in LPS-stimulated RAW264.7 cells using the multiplex biometric immunoassay. Phosphorylation of AP-1, NF-κB, IRF3, IκB-α, IKKα/β, Akt, TAK1, TBK1, IRAK-1 and IRAK-4 were examined in LPS-stimulated RAW264.7 cells and THP-1 cells using Western blotting. Nuclear localizations of AP-1, NF-κB and IRF3 were also examined using Western blotting. RL reduced the secretion of various pro-inflammatory cytokines and chemokines regulated by transcription factors AP-1, NF-κB and IRF3. Phosphorylation and nuclear protein levels of these transcription factors were decreased by RL treatment. Moreover, RL inhibited the activation/phosphorylation of IκB-α, IKKα/β, TAK1, TBK1 and IRAK-1. Suppression of the IRAK-1/TAK1 and TBK1/IRF3 signalling pathways was associated with the effect of RL on inflammatory mediators in LPS-stimulated RAW264.7 and THP-1 cells. This provides further pharmacological basis for the clinical application of RL in the treatment of inflammatory disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

NIK is required for NF-κB-mediated induction of BAG3 upon inhibition of constitutive protein degradation pathways.

PubMed

Rapino, F; Abhari, B A; Jung, M; Fulda, S

2015-03-12

Recently, we reported that induction of the co-chaperone Bcl-2-associated athanogene 3 (BAG3) is critical for recovery of rhabdomyosarcoma (RMS) cells after proteotoxic stress upon inhibition of the two constitutive protein degradation pathways, that is, the ubiquitin-proteasome system by Bortezomib and the aggresome-autophagy system by histone deacetylase 6 (HDAC6) inhibitor ST80. In the present study, we investigated the molecular mechanisms mediating BAG3 induction under these conditions. Here, we identify nuclear factor-kappa B (NF-κB)-inducing kinase (NIK) as a key mediator of ST80/Bortezomib-stimulated NF-κB activation and transcriptional upregulation of BAG3. ST80/Bortezomib cotreatment upregulates mRNA and protein expression of NIK, which is accompanied by an initial increase in histone H3 acetylation. Importantly, NIK silencing by siRNA abolishes NF-κB activation and BAG3 induction by ST80/Bortezomib. Furthermore, ST80/Bortezomib cotreatment stimulates NF-κB transcriptional activity and upregulates NF-κB target genes. Genetic inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) or by knockdown of p65 blocks the ST80/Bortezomib-stimulated upregulation of BAG3 mRNA and protein expression. Interestingly, inhibition of lysosomal activity by Bafilomycin A1 inhibits ST80/Bortezomib-stimulated IκBα degradation, NF-κB activation and BAG3 upregulation, indicating that IκBα is degraded via the lysosome in the presence of Bortezomib. Thus, by demonstrating a critical role of NIK in mediating NF-κB activation and BAG3 induction upon ST80/Bortezomib cotreatment, our study provides novel insights into mechanisms of resistance to proteotoxic stress in RMS.

Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats.

PubMed

Li, Jian-Mei; Ge, Chen-Xu; Xu, Min-Xuan; Wang, Wei; Yu, Rong; Fan, Chen-Yu; Kong, Ling-Dong

2015-02-01

Hypothalamic astrogliosis and inflammation cause neural injury, playing a critical role in metabolic syndrome development. This study investigated whether and how fructose caused hypothalamic astrogliosis and inflammation in vivo and in vitro. The inhibitory effects of betaine on hypothalamic neural injury, astrogliosis, and inflammation were explored to address its improvement of fructose-induced metabolic syndrome. Rats or astrocytes were exposed to fructose and then treated with betaine. Neural injury, proinflammatory markers, Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway, and histone deacetylases 3 (HDAC3) expressions were evaluated. The reduction of pro-opiomelanocortin and melanocortin 4 receptor positive neurons in fructose-fed rats was ameliorated by betaine. Moreover, fructose induced astrogliosis and proinflammatory cytokine production by increasing TLR4, MyD88 (where MyD88 is myeloid differentiation factor 88), and NF-κB expression in rat hypothalamus and astrocytes. HDAC3 overexpression preserved the prolonged inflammation in fructose-stimulated astrocytes by regulating nuclear NF-κB-dependent transcription. Betaine suppressed TLR4/NF-κB pathway activation and HDAC3 expression, contributing to its inhibition of hypothalamic astrogliosis and inflammation in animal and cell models. These findings suggest that betaine inhibits fructose-caused astrogliosis and inflammation by the suppression of TLR4/NF-κB pathway activation and HDAC3 expression to protect against hypothalamic neural injury, which, at least partly, contributes to the improvement of fructose-induced metabolic syndrome. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The regulation of Jmjd3 upon the expression of NF-κB downstream inflammatory genes in LPS activated vascular endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Shaoqing; Graduate School of Medicine, Nanchang University, Nanchang; Chen, Xia

Inflammatory mediators and adhesion molecules have been implicated in a variety of diseases including atherosclerosis. As both the mediator-releasing and targeted cells, vascular endothelial cells play key role in pathological processes. NF-κB signaling regulates a cluster of inflammatory factors in LPS-activated vascular endothelial cells but the underlying mechanisms remain largely unknown. Here, we investigated the epigenetic regulation of LPS upon the expression of inflammatory mediators and adhesion molecules. We found that LPS treatment promoted jmjd3 expression, enhanced Jmjd3 nuclear accumulation in human vascular endothelial cells. In addition, LPS enhanced the demethylation of H3K27me3, a specific substrate of Jmjd3. LPS treatmentmore » recruited Jmjd3 and NF-κB to the promoter region of target genes, suggesting Jmjd3 synergizes with NF-κB to activate the expression of target genes. We further found that Jmjd3 attenuated the methylation status in promoter region of target genes, culminating in target gene expression. Our findings unveil epigenetic regulations of LPS upon NF-κB pathway and identify Jmjd3 as a critical modulator of NF-κB pathway and potential therapeutic target for NF-κB related diseases including atherosclerosis.« less

Smoothing single-crystalline SiC surfaces by reactive ion etching using pure NF{sub 3} and NF{sub 3}/Ar mixture gas plasmas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tasaka, Akimasa, E-mail: aki-tasaka-load@yahoo.co.jp; Kotaka, Yuki; Oda, Atsushi

2014-09-01

In pure NF{sub 3} plasma, the etching rates of four kinds of single-crystalline SiC wafer etched at NF{sub 3} pressure of 2 Pa were the highest and it decreased with an increase in NF{sub 3} pressure. On the other hand, they increased with an increase in radio frequency (RF) power and were the highest at RF power of 200 W. A smooth surface was obtained on the single-crystalline 4H-SiC after reactive ion etching at NF{sub 3}/Ar gas pressure of 2 Pa and addition of Ar to NF{sub 3} plasma increased the smoothness of SiC surface. Scanning electron microscopy observation revealed that the numbermore » of pillars decreased with an increase in the Ar-concentration in the NF{sub 3}/Ar mixture gas. The roughness factor (R{sub a}) values were decreased from 51.5 nm to 25.5 nm for the As-cut SiC, from 0.25 nm to 0.20 nm for the Epi-SiC, from 5.0 nm to 0.7 nm for the Si-face mirror-polished SiC, and from 0.20 nm to 0.16 nm for the C-face mirror-polished SiC by adding 60% Ar to the NF{sub 3} gas. Both the R{sub a} values of the Epi- and the C-face mirror-polished wafer surfaces etched using the NF{sub 3}/Ar (40:60) plasma were similar to that treated with mirror polishing, so-called the Catalyst-Referred Etching (CARE) method, with which the lowest roughness of surface was obtained among the chemical mirror polishing methods. Etching duration for smoothing the single-crystalline SiC surface using its treatment was one third of that with the CARE method.« less

Ni-Co nanoparticles immobilized on a 3D Ni foam template as a highly efficient catalyst for borohydride electrooxidation in alkaline medium

NASA Astrophysics Data System (ADS)

Guo, Meisong; Cheng, Yu; Yu, Yanan; Hu, Jingbo

2017-09-01

Proton exchange membrane (PEM) fuel cells have drawn a great deal of attention due to the rapidly growing energy consumption. Recently, Ni- and Co-based materials have been considered as promising electorcatalysts owing to their multi-functionality. In this work, Ni and Co nanoparticles are directly immobilized on a three-dimensional Ni foam substrate (Ni-Co/NF) without any conductive agents or polymer binder by a facile ion implantation method. The structure and morphology of the Ni-Co/NF electrode were characterized by scanning electron microscopy, powder X-ray diffraction, and X-ray photoelectron spectroscopy. The performance of the Ni-Co/NF electrode in the electrochemical oxidation of NaBH4 is investigated by cyclic voltammetry and chronoamperometry. The Ni-Co/NF electrode exhibited excellent electrocatalytic activity and good stability during electrochemical reactions. These properties are attributed to the 3D porous structure of the Ni foam and the synergistic effect of Ni and Co nanoparticles. The enhanced electrocatalytic performance in NaBH4 electrooxidation compared with either Ni or Co nanoparticles alone suggests that the Ni-Co/NF is promising for fuel cell applications.

High-performance polyamide thin-film composite nanofiltration membrane: Role of thermal treatment

NASA Astrophysics Data System (ADS)

Liu, Baicang; Wang, Shuai; Zhao, Pingju; Liang, Heng; Zhang, Wen; Crittenden, John

2018-03-01

Nanofiltration (NF) membranes have many excellent applications (e.g., removing multivalent ions and pretreating water before reverse osmosis, RO), but their relatively high cost limits their application. Especially in recent years, researchers have paid substantial attention to reducing the cost of NF membranes. In this paper, high-performance NF membranes were fabricated using interfacial polymerization (IP) methods. The polymer concentration, IP solution concentration, and thermal treatment conditions were varied. The synthesized membranes were characterized using scanning electron microscopy (SEM), atomic force microscopy (AFM), a contact angle goniometer, X-ray photoelectron spectroscopy (XPS), attenuated total reflectance fourier transform infrared (ATR-FTIR) spectroscopy, and performance tests. The results show that water flux was significantly improved using a hot-water thermal treatment method. Our fabricated thermal-treated NF membrane had an approximately 15% higher water permeability with a value of 13.6 L/(m2 h bar) than that of the commercially available GE HL membrane with a value of 11.8 L/(m2 h bar). Our membranes had the same MgSO4 rejection as that of the GE HL membrane. We found that the thermal treatment causes the NF membrane surface to be smoother and have a high crosslinking degree.

Specific or nonspecific? Evaluation of band, baseline, and cognitive specificity of sensorimotor rhythm- and gamma-based neurofeedback.

PubMed

Kober, Silvia Erika; Witte, Matthias; Neuper, Christa; Wood, Guilherme

2017-10-01

Neurofeedback (NF) is often criticized because of the lack of empirical evidence of its specificity. Our present study thus focused on the specificity of NF on three levels: band specificity, cognitive specificity, and baseline specificity. Ten healthy middle-aged individuals performed ten sessions of SMR (sensorimotor rhythm, 12-15Hz) NF training. A second group (N=10) received feedback of a narrow gamma band (40-43Hz). Effects of NF on EEG resting measurements (tonic EEG) and cognitive functions (memory, intelligence) were evaluated using a pre-post design. Both training groups were able to linearly increase the target training frequencies (either SMR or gamma), indicating the trainability of these EEG frequencies. Both NF training protocols led to nonspecific changes in other frequency bands during NF training. While SMR NF only led to concomitant changes in slower frequencies, gamma training affected nearly the whole power spectrum. SMR NF specifically improved memory functions. Gamma training showed only marginal effects on cognitive functions. SMR power assessed during resting measurements significantly increased after SMR NF training compared to a pre-assessment, indicating specific effects of SMR NF on baseline/tonic EEG. The gamma group did not show any pre-post changes in their EEG resting activity. In conclusion, SMR NF specifically affects cognitive functions (cognitive specificity) and tonic EEG (baseline specificity), while increasing SMR during NF training nonspecifically affects slower EEG frequencies as well (band non-specificity). Gamma NF was associated with nonspecific effects on the EEG power spectrum during training, which did not lead to considerable changes in cognitive functions or baseline EEG activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel synthetic curcumin analogs as potent antiangiogenic agents in colorectal cancer.

PubMed

Rajitha, Balney; Nagaraju, Ganji Purnachandra; Shaib, Walid L; Alese, Olatunji B; Snyder, James P; Shoji, Mamoru; Pattnaik, Subasini; Alam, Afroz; El-Rayes, Bassel F

2017-01-01

The transcription factor NF-κB plays a central role in angiogenesis in colorectal cancer (CRC). Curcumin is a natural dietary product that inhibits NF-κB. The objective of this study is to evaluate the antiangiogenic effects of curcumin and two potent synthetic analogues (EF31 and UBS109) in CRC. IC 50 values for curcumin, EF31, and UBS109 were determined in the HCT116 and HT-29 cell lines. HUVEC tube formation, egg CAM assay, and matrigel plug assays revealed decreased angiogenesis in cell lines treated with curcumin, EF31, or UBS109. Curcumin and its analogues significantly inhibited VEGF-A synthesis and secretion in both cell lines in association with loss of HIF-1α, COX-2, and p-STAT-3 expression. Nuclear NF-κB expression was inhibited by curcumin, EF31, and UBS109. Transfection of p65-NF-κB in HCT116 and HT-29 cells resulted in increased expression of HIF-1α, COX-2, STAT-3, and VEGF-A. Treatment with curcumin, EF31, or UBS109 inhibited these effects in transfected cell lines. In mice carrying HCT116 and HT-29 cell xenografts, EF31 and UBS109 inhibited subcutaneous tumor growth and potentiated the effects of oxaliplatin and 5-FU. Tumors from treated animals revealed inhibition of HIF-1α, COX-2, p-STAT-3, and VEGF expression. Our findings suggest that inhibition of NF-κB leading to decreased transcription and expression of HIF-1α, COX-2, STAT-3, and VEGF is a rational approach for antiangiogenic therapy in CRC. The distinctive properties of EF31 and UBS109 make them promising therapeutic agents for development in CRC as single agents or as part of combination chemotherapy regimens. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Protective effect of geraniol inhibits inflammatory response, oxidative stress and apoptosis in traumatic injury of the spinal cord through modulation of NF-κB and p38 MAPK.

PubMed

Wang, Jiansheng; Su, Baishan; Zhu, Hongbin; Chen, Chao; Zhao, Gang

2016-12-01

Geraniol is a type of monoterpenoid with a rose scent and a slightly sweet flavor. It is found in the volatile oil of various plants, and has anti-inflammatory and anti-oxidant effects. The present study aimed to investigate the protective effect of geraniol in inhibiting the inflammatory response, oxidative stress and apoptosis in traumatic spinal cord injury (SCI), as well as to analyze the mechanism underlying its effect. Adult male Sprague-Dawley rats were induced to traumatic SCI through a surgical procedure and were defined as the SCI model group. SCI or normal rats were then administered 250 mg/kg/day geraniol for 4 weeks. The Basso, Beattie and Bresnahan (BBB) test and the spinal cord water content were used to analyze the effect of geraniol against traumatic SCI in rats. The inflammatory response, oxidative stress, and caspase-9 and -3 activities were measured using commercial ELISA kits. In addition, the associated mechanism was analyzed, using western blot analysis to determine the protein expression levels of nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK). The results of the present study demonstrated that BBB scores were significantly increased and the spinal cord water content was significantly inhibited in SCI rats after 3 weeks of geraniol treatment. Furthermore, the inflammatory response, oxidative stress, and the caspase-9 and -3 activities were significantly suppressed upon treatment with geraniol. Finally, the mechanism of geraniol against traumatic SCI downregulated the NF-κB and p38 MAPK pathways in SCI rats. Therefore, the protective effect of geraniol is suggested to inhibit the inflammatory response, oxidative stress and apoptosis in traumatic SCI through the modulation of NF-κB and p38 MAPK.

Oxidized Low-Density Lipoprotein Suppresses Expression of Prostaglandin E Receptor Subtype EP3 in Human THP-1 Macrophages

PubMed Central

Sui, Xuxia; Liu, Yanmin; Li, Qi; Liu, Gefei; Song, Xuhong; Su, Zhongjing; Chang, Xiaolan; Zhou, Yingbi; Liang, Bin; Huang, Dongyang

2014-01-01

EP3, one of four prostaglandin E2 (PGE2) receptors, is significantly lower in atherosclerotic plaques than in normal arteries and is localized predominantly in macrophages of the plaque shoulder region. However, mechanisms behind this EP3 expression pattern are still unknown. We investigated the underlying mechanism of EP3 expression in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages with oxidized low-density lipoprotein (oxLDL) treatment. We found that oxLDL decreased EP3 expression, in a dose-dependent manner, at both the mRNA and protein levels. Moreover, oxLDL inhibited nuclear factor-κB (NF-κB)-dependent transcription of the EP3 gene by the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Finally, chromatin immunoprecipitation revealed decreased binding of NF-κB to the EP3 promoter with oxLDL and PPAR-γ agonist treatment. Our results show that oxLDL suppresses EP3 expression by activation of PPAR-γ and subsequent inhibition of NF-κB in macrophages. These results suggest that down-regulation of EP3 expression by oxLDL is associated with impairment of EP3-mediated anti-inflammatory effects, and that EP3 receptor activity may exert a beneficial effect on atherosclerosis. PMID:25333975

Construction of an ultrahigh-density genetic linkage map for Jatropha curcas L. and identification of QTL for fruit yield.

PubMed

Xia, Zhiqiang; Zhang, Shengkui; Wen, Mingfu; Lu, Cheng; Sun, Yufang; Zou, Meiling; Wang, Wenquan

2018-01-01

As an important biofuel plant, the demand for higher yield Jatropha curcas L. is rapidly increasing. However, genetic analysis of Jatropha and molecular breeding for higher yield have been hampered by the limited number of molecular markers available. An ultrahigh-density linkage map for a Jatropha mapping population of 153 individuals was constructed and covered 1380.58 cM of the Jatropha genome, with average marker density of 0.403 cM. The genetic linkage map consisted of 3422 SNP and indel markers, which clustered into 11 linkage groups. With this map, 13 repeatable QTLs (reQTLs) for fruit yield traits were identified. Ten reQTLs, qNF - 1 , qNF - 2a , qNF - 2b , qNF - 2c , qNF - 3 , qNF - 4 , qNF - 6 , qNF - 7a , qNF - 7b and qNF - 8, that control the number of fruits (NF) mapped to LGs 1, 2, 3, 4, 6, 7 and 8, whereas three reQTLs, qTWF - 1 , qTWF - 2 and qTWF - 3, that control the total weight of fruits (TWF) mapped to LGs 1, 2 and 3, respectively. It is interesting that there are two candidate critical genes, which may regulate Jatropha fruit yield. We also identified three pleiotropic reQTL pairs associated with both the NF and TWF traits. This study is the first to report an ultrahigh-density Jatropha genetic linkage map construction, and the markers used in this study showed great potential for QTL mapping. Thirteen fruit-yield reQTLs and two important candidate genes were identified based on this linkage map. This genetic linkage map will be a useful tool for the localization of other economically important QTLs and candidate genes for Jatropha .

Gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice

PubMed Central

Fang, Yu; Chen, Hao; Hu, Yuhui; Djukic, Zorka; Tevebaugh, Whitney; Shaheen, Nicholas J.; Orlando, Roy C.; Hu, Jianguo

2013-01-01

The barrier function of the esophageal epithelium is a major defense against gastroesophageal reflux disease. Previous studies have shown that reflux damage is reflected in a decrease in transepithelial electrical resistance associated with tight junction alterations in the esophageal epithelium. To develop novel therapies, it is critical to understand the molecular mechanisms whereby contact with a refluxate impairs esophageal barrier function. In this study, surgical models of duodenal and mixed reflux were developed in mice. Mouse esophageal epithelium was analyzed by gene microarray. Gene set enrichment analysis showed upregulation of inflammation-related gene sets and the NF-κB pathway due to reflux. Significance analysis of microarrays revealed upregulation of NF-κB target genes. Overexpression of NF-κB subunits (p50 and p65) and NF-κB target genes (matrix metalloproteinases-3 and -9, IL-1β, IL-6, and IL-8) confirmed activation of the NF-κB pathway in the esophageal epithelium. In addition, real-time PCR, Western blotting, and immunohistochemical staining also showed downregulation and mislocalization of claudins-1 and -4. In a second animal experiment, treatment with an NF-κB inhibitor, BAY 11-7085 (20 mg·kg−1·day−1 ip for 10 days), counteracted the effects of duodenal and mixed reflux on epithelial resistance and NF-κB-regulated cytokines. We conclude that gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice and that targeting the NF-κB pathway may strengthen esophageal barrier function against reflux. PMID:23639809

Patients with chronic insomnia disorder have increased serum levels of neurofilaments, neuron-specific enolase and S100B: does organic brain damage exist?

PubMed

Zhang, Ping; Tan, Cheng-Wen; Chen, Gui-Hai; Ge, Yi-Jun; Xu, Jing; Xia, Lan; Wang, Fang; Li, Xue-Yan; Kong, Xiao-Yi

2018-02-13

The aims of this study were to investigate whether serum levels of neurofilaments heavy chain (NfH) and light chain (NfL), neuron-specific enolase (NSE) and S100 calcium binding protein B (S100B): (1) change, (2) alleviate in post-therapy and (3) are associated with sleep quality and cognitive dysfunction, in patients with chronic insomnia disorder (CID). Forty CID outpatients constituted free-therapy group (ft-CID), in which twenty-four patients completed follow-up after six-month treatment to form re-visiting group (rv-CID), and twenty healthy good sleepers constituted control group (HC). All subjects completed questionnaires, polysomnography, Chinese-Beijing Version of Montreal Cognitive Assessment (MoCA-C) and Nine Box Maze Test (NBMT) to assess sleep and neuropsychological function. The serum levels of NfH, NfL, NSE and S100B were detected using enzyme-linked immunosorbent assay. The ft-CID had higher levels of NfH, NfL, NSE and S100B than the HC. Of note, the levels of NfH, NfL and NSE were significantly reduced in the rv-CID compared to the ft-CID, but not the level of S100B. Principal components analysis revealed that in these serum biomarkers, NfL and S100B had a substantial correlation with subjective and objective sleep parameters. The CID patients had elevated serum levels of NfH, NfL, NSE and S100B, indicating existence of damaged brain microstructure, including neurons, astrocytes and neuronal terminals, which were associated with the insomniac severity or/and cognitive dysfunction and could significantly reduce after effective therapy apart from the S100B. Copyright © 2018 Elsevier B.V. All rights reserved.

Theories of time-dependent and time-independent nearside-farside reactive scattering dynamics

NASA Astrophysics Data System (ADS)

Monks, Phillip David Durrant

The first application of nearside-farside (NF) theory is made to the time-dependent partial wave series (PWS) representation of the scattering amplitude for the reaction H + D[2](v = 0,j = 0, m = 0) → HD(v' = 3,j' = 0, m'= 0) + D. Time-dependent NF angular distributions and time-dependent NF local angular momenta (LAMs) are defined and used to analyse the dynamics in terms of time- direct and time-delayed reaction mechanisms. The concept of a cumulative time-evolving differential cross section (DCS) is introduced and used to provide a new method for visualising the time evolution of a chemical reaction. Time-independent NF DCS and LAM analyses of the H + D[2] reaction are presented, highlighting a distinctive "trench-ridge" feature present in the full and N LAMs. It is used to define a cut line which separates the energy-analogs of the two time- distinct reaction mechanisms. This trench-ridge feature is shown to be an interference between the time-direct (backward-scattered) and time-delayed (forward-scattered) reaction mechanisms. Resummation PWS theory is used to "clean" plots of the NF DCSs and LAMs of unphysical effects. A limitation of the resummation theory is described, whereby unphysical behaviour is sometimes introduced into the N and F subamplitudes. A technique for predicting and avoiding these undesired effects is used to further improve the usefulness of the resummation technique. The fundamental identity for NF local angular momenta is stated and derived by two methods. This identity gives rise to a CLAM plot (where CLAM denotes Cross section x LAM), which provides insight into the empirical obsei'vation that DCS and LAM analyses give consistent, yet complementary, information on the reaction dynamics. Applications are reported for the H + D[2] reaction, as well as for F + H[2](v = 0,j=0, m = 0)→ FH(v' = 3,j' = 3, m' = 0) + H. The angular time-delay for a state-to-state reactive collision often displays complicated behaviour. It is shown for the H + D[2] and F + H[2] reactions that this behaviour is caused by NF interference. The fundamental identity for NF angular time-delays is stated, and CATD (Cross section x Angular Time-Delay) results are reported, which provide further insight into the properties of the angular time-delay.

miR-19a promotes colitis-associated colorectal cancer by regulating tumor necrosis factor alpha-induced protein 3-NF-κB feedback loops.

PubMed

Wang, T; Xu, X; Xu, Q; Ren, J; Shen, S; Fan, C; Hou, Y

2017-06-08

Chronic inflammation is believed to have a crucial role in colon cancer development. MicroRNA (miRNA) deregulation is common in human colorectal cancers, but little is known regarding whether miRNA drives tumor progression by regulating inflammation. Here, we showed that miR-19a can promote colitis and colitis-associated colon cancer (CAC) development using a CAC mouse model and an acute colitis mouse model. Tumor necrosis factor-α (TNF-α) stimulation can increase miR-19a expression, and upregulated miR-19a can in turn activate nuclear factor (NF)-κB signaling and TNF-α production by targeting TNF alpha-induced protein 3 (TNFAIP3). miR-19a inhibition can also alleviate CAC in vivo. Moreover, the regulatory effects of miR-19a on TNFAIP3 and NF-κB signaling were confirmed using tumor samples from patients with colon cancer. These new findings demonstrate that miR-19a has a direct role in upregulating NF-κB signaling and that miR-19a has roles in inflammation and CAC.

Berberine inhibits the ischemia-reperfusion injury induced inflammatory response and apoptosis of myocardial cells through the phosphoinositide 3-kinase/RAC-α serine/threonine-protein kinase and nuclear factor-κB signaling pathways.

PubMed

Wang, Lixin; Ma, Hao; Xue, Yan; Shi, Haiyan; Ma, Teng; Cui, Xiaozheng

2018-02-01

Myocardial ischemia-reperfusion injury is one of the most common cardiovascular diseases, and can lead to serious damage and dysfunction of the myocardial tissue. Previous studies have demonstrated that berberine exhibits ameliorative effects on cardiovascular disease. The present study further investigated the efficacy and potential mechanism underlying the effects of berberine on ischemia-reperfusion injury in a mouse model. Inflammatory markers were measured in the serum and levels of inflammatory proteins in myocardial cells were investigated after treatment with berberine. In addition, the apoptosis of myocardial cells was investigated after berberine treatment. Apoptosis-associated gene expression levels and apoptotic signaling pathways were analyzed in myocardial cells after treatment with berberine. The phosphoinositide 3-kinase (PI3K)/RAC-α serine/threonine-protein kinase (AKT) and nuclear factor (NF)-κB signaling pathways were also analyzed in myocardial cells after treatment with berberine. Histological analysis was used to analyze the potential benefits of berberine in ischemia-reperfusion injury. The present study identified that inflammatory responses and inflammatory factors were decreased in the myocardial cells of the mouse model of ischemia-reperfusion injury. Mechanism analysis demonstrated that berberine inhibited apoptotic protease-activating factor 1, caspase-3 and caspase-9 expression in myocardial cells. The expression of Bcl2-associated agonist of cell death, Bcl-2-like protein 1 and cellular tumor antigen p53 was upregulated. Expression of NF-κB p65, inhibitor of NF-κB kinase subunit β (IKK-β), NF-κB inhibitor α (IκBα), and NF-κB activity, were inhibited in myocardial cells in the mouse model of ischemia-reperfusion injury. In conclusion, the results of the present study indicate that berberine inhibits inflammatory responses through the NF-κB signaling pathway and suppresses the apoptosis of myocardial cells via the PI3K/AKT signaling pathway in a mouse model of ischemia-reperfusion injury. These results suggest that berberine is a potential drug for the treatment of patients with ischemia-reperfusion injury.

Berberine inhibits the ischemia-reperfusion injury induced inflammatory response and apoptosis of myocardial cells through the phosphoinositide 3-kinase/RAC-α serine/threonine-protein kinase and nuclear factor-κB signaling pathways

PubMed Central

Wang, Lixin; Ma, Hao; Xue, Yan; Shi, Haiyan; Ma, Teng; Cui, Xiaozheng

2018-01-01

Myocardial ischemia-reperfusion injury is one of the most common cardiovascular diseases, and can lead to serious damage and dysfunction of the myocardial tissue. Previous studies have demonstrated that berberine exhibits ameliorative effects on cardiovascular disease. The present study further investigated the efficacy and potential mechanism underlying the effects of berberine on ischemia-reperfusion injury in a mouse model. Inflammatory markers were measured in the serum and levels of inflammatory proteins in myocardial cells were investigated after treatment with berberine. In addition, the apoptosis of myocardial cells was investigated after berberine treatment. Apoptosis-associated gene expression levels and apoptotic signaling pathways were analyzed in myocardial cells after treatment with berberine. The phosphoinositide 3-kinase (PI3K)/RAC-α serine/threonine-protein kinase (AKT) and nuclear factor (NF)-κB signaling pathways were also analyzed in myocardial cells after treatment with berberine. Histological analysis was used to analyze the potential benefits of berberine in ischemia-reperfusion injury. The present study identified that inflammatory responses and inflammatory factors were decreased in the myocardial cells of the mouse model of ischemia-reperfusion injury. Mechanism analysis demonstrated that berberine inhibited apoptotic protease-activating factor 1, caspase-3 and caspase-9 expression in myocardial cells. The expression of Bcl2-associated agonist of cell death, Bcl-2-like protein 1 and cellular tumor antigen p53 was upregulated. Expression of NF-κB p65, inhibitor of NF-κB kinase subunit β (IKK-β), NF-κB inhibitor α (IκBα), and NF-κB activity, were inhibited in myocardial cells in the mouse model of ischemia-reperfusion injury. In conclusion, the results of the present study indicate that berberine inhibits inflammatory responses through the NF-κB signaling pathway and suppresses the apoptosis of myocardial cells via the PI3K/AKT signaling pathway in a mouse model of ischemia-reperfusion injury. These results suggest that berberine is a potential drug for the treatment of patients with ischemia-reperfusion injury. PMID:29403554

Targeting inflammatory mediators with ferulic acid, a dietary polyphenol, for the suppression of monosodium urate crystal-induced inflammation in rats.

PubMed

Doss, Hari Madhuri; Dey, Chandrima; Sudandiradoss, C; Rasool, Mahaboob Khan

2016-03-01

The aim of this study was to investigate the anti-inflammatory effect of ferulic acid, a dietary phenol, on monosodium urate (MSU) crystal-induced inflammation in rats, an experimental model for acute gouty arthritis. For the purpose of comparison, colchicine was used as a reference drug. Paw edema, levels/activities of elastase, lysosomal enzymes (acid phosphatase and β-galactosidase), nitric oxide, lipid peroxidation, antioxidant status and pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β), and histology of ankle joints were evaluated in rats with MSU crystal-induced inflammation. The messenger RNA (mRNA) expression of pro-inflammatory cytokines (TNF-α and IL-1β), NLRP3 (nucleotide oligomerization domain (NOD)-like receptor family, pyrin domain containing 3) inflammasomes, caspase-1, and the transcription factor nuclear factor kappa B p65 (NF-κB p65) was determined by real-time polymerase chain reaction (PCR) analysis. The protein expression of NF-κB p65 and TNF-α was detected by immunohistochemical analysis. Further, a molecular docking analysis was conducted to determine the ligand efficiency of ferulic acid towards NF-κB, apoptosis-associated speck-like protein containing a CARD (PYCARD/ASC), NLRP3, and pro-caspase-1. In the joint homogenate of rats with MSU crystal-induced inflammation, treatment with ferulic acid (30mg/kg body weight (b.wt)) decreased paw edema; the level/activity of elastase, lysosomal enzymes, nitric oxide, lipid peroxidation, and pro-inflammatory cytokines (TNF-α and IL-1β); and the mRNA expression of NLRP3 inflammasomes, caspase-1, pro-inflammatory cytokines, and NF-κB p65. In addition, the protein expression of NF-κB p65 and TNF-α was also found to be significantly decreased. However, the antioxidant status (superoxide dismutase (SOD) and catalase (CAT)) were found to be increased. The molecular docking analysis showed that ferulic acid exhibited significant ligand efficiency towards pro-caspase-1, NF-κB, PYCARD/ASC, and NLRP3. Our findings demonstrate the potential anti-inflammatory effect of ferulic acid on MSU crystal-induced inflammation in rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Fumaric acid attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling.

PubMed

Roh, Kyung-Baeg; Jung, Eunsun; Park, Deokhoon; Lee, Jongsung

2013-08-01

Eotaxin-1 is a potent chemoattractant for eosinophils and a critical mediator during the development of eosinophilic inflammation. Fumaric acid is an intermediate product of the citric acid cycle, which is source of intracellular energy. Although fumaric acid ameliorates psoriasis and multiple sclerosis, its involvement in eotaxin-1-mediated effects has not been assessed. In this study, we investigated the effects of fumaric acid on eotaxin-1 expression in a mouse fibroblast cell line. We found that fumaric acid significantly inhibited tumor necrosis factor-α (TNF-α-induced eotaxin-1 expression. This fumaric acid effect was mediated through the inhibition of p38 mitogen-activated protein kinase (MAPK)-dependent nuclear factor (NF)-κB signaling. We also found that fumaric acid operates downstream of MEKK3 during TNF-α-induced NF-κB signaling, which upregulated eotaxin-1 expression. In addition, fumaric acid attenuated expression of CC-chemokine receptor 3 (CCR3), an eotaxin-1 receptor, and adhesion molecules that play important roles in eosinophil binding to induce allergic inflammation. Taken together, these findings indicate that inhibiting TNF-α-induced eotaxin-1 expression by fumaric acid occurs primarily through suppression of NF-κB signaling, which is mediated by inhibiting p38 MAPK and suggest that fumaric acid may be used as a complementary treatment option for eotaxin-1-mediated diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

Functional genomic characterization of virulence factors from necrotizing fasciitis-causing strains of Aeromonas hydrophila.

PubMed

Grim, Christopher J; Kozlova, Elena V; Ponnusamy, Duraisamy; Fitts, Eric C; Sha, Jian; Kirtley, Michelle L; van Lier, Christina J; Tiner, Bethany L; Erova, Tatiana E; Joseph, Sandeep J; Read, Timothy D; Shak, Joshua R; Joseph, Sam W; Singletary, Ed; Felland, Tracy; Baze, Wallace B; Horneman, Amy J; Chopra, Ashok K

2014-07-01

The genomes of 10 Aeromonas isolates identified and designated Aeromonas hydrophila WI, Riv3, and NF1 to NF4; A. dhakensis SSU; A. jandaei Riv2; and A. caviae NM22 and NM33 were sequenced and annotated. Isolates NF1 to NF4 were from a patient with necrotizing fasciitis (NF). Two environmental isolates (Riv2 and -3) were from the river water from which the NF patient acquired the infection. While isolates NF2 to NF4 were clonal, NF1 was genetically distinct. Outside the conserved core genomes of these 10 isolates, several unique genomic features were identified. The most virulent strains possessed one of the following four virulence factors or a combination of them: cytotoxic enterotoxin, exotoxin A, and type 3 and 6 secretion system effectors AexU and Hcp. In a septicemic-mouse model, SSU, NF1, and Riv2 were the most virulent, while NF2 was moderately virulent. These data correlated with high motility and biofilm formation by the former three isolates. Conversely, in a mouse model of intramuscular infection, NF2 was much more virulent than NF1. Isolates NF2, SSU, and Riv2 disseminated in high numbers from the muscular tissue to the visceral organs of mice, while NF1 reached the liver and spleen in relatively lower numbers on the basis of colony counting and tracking of bioluminescent strains in real time by in vivo imaging. Histopathologically, degeneration of myofibers with significant infiltration of polymorphonuclear cells due to the highly virulent strains was noted. Functional genomic analysis provided data that allowed us to correlate the highly infectious nature of Aeromonas pathotypes belonging to several different species with virulence signatures and their potential ability to cause NF. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Mixed-Effects Modeling of Neurofeedback Self-Regulation Performance: Moderators for Learning in Children with ADHD.

PubMed

Zuberer, Agnieszka; Minder, Franziska; Brandeis, Daniel; Drechsler, Renate

2018-01-01

Neurofeedback (NF) has gained increasing popularity as a training method for children and adults with attention deficit hyperactivity disorder (ADHD). However, it is unclear to what extent children learn to regulate their brain activity and in what way NF learning may be affected by subject- and treatment-related factors. In total, 48 subjects with ADHD (age 8.5-16.5 years; 16 subjects on methylphenidate (MPH)) underwent 15 double training sessions of NF in either a clinical or a school setting. Four mixed-effects models were employed to analyze learning: training within-sessions, across-sessions, with continuous feedback, and with transfer in which performance feedback is delayed. Age and MPH affected the NF performance in all models. Cross-session learning in the feedback condition was mainly moderated by age and MPH, whereas NF learning in the transfer condition was mainly boosted by MPH. Apart from IQ and task types, other subject-related or treatment-related effects were unrelated to NF learning. This first study analyzing moderators of NF learning in ADHD with a mixed-effects modeling approach shows that NF performance is moderated differentially by effects of age and MPH depending on the training task and time window. Future studies may benefit from using this approach to analyze NF learning and NF specificity. The trial name Neurofeedback and Computerized Cognitive Training in Different Settings for Children and Adolescents With ADHD is registered with NCT02358941.

The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-kappaB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats.

PubMed

Ochaion, A; Bar-Yehuda, S; Cohen, S; Amital, H; Jacobson, K A; Joshi, B V; Gao, Z G; Barer, F; Patoka, R; Del Valle, L; Perez-Liz, G; Fishman, P

2008-08-15

The A(3) adenosine receptor (A(3)AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant- and collagen-induced arthritis. In this study we present a novel A(3)AR agonist, CF502, with high affinity and selectivity at the human A(3)AR. CF502 induced a dose dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes (FLS) via de-regulation of the nuclear factor-kappa B (NF-kappaB) signaling pathway. Furthermore, CF502 markedly suppressed the clinical and pathological manifestations of adjuvant-induced arthritis (AIA) in a rat experimental model when given orally at a low dose (100 microg/kg). As is typical of other G-protein coupled receptors, the A(3)AR expression level was down-regulated shortly after treatment with agonist CF502 in paw and in peripheral blood mononuclear cells (PBMCs) derived from treated AIA animals. Subsequently, a decrease in the expression levels of protein kinase B/Akt (PKB/Akt), IkappaB kinase (IKK), I kappa B (IkappaB), NF-kappaB and tumor necrosis factor-alpha (TNF-alpha) took place. In addition, the expression levels of glycogen synthase kinase-3 beta (GSK-3beta), beta-catenin, and poly(ADP-ribose)polymerase (PARP), known to control the level and activity of NF-kappaB, were down-regulated upon treatment with CF502. Taken together, CF502 inhibits FLS growth and the inflammatory manifestations of arthritis, supporting the development of A(3)AR agonists for the treatment of rheumatoid arthritis.

1,25(OH)2D3 promotes chondrocyte apoptosis and restores physical function in rheumatoid arthritis through the NF-κB signal pathway.

PubMed

Tian, Run; Li, Xiaofang; Li, Yue; Wang, Kunzheng; Wang, Chunsheng; Yang, Pei

2018-06-26

We explored the modulatory effect of 1,25(OH) 2 D 3 on chondrocytes and physical function in rats with RA and its mechanism underlying the regulation of NF-κB signal pathway. RA patients and healthy volunteers were selected. Sprague-Dawley (SD) rats were used to establish RA models. The paw volume of rats was estimated. Chondrocytes were isolated from RA rats. The protein levels in both cartilage tissues and chondrocytes were determined using western blotting. Apoptosis was evaluated using TUNEL assay. Serum levels of IL-1β, IL-6, IL-10 and IL-17 were measured by enzyme-linked immunosorbent assay (ELISA). Serum levels of 1,25(OH) 2 D 3 were lower in RA patients than in healthy volunteers. Rats in the RA + VD 3 group were lighter than those in normal and PBS groups, with an increased paw volume, severer joint swelling, higher expression levels of p-IκBα, p-p65, IL-1β, IL-6, and IL-17, and lower expression level of IL-10, while those in RA and RA + VD 3 + NF-κB group differed more significantly. In addition, by comparing RA rats and RA + NF-κB rats, we found that TNF-α stimulation exacerbated RA, increased expression levels of p-IκBα, p-p65, IL-1β, IL-6, and IL-17, and decreased the expression level of IL-10. Compared with RA chondrocytes, chondrocytes from RA + VD 3 rats exhibited lower expression levels of p-IκBα and p-p65, and had more apoptotic cells, while those from RA + NF-κB rats showed an opposite trend. Taken together, 1,25(OH) 2 D 3 accelerates chondrocyte apoptosis and improve physical function in rats with RA by the inhibition of NF-κB signal pathway. Copyright © 2018. Published by Elsevier Masson SAS.

Magnesium isoglycyrrhizinate blocks fructose-induced hepatic NF-κB/NLRP3 inflammasome activation and lipid metabolism disorder.

PubMed

Zhao, Xiao-Juan; Yang, Yan-Zi; Zheng, Yan-Jing; Wang, Shan-Chun; Gu, Hong-Mei; Pan, Ying; Wang, Shui-Juan; Xu, Hong-Jiang; Kong, Ling-Dong

2017-08-15

Magnesium isoglycyrrhizinate as a hepatoprotective agent possesses immune modulation and anti-inflammation, and treats liver diseases. But its effects on immunological-inflammatory and metabolic profiles for metabolic syndrome with liver injury and underlying potential mechanisms are not fully understood. In this study, magnesium isoglycyrrhizinate alleviated liver inflammation and lipid accumulation in fructose-fed rats with metabolic syndrome. It also suppressed hepatic inflammatory signaling activation by reducing protein levels of phosphorylation of nuclear factor-kappa B p65 (p-NF-κB p65), inhibitor of nuclear factor kappa-B kinase α/β (p-IKKα/β) and inhibitor of NF-κB α (p-IκBα) as well as nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC) and Caspase-1 in rats, being consistent with its reduction of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-6 levels. Furthermore, magnesium isoglycyrrhizinate modulated lipid metabolism-related genes characterized by up-regulating peroxisome proliferator-activated receptor-α (PPAR-α) and carnitine palmitoyl transferase-1 (CPT-1), and down-regulating sensor for fatty acids to control-1 (SREBP-1) and stearoyl-CoA desaturase 1 (SCD-1) in the liver of fructose-fed rats, resulting in the reduction of triglyceride and total cholesterol levels. These effective actions were further confirmed in fructose-exposed BRL-3A and HepG2 cells. The molecular mechanisms underpinning these observations suggest that magnesium isoglycyrrhizinate may inhibit NF-κB/NLRP3 inflammasome activation to reduce immunological-inflammatory response, which in turn may prevent liver lipid metabolic disorder and accumulation under high fructose condition. Thus, blockade of NF-κB/NLRP3 inflammasome activation and lipid metabolism disorder by magnesium isoglycyrrhizinate may be the potential therapeutic approach for improving fructose-induced liver injury with metabolic syndrome in clinic. Copyright © 2017 Elsevier B.V. All rights reserved.

Constitutive Activation of NF-kappaB in Prostate Carcinoma Cells Through a Positive Feedback Loop: Implication of Inducible IKK-Related Kinase (IKKi)

DTIC Science & Technology

2004-08-01

development in different tissues is strongly considered ( Greten and Karen, 2004). To assess the effect of w.t. IKKi and kinase inactive IKKi mutant...11: 1357-1362, 1999. 3. Greten FR, Karin M. The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett. 206(2

Selenium reduces the proapoptotic signaling associated to NF-kappaB pathway and stimulates glutathione peroxidase activity during excitotoxic damage produced by quinolinate in rat corpus striatum.

PubMed

Santamaría, Abel; Vázquez-Román, Beatriz; La Cruz, Verónica Pérez-De; González-Cortés, Carolina; Trejo-Solís, Ma Cristina; Galván-Arzate, Sonia; Jara-Prado, Aurelio; Guevara-Fonseca, Jorge; Ali, Syed F

2005-12-15

Quinolinate (QUIN) neurotoxicity has been attributed to degenerative events in nerve tissue produced by sustained activation of N-methyl-D-aspartate receptor (NMDAr) and oxidative stress. We have recently described the protective effects that selenium (Se), an antioxidant, produces on different markers of QUIN-induced neurotoxicity (Santamaría et al., 2003, J Neurochem 86:479-488.). However, the mechanisms by which Se exerts its protective actions remain unclear. Since some of these events are thought to be related with inhibition of deadly molecular cascades through the activation of antioxidant selenoproteins, in this study we investigated the effects of Se on QUIN-induced cell damage elicited by the nuclear factor kappaB (NF-kappaB) pathway, as well as the time-course response of striatal glutathione peroxidase (GPx) activity. Se (sodium selenite, 0.625 mg/kg/day, i.p.) was administered to rats for 5 days, and 120 min after the last administration, animals received a single striatal injection of QUIN (240 nmol/mul). Twenty-four hours later, their striata were tested for the expression of IkappaB-alpha (the NF-kappaB cytosolic binding protein), the immunohistochemical expression of NF-kappaB (evidenced as nuclear expression of P65), caspase-3-like activation, and DNA fragmentation. Additional groups were killed at 2, 6, and 24 h for measurement of GPx activity. Se reduced the QUIN-induced decrease in IkappaB-alpha expression, evidencing a reduction in its cytosolic degradation. Se also prevented the QUIN-induced increase in P65-immunoreactive cells, suggesting a reduction of NF-kappaB nuclear translocation. Caspase-3-like activation and DNA fragmentation produced by QUIN were also inhibited by Se. Striatal GPx activity was stimulated by Se at 2 and 6 h, but not at 24 h postlesion. Altogether, these data suggest that the protective effects exerted by Se on QUIN-induced neurotoxicity are partially mediated by the inhibition of proapoptotic events underlying IkappaB-alpha degradation, NF-kappaB nuclear translocation, and caspase-3-like activation in the rat striatum, probably involving the early activation of GPx.

Food nitrogen footprint reductions related to a balanced Japanese diet.

PubMed

Oita, Azusa; Nagano, Ichiro; Matsuda, Hiroyuki

2018-04-01

Dietary choices largely affect human-induced reactive nitrogen accumulation in the environment and resultant environmental problems. A nitrogen footprint (NF) is an indicator of how an individual's consumption patterns impact nitrogen pollution. Here, we examined the impact of changes in the Japanese diet from 1961 to 2011 and the effect of alternative diets (the recommended protein diet, a pescetarian diet, a low-NF food diet, and a balanced Japanese diet) on the food NF. The annual per capita Japanese food NF has increased by 55% as a result of dietary changes since 1961. The 1975 Japanese diet, a balanced omnivorous diet that reportedly delays senescence, with a protein content similar to the current level, reduced the current food NF (15.2 kg N) to 12.6 kg N, which is comparable to the level in the recommended protein diet (12.3 kg N). These findings will help consumers make dietary choices to reduce their impacts on nitrogen pollution.

A reduced graphene oxide nanofiltration membrane intercalated by well-dispersed carbon nanotubes for drinking water purification.

PubMed

Chen, Xianfu; Qiu, Minghui; Ding, Hao; Fu, Kaiyun; Fan, Yiqun

2016-03-14

In this study, we report a promising rGO-CNT hybrid nanofiltration (NF) membrane that was fabricated by loading reduced graphene oxide that was intercalated with carbon nanotubes (rGO-CNTs) onto an anodic aluminum oxide (AAO) microfiltration membrane via a facile vacuum-assisted filtration process. To create this NF membrane, the CNTs were first dispersed using block copolymers (BCPs); the effects of the types and contents of BCPs used on the dispersion of CNTs have been investigated. The as-prepared rGO-CNT hybrid NF membranes were then used for drinking water purification to retain the nanoparticles, dyes, proteins, organophosphates, sugars, and particularly humic acid. Experimentally, it is shown that the rGO-CNT hybrid NF membranes have high retention efficiency, good permeability and good anti-fouling properties. The retention was above 97.3% even for methyl orange (327 Da); for other objects, the retention was above 99%. The membrane's permeability was found to be as high as 20-30 L m(-2) h(-1) bar(-1). Based on these results, we can conclude that (i) the use of BCPs as a surfactant can enhance steric repulsion and thus disperse CNTs effectively; (ii) placing well-dispersed 1D CNTs within 2D graphene sheets allows an uniform network to form, which can provide many mass transfer channels through the continuous 3D nanostructure, resulting in the high permeability and separation performance of the rGO-CNT hybrid NF membranes.

Phytochemicals and botanical extracts regulate NF-κB and Nrf2/ARE reporter activities in DI TNC1 astrocytes

PubMed Central

Ajit, Deepa; Simonyi, Agnes; Li, Runting; Chen, Zihong; Hannink, Mark; Fritsche, Kevin L.; Mossine, Valeri V.; Smith, Robert E.; Dobbs, Thomas K.; Luo, Rensheng; Folk, William R.; Gu, Zezong; Lubahn, Dennis B.; Weisman, Gary A.; Sun, Grace Y.

2016-01-01

The increase in oxidative stress and inflammatory responses associated with neurodegenerative diseases has drawn considerable attention towards understanding the transcriptional signaling pathways involving NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and Nrf2 (Nuclear Factor Erythroid 2-like 2). Our recent studies with immortalized murine microglial cells (BV-2) demonstrated effects of botanical polyphenols to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) and enhance Nrf2-mediated antioxidant responses (Sun et al., 2015). In this study, an immortalized rat astrocyte (DI TNC1) cell line expressing a luciferase reporter driven by the NF-κB or the Nrf2/Antioxidant Response Element (ARE) promoter was used to assess regulation of these two pathways by phytochemiscals such as quercetin, rutin, cyanidin, cyanidin-3-O-glucoside, as well as botanical extracts from Withania somnifera (Ashwagandha), Sutherlandia frutescens (Sutherlandia) and Euterpe oleracea (Açaí). Quercetin effectively inhibited LPS-induced NF-κB reporter activity and stimulated Nrf2/ARE reporter activity in DI TNC1 astrocytes. Cyanidin and the glycosides showed similar effects but only at much higher concentrations. All three botanical extracts effectively inhibited LPS-induced NF-κB reporter activity. These extracts were capable of enhancing ARE activity by themselves and further enhanced ARE activity in the presence of LPS. Quercetin and botanical extracts induced Nrf2 and HO-1 protein expression. Interestingly, Ashwagandha extract was more active in inducing Nrf2 and HO-1 expression in DI TNC1 astrocytes as compared to Sutherlandia and Açaí extracts. In summary, this study demonstrated NF-kB and Nrf2/ARE promotor activities in DI TNC1 astrocytes, and further showed differences in ability for specific botanical polyphenols and extracts to down-regulate LPS-induced NF-kB and up-regulate the NRF2/ARE activities in these cells. PMID:27166148

6-Shogaol from dried ginger inhibits growth of prostate cancer cells both in vitro and in vivo through inhibition of STAT3 and NF-κB signaling.

PubMed

Saha, Achinto; Blando, Jorge; Silver, Eric; Beltran, Linda; Sessler, Jonathan; DiGiovanni, John

2014-06-01

Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Prostate cancer is the most common nonskin neoplasm and second leading cause of death in men. 6-Shogaol (6-SHO), a potent bioactive compound in ginger (Zingiber officinale Roscoe), has been shown to possess anti-inflammatory and anticancer activity. In the present study, the effect of 6-SHO on the growth of prostate cancer cells was investigated. 6-SHO effectively reduced survival and induced apoptosis of cultured human (LNCaP, DU145, and PC3) and mouse (HMVP2) prostate cancer cells. Mechanistic studies revealed that 6-SHO reduced constitutive and interleukin (IL)-6-induced STAT3 activation and inhibited both constitutive and TNF-α-induced NF-κB activity in these cells. In addition, 6-SHO decreased the level of several STAT3 and NF-κB-regulated target genes at the protein level, including cyclin D1, survivin, and cMyc and modulated mRNA levels of chemokine, cytokine, cell cycle, and apoptosis regulatory genes (IL-7, CCL5, BAX, BCL2, p21, and p27). 6-SHO was more effective than two other compounds found in ginger, 6-gingerol, and 6-paradol at reducing survival of prostate cancer cells and reducing STAT3 and NF-κB signaling. 6-SHO also showed significant tumor growth inhibitory activity in an allograft model using HMVP2 cells. Overall, the current results suggest that 6-SHO may have potential as a chemopreventive and/or therapeutic agent for prostate cancer and that further study of this compound is warranted. ©2014 American Association for Cancer Research.

Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahu, Geetaram; Farley, Kalamo; El-Hage, Nazira

Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcriptionmore » elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. - Highlights: • Cocaine induces the initiation phase of HIV transcription by activating NF-ĸB. • Cocaine induced NF-ĸB phosphorylation promotes its interaction with P300. • Cocaine enhances the elongation phase of HIV transcription by stimulating MSK1. • Cocaine activated MSK1 catalyzes the phosphorylation of histone H3 at its Ser10. • Cocaine induced H3S10 phosphorylation facilitates the recruitment of P-TEFb at LTR.« less

Treatment with 1,25(OH)2D3induced HDAC2 expression and reduced NF-κB p65 expression in a rat model of OVA-induced asthma

PubMed Central

Zhou, Y.; Wang, G.F.; Yang, L.; Liu, F.; Kang, J.Q.; Wang, R.L.; Gu, W.; Wang, C.Y.

2015-01-01

Recent evidence indicates that a deficiency of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) may influence asthma pathogenesis; however, its roles in regulating specific molecular transcription mechanisms remain unclear. We aimed to investigate the effect of 1,25(OH)2D3 on the expression and enzyme activity of histone deacetylase 2 (HDAC2) and its synergistic effects with dexamethasone (Dx) in the inhibition of inflammatory cytokine secretion in a rat asthma model. Healthy Wistar rats were randomly divided into 6 groups: control, asthma, 1,25(OH)2D3 pretreatment, 1,25(OH)2D3 treatment, Dx treatment, and Dx and 1,25(OH)2D3 treatment. Pulmonary inflammation was induced by ovalbumin (OVA) sensitization and challenge (OVA/OVA). Inflammatory cells and cytokines in the bronchoalveolar lavage (BAL) fluid and histological changes in lung tissue were examined. Nuclear factor kappa B (NF-κB) p65 and HDAC2 expression levels were assessed with Western blot analyses and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Enzyme activity measurements and immunohistochemical detection of HDAC2 were also performed. Our data demonstrated that 1,25(OH)2D3 reduced the airway inflammatory response and the level of inflammatory cytokines in BAL. Although NF-κB p65 expression was attenuated in the pretreatment and treatment groups, the expression and enzyme activity of HDAC2 were increased. In addition, 1,25(OH)2D3 and Dx had synergistic effects on the suppression of total cell infusion, cytokine release, and NF-κB p65 expression, and they also increased HDAC2 expression and activity in OVA/OVA rats. Collectively, our results indicated that 1,25(OH)2D3might be useful as a novel HDAC2 activator in the treatment of asthma. PMID:25923460

Toxicological evaluation of aerosols of a tobacco extract formulation and nicotine formulation in acute and short-term inhalation studies.

PubMed

Werley, Michael S; Jerome, Ann M; Oldham, Michael J

2014-03-01

A formulation of tobacco extract containing 4% nicotine (TE) and similar nicotine formulation containing vehicle and 4% nicotine (NF) were evaluated using animal inhalation assays. Two 4-h inhalation exposures at 1 and 2 mg/L aerosol exposure concentrations, respectively, of the tobacco extract with 4% nicotine formulation showed that the LC50 was greater than 2 mg/L, the maximum concentration tested. All inhalation exposures were conducted using the capillary aerosol generator (CAG). Increasing aerosol TPM concentrations (0, 10, 50, 200, 1000 mg/m(3) TE and 0, 50, 200, 500, 1000 mg/m(3) NF) were generated via the CAG and used to expose groups of male and female rats for 4-h per day for 14 days. In life monitors for potential effects included clinical observations, weekly body weights and food consumption. Post mortem evaluations included gross tissue findings, hematology, clinical chemistry, serum plasma and nicotine levels, absolute and normalized organ and tissue weights, and histopathology of target organs. Treatment-related changes were observed in body weights, hematology, clinical chemistry, organ weights and histopathological findings for TE at the 200 and 1000 mg/m(3) exposure levels, and in the 500 and 1000 mg/m(3) exposure groups for NF. Under the conditions of these studies, the no-observed-adverse-effect level in the rat was approximately 50 mg/m(3) for the TE aerosol-exposed groups, and approximately 200 mg/m(3) in the NF aerosol-exposed groups.

[Mechanisms for effect of osthole on inhibiting the growth and invasion of bladder cancer cells].

PubMed

Liu, Jun; Xu, Ran; Zhao, Xiaokun

2016-04-01

To investigate the effect of osthole on epidermal growth factor receptor tyrosine kinase (EGFR-TPK), matrix-metalloproteinase-2 (MMP-2), aminopeptidase N (APN) in bladder cancer cell and the underlying mechanism.
 The T24 cell lines were cultured. The inhibitory effects of osthole on EGFR-TPK, APN and MMP-2 were evaluated by spectrophotometric and MTT assay. The caspase-3 activity and the expression COX-2 and VEGF in T24 were examined. The activity of NF-κB was determined by electrophoretic mobility shift assay.
 The half inhibition concentrations (IC50) of osthole on EGFR-TPK, APN and MMP-2 were (45.33±3.98), (28.21±3.23) and (8.11±0.54) µmol/L, respectively. The growth inhibitory rates for T24 cells were increased in a dose-dependent manner (P<0.05). The caspase-3 activities were significantly increased in T24 cells in the osthole group compared with control group, while the expression of angiogenesis related-protein COX-2, VEGF, and NF-κB in T24 cells were decreased.
 Through the inhibitory effect on EGFR-TPK, APN and MMP-2, osthole can decrease COX-2, VEGF and NF-κB expression while increase the activity of caspase-3, eventually blocking the growth and invasion of bladder cancer cell.

Glycyrrhetinic acid inhibits ICAM-1 expression via blocking JNK and NF-κB pathways in TNF-α-activated endothelial cells

PubMed Central

Chang, Ying-ling; Chen, Chien-lin; Kuo, Chao-Lin; Chen, Bor-chyuan; You, Jyh-sheng

2010-01-01

Aim: To investigate the effects of glycyrrhetinic acid (GA), an active component extracted from the root of Glycyrrhizae glabra, on the expression of intercellular adhesion molecule-1 (ICAM-1) in tumor necrosis factor-α (TNF-α)-activated human umbilical vein endothelial cells (HUVEC). Methods: ICAM-1 mRNA and protein levels were detected using RT-PCR and cell enzyme-linked immunosorbent assays. The adherence of human monocytic THP-1 cells labeled with [3H]thymidine to HUVEC was determined by counting radioactivity with a scintillation counter. The activation of mitogen-activated protein kinases as well as the degradation of IκB and nuclear factor-κB (NF-κB) or phospho-c-Jun in the nucleus were detected by western blots. NF-κB binding activity was detected using electrophoretic mobility shift assay. Results: GA (50 and 100 μmol/L) significantly inhibits TNF-α-induced ICAM-1 mRNA and protein expressions, as well as THP-1 cell adhesiveness in HUVEC. GA selectively inhibited TNF-α-activated signal pathway of c-Jun N-terminal kinase (JNK), without affecting extracellular signal-regulated kinase 1/2 and p38. Furthermore, GA apparently inhibited IκB/NF-κB signaling system by preventing IκB degradation, NF-κB translocation, and NF-κB/DNA binding activity. Finally, pretreatment with GA or the inhibitors of NF-κB, JNK, and p38 reduced the ICAM-1 protein expression induced by TNF-α. Conclusion: GA inhibits TNF-α-stimulated ICAM-1 expression, leading to a decrease in adherent monocytes to HUVEC. This inhibition is attributed to GA interruption of both JNK/c-Jun and IκB/NF-κB signaling pathways, which decrease activator protein-1 (AP-1) and NF-κB mediated ICAM-1 expressions. The results suggest that GA may provide a beneficial effect in treating vascular diseases associated with inflammation, such as atherosclerosis. PMID:20418897

Effects of molecular model, ionic strength, divalent ions, and hydrophobic interaction on human neurofilament conformation

NASA Astrophysics Data System (ADS)

Lee, Joonseong; Kim, Seonghoon; Chang, Rakwoo; Jayanthi, Lakshmi; Gebremichael, Yeshitila

2013-01-01

The present study examines the effects of the model dependence, ionic strength, divalent ions, and hydrophobic interaction on the structural organization of the human neurofilament (NF) brush, using canonical ensemble Monte Carlo (MC) simulations of a coarse-grained model with the amino-acid resolution. The model simplifies the interactions between the NF core and the sidearm or between the sidearms by the sum of excluded volume, electrostatic, and hydrophobic interactions, where both monovalent salt ions and solvents are implicitly incorporated into the electrostatic interaction potential. Several important observations are made from the MC simulations of the coarse-grained model NF systems. First, the mean-field type description of monovalent salt ions works reasonably well in the NF system. Second, the manner by which the NF sidearms are arranged on the surface of the NF backbone core has little influence on the lateral extension of NF sidearms. Third, the lateral extension of the NF sidearms is highly affected by the ionic strength of the system: at low ionic strength, NF-M is most extended but at high ionic strength, NF-H is more stretched out because of the effective screening of the electrostatic interaction. Fourth, the presence of Ca2 + ions induces the attraction between negatively charged residues, which leads to the contraction of the overall NF extension. Finally, the introduction of hydrophobic interaction does not change the general structural organization of the NF sidearms except that the overall extension is contracted.

Human Oncoprotein MDM2 Up-regulates Expression of NF-κB2 Precursor p100 Conferring a Survival Advantage to Lung Cells

PubMed Central

Vaughan, Catherine; Mohanraj, Lathika; Singh, Shilpa; Dumur, Catherine I.; Ramamoorthy, Mahesh; Garrett, Carleton T.; Windle, Brad; Yeudall, W. Andrew; Deb, Sumitra

2011-01-01

The current model predicts that MDM2 is primarily overexpressed in cancers with wild-type (WT) p53 and contributes to oncogenesis by degrading p53. Following a correlated expression of MDM2 and NF-κB2 transcripts in human lung tumors, we have identified a novel transactivation function of MDM2. Here, we report that in human lung tumors, overexpression of MDM2 was found in approximately 30% of cases irrespective of their p53 status, and expression of MDM2 and NF-κB2 transcripts showed a highly significant statistical correlation in tumors with WT p53. We investigated the significance of this correlated expression in terms of mechanism and biological function. Increase in MDM2 expression from its own promoter in transgenic mice remarkably enhanced expression of NF-κB2 compared with its non-transgenic littermates. Knockdown or elimination of endogenous MDM2 expression in cultured non-transformed or lung tumor cells drastically reduced expression of NF-κB2 transcripts, suggesting a normal physiological role of MDM2 in regulating NF-κB2 transcription. MDM2 could up-regulate expression of NF-κB2 transcripts when its p53-interaction domain was blocked with Nutlin-3, indicating that the MDM2-p53 interaction is dispensable for up-regulation of NF-κB2 expression. Consistently, analysis of functional domains of MDM2 indicated that although the p53-interaction domain of MDM2 contributes to the up-regulation of the NFκB2 promoter, MDM2 does not require direct interactions with p53 for this function. Accordingly, MDM2 overexpression in non-transformed or lung cancer cells devoid of p53 also generated a significant increase in the expression of NF-κB2 transcript and its targets CXCL-1 and CXCL-10, whereas elimination of MDM2 expression had the opposite effects. MDM2-mediated increase in p100/NF-κB2 expression reduced cell death mediated by paclitaxel. Furthermore, knockdown of NF-κB2 expression retarded cell proliferation. Based on these data, we propose that MDM2-mediated NF-κB2 up-regulation is a combined effect of p53-dependent and independent mechanisms and that it confers a survival advantage to lung cancer cells. PMID:22701761

Over-expression of Flt3 induces NF-kappaB pathway and increases the expression of IL-6.

PubMed

Takahashi, Shinichiro; Harigae, Hideo; Ishii, Keiko Kumura; Inomata, Mitsue; Fujiwara, Tohru; Yokoyama, Hisayuki; Ishizawa, Kenichi; Kameoka, Junichi; Licht, Jonathan D; Sasaki, Takeshi; Kaku, Mitsuo

2005-08-01

Activating mutations or over-expression of the Flt3 is prevalent in acute myeloblastic leukemia (AML), associated with activation of Ras/MAP kinase and other signaling pathways. In this study, we addressed the role of Flt3 in the activation of nuclear factor-kappa B (NF-kappaB), which is a target molecule of these kinase pathways. In BaF3 cells stably expressing Flt3, a NF-kappaB-responsive reporter was upregulated and its target gene, IL-6, was increased by the involvement of Flt3-ERK/MAPK-NF-kappaB pathway. Furthermore, we found a modest positive correlation (r=0.35, p=0.096) between Flt3 and IL-6 mRNA expression in 24 AML specimens. These results suggest a role of Flt3 over-expression in NF-kappaB pathway.

S100A8 and S100A9 Induce Cytokine Expression and Regulate the NLRP3 Inflammasome via ROS-Dependent Activation of NF-κB1

PubMed Central

Simard, Jean-Christophe; Cesaro, Annabelle; Chapeton-Montes, Julie; Tardif, Mélanie; Antoine, Francis; Girard, Denis; Tessier, Philippe A.

2013-01-01

S100A8 and S100A9 are cytoplasmic proteins expressed by phagocytes. High concentrations of these proteins have been correlated with various inflammatory conditions, including autoimmune diseases such as rheumatoid arthritis and Crohn’s disease, as well as autoinflammatory diseases. In the present study, we examined the effects of S100A8 and S100A9 on the secretion of cytokines and chemokines from PBMCs. S100A8 and S100A9 induced the secretion of cytokines such as IL-6, IL-8, and IL-1β. This secretion was associated with the activation and translocation of the transcription factor NF-κB. Inhibition studies using antisense RNA and the pharmacological agent BAY-117082 confirmed the involvement of NF-κB in IL-6, IL-8, and IL-1β secretion. S100A8- and S100A9-mediated activation of NF-κB, the NLR family, pyrin domain-containing 3 (NLRP3) protein, and pro-IL-1β expression was dependent on the generation of reactive oxygen species. This effect was synergistically enhanced by ATP, a known inflammasome activator. These results suggest that S100A8 and S100A9 enhance the inflammatory response by inducing cytokine secretion of PBMCs. PMID:23977231

Co-production of hydrogen and carbon nanotubes on nickel foam via methane catalytic decomposition

NASA Astrophysics Data System (ADS)

Ping, Dan; Wang, Chaoxian; Dong, Xinfa; Dong, Yingchao

2016-04-01

The co-production of COx-free hydrogen and carbon nanotubes (CNTs) was achieved on 3-dimensional (3D) macroporous nickel foam (NF) via methane catalytic decomposition (MCD) over nano-Ni catalysts using chemical vapor deposition (CVD) technique. By a simple coating of a NiO-Al2O3 binary mixture sol followed by a drying-calcination-reduction treatment, NF supported composite catalysts (denoted as NiyAlOx/NF) with Al2O3 transition-layer incorporated with well-dispersed nano-Ni catalysts were successfully prepared. The effects of Ni loading, calcination temperature and reaction temperature on the performance for simultaneous production of COx-free hydrogen and CNTs were investigated in detail. Catalysts before and after MCD were characterized by XRD, TPR, SEM, TEM, TG and Raman spectroscopy technology. Results show that increasing Ni loading, lowering calcination temperature and optimizing MCD reaction temperature resulted in high production efficiency of COx-free H2 and carbon, but broader diameter distribution of CNTs. Through detailed parameter optimization, the catalyst with a Ni/Al molar ratio of 0.1, calcination temperature of 550 °C and MCD temperature of 650 °C was favorable to simultaneously produce COx-free hydrogen with a growth rate as high as 10.3% and CNTs with uniform size on NF.

UPP mediated Diabetic Retinopathy via ROS/PARP and NF-κB inflammatory factor pathways.

PubMed

Luo, D-W; Zheng, Z; Wang, H; Fan, Y; Chen, F; Sun, Y; Wang, W-J; Sun, T; Xu, X

2015-01-01

Diabetic retinopathy (DR) is a leading cause of blindness in adults at working age. Human diabetic retinopathy is characterized by the basement membrane thick, pericytes loss, microaneurysms formation, retina neovascularization and vitreous hemorrhage. To investigate whether UPP activated ROS/PARP and NF-κB inflammatory factor pathways in Diabetic Retinopathy, human retinal endothelial cells (HRECs) and rats with streptozotocin-induced diabetes were used to determine the effect of UPP on ROS generation, cell apoptosis, mitochondrial membrane potential (ΔΨm) and inflammatory factor protein expression, through flow cytometry assay, immunohistochemistry, Real-time PCR, Western blot analysis and ELISA. The levels of ROS and apoptosis and the expressions of UPP (Ub and E3) and inflammatory factor protein were increased in high glucose-induced HRECs and retina of diabetic rats, while ΔΨm was decreased. The UPP inhibitor and UbshRNA could attenuate these effects through inhibiting the pathway of ROS/PARP and the expression of NF-κB inflammatory factors, and the increased UPP was a result of high glucose-induced increase of ROS generation and NF-κBp65 expression, accompanied with the decrease of ΔΨm. Clinical study showed the overexpression of UPP and detachment of epiretinal membranes in proliferative DR (PDR) patients. It has been indicated that the pathogenic effect of UPP on DR was involved in the increase of ROS generation and NF-κB expression, which associated with the ROS/PARP and NF-κB inflammatory factor pathways. Our study supports a new insight for further application of UPP inhibitor in DR treatment.

Prevention of Asthma Exacerbation in a Mouse Model by Simultaneous Inhibition of NF-κB and STAT6 Activation Using a Chimeric Decoy Strategy.

PubMed

Miyake, Tetsuo; Miyake, Takashi; Sakaguchi, Makoto; Nankai, Hirokazu; Nakazawa, Takahiro; Morishita, Ryuichi

2018-03-02

Transactivation of inflammatory and immune mediators in asthma is tightly regulated by nuclear factor κB (NF-κB) and signal transducer and activator of transcription 6 (STAT6). Therefore, we investigated the efficacy of simultaneous inhibition of NF-κB and STAT6 using a chimeric decoy strategy to prevent asthma exacerbation. The effects of decoy oligodeoxynucleotides were evaluated using an ovalbumin-induced mouse asthma model. Ovalbumin-sensitized mice received intratracheal administration of decoy oligodeoxynucleotides 3 days before ovalbumin challenge. Fluorescent-dye-labeled decoy oligodeoxynucleotides could be detected in lymphocytes and macrophages in the lung, and activation of NF-κB and STAT6 was inhibited by chimeric decoy oligodeoxynucleotide transfer. Consequently, treatment with chimeric or NF-κB decoy oligodeoxynucleotides protected against methacholine-induced airway hyperresponsiveness, whereas the effect of chimeric decoy oligodeoxynucleotides was significantly greater than that of NF-κB decoy oligodeoxynucleotides. Treatment with chimeric decoy oligodeoxynucleotides suppressed airway inflammation through inhibition of overexpression of interleukin-4 (IL-4), IL-5, and IL-13 and inflammatory infiltrates. Histamine levels in the lung were reduced via suppression of mast cell accumulation. A significant reduction in mucin secretion was observed due to suppression of MUC5AC gene expression. Interestingly, the inhibitory effects on IL-5, IL-13, and histamine secretion were achieved by transfer of chimeric decoy oligodeoxynucleotides only. This novel therapeutic approach could be useful to treat patients with various types of asthma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Wine polyphenols exert antineoplasic effect on androgen resistant PC-3 cell line through the inhibition of the transcriptional activity of COX-2 promoter mediated by NF-kβ.

PubMed

Ferruelo, A; de Las Heras, M M; Redondo, C; Ramón de Fata, F; Romero, I; Angulo, J C

2014-09-01

Mediterranean diet may play a role in the prevention of prostate cancer (PCa) development and progression. Cyclooxygenase-2 (COX-2) expression is associated with increased cellular proliferation, prevents apoptosis and favors tumor invasion. We intend to clarify whether resveratrol and other polyphenols effectively inhibit COX-2 activity and induce apoptosis in hormone-resistant PC-3 cell line. PC-3 cells were cultured and treated with different concentrations of gallic acid, tannic acid, quercetin, and resveratrol in presence of phorbol myristate acetate (PMA; 50 μg/ml) that induces COX-2 expression. Total RNA was extracted and COX-2 expression was analyzed by relative quantification real-time PCR (ΔΔCt method). COX-2 activity was determined by PGE-2 detection using ELISA. Caspase 3/7 luminescence assay was used to disclose apoptosis. Transitory transfection with short human COX-2 (phPES2 -327/+59) and p5xNF-kβ-Luc plasmids determined COX-2 promoter activity and specifically that dependant of NF-kβ. COX-2 expression was not modified in media devoid of PMA. However, under PMA induction tannic acid (2.08 ±.21), gallic acid (2.46 ±.16), quercetin (1.78 ±.14) and resveratrol (1.15 ±.16) significantly inhibited COX-2 mRNA with respect to control (3.14 ±.07), what means a 34%, 23%, 46% and 61% reduction, respectively. The inhibition in the levels of PGE-2 followed a similar pattern. All compounds studied induced apoptosis at 48 h, although at a different rate. PMA caused a rise in activity 7.4 ±.23 times phPES2 -327/+59 and 2.0 ±.1 times p5xNF-kβ-Luc at 6h compared to basal. Resveratrol suppressed these effects 17.1 ±.21 and 32.4 ±.18 times, respectively. Similarly, but to a lesser extent, the rest of evaluated polyphenols diminished PMA inductor effect on the activity of both promoters. Polyphenols inhibit transcriptional activity of COX-2 promoter mediated by NF-kβ. This effect could explain, at least in part, the induction of apoptosis in vitro by these substances in castration resistant PCa. Copyright © 2014 AEU. Published by Elsevier Espana. All rights reserved.

Uniform lateral etching of tungsten in deep trenches utilizing reaction-limited NF3 plasma process

NASA Astrophysics Data System (ADS)

Kofuji, Naoyuki; Mori, Masahito; Nishida, Toshiaki

2017-06-01

The reaction-limited etching of tungsten (W) with NF3 plasma was performed in an attempt to achieve the uniform lateral etching of W in a deep trench, a capability required by manufacturing processes for three-dimensional NAND flash memory. Reaction-limited etching was found to be possible at high pressures without ion irradiation. An almost constant etching rate that showed no dependence on NF3 pressure was obtained. The effect of varying the wafer temperature was also examined. A higher wafer temperature reduced the threshold pressure for reaction-limited etching and also increased the etching rate in the reaction-limited region. Therefore, the control of the wafer temperature is crucial to controlling the etching amount by this method. We found that the uniform lateral etching of W was possible even in a deep trench where the F radical concentration was low.

Mangiferin inhibits mastitis induced by LPS via suppressing NF-ĸB and NLRP3 signaling pathways.

PubMed

Qu, Shihui; Wang, Wenqing; Li, Depeng; Li, Shumin; Zhang, Like; Fu, Yunhe; Zhang, Naisheng

2017-02-01

During the past era, small molecules derived from various plants have attracted extensive attention for their versatile medicinal benefits. Among these, one organic molecule called mangiferin from certain plant species including mangoes and honey bush tea is widely used in treating inflammation. In this study, a LPS-induced mastitis model in mouse is established to investigate the anti-inflammatory effects and mechanism of mangiferin. The result shows that mangiferin significantly alleviates LPS-induced histopathology, meanwhile, also decreases LPS-induced MPO activity. Furthermore, mangiferin treatment remarkably impeded the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. In addition, mangiferin was found to inhibit LPS-induced NF-ĸB and NLRP3 inflammasome activation. In conclusion, these results suggested that LPS-induced mastitis can be abated by mangiferin through inhibiting NF-ĸB and NLRP3 signaling pathways. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimization and analysis of NF3 in situ chamber cleaning plasmas

NASA Astrophysics Data System (ADS)

Ji, Bing; Yang, James H.; Badowski, Peter R.; Karwacki, Eugene J.

2004-04-01

We report on the optimization and analysis of a dilute NF3 in situ plasma-enhanced chemical vapor deposition chamber cleaning plasma for an Applied Materials P-5000 DxL chamber. Using design of experiments methodology, we identified and optimized operating conditions within the following process space: 10-15 mol % NF3 diluted with helium, 200-400 sccm NF3 flow rate, 2.5-3.5 Torr chamber pressure, and 950 W rf power. Optical emission spectroscopy and Fourier transform infrared spectroscopy were used to endpoint the cleaning processes and to quantify plasma effluent emissions, respectively. The results demonstrate that dilute NF3-based in situ chamber cleaning can be a viable alternative to perfluorocarbon-based in situ cleans with added benefits. The relationship between chamber clean time and fluorine atom density in the plasma is also investigated.

Baicalin supplementation reduces serum biomarkers of skeletal muscle wasting and may protect against lean body mass reduction in cancer patients: Results from a pilot open-label study.

PubMed

Emanuele, Enzo; Bertona, Marco; Pareja-Galeano, Helios; Fiuza-Luces, Carmen; Morales, Javier Salvador; Sanchis-Gomar, Fabian; Lucia, Alejandro

2016-07-01

Muscle wasting in patients with cancer has been linked to an increased activity of nuclear factor κB (NF-κB) and higher circulating levels of activin-A (ActA), a negative growth factor for muscle mass. Baicalin is a natural flavonoid that can reduce skeletal muscle atrophy in animal models of cancer cachexia by inhibiting NF-κB. This pilot open-label study assessed the effects of baicalin supplementation (50 mg daily for 3 months) in cancer patients who showed involuntary weight loss >5% over the past 6 months. A total of 20 patients were investigated. Participants were evaluated at baseline and at the end of the 3-month study period for the following endpoints: 1) changes from baseline in serum NF-κB and ActA levels; and 2) change from baseline in lean body mass (LBM). We observed significant reduction in both NF-κB (p<0.05) and ActA (p<0.05) serum levels from baseline to 3 months. At 3 months, patients also showed a significant mean increase in LBM (+0.8 kg, p<0.05 compared with baseline). Our pilot open-label data suggest that baicalin supplementation is potentially useful for contrasting lean body mass reduction in cancer patients with involuntary weight loss, an effect which is likely mediated by the inhibition of negative growth factors for muscle mass.

NF45 inhibits cardiomyocyte apoptosis following myocardial ischemia-reperfusion injury.

PubMed

Liu, Xiaojuan; Zhang, Chi; Qian, Long; Zhang, Chao; Wu, Kunpeng; Yang, Chen; Yan, Daliang; Wu, Xiang; Shi, Jiahai

2015-12-01

Cardiomyocyte apoptosis, which occurs during ischemia and reperfusion injury, can cause irreversible damage to cardiac function. There is accumulating evidence that nuclear factor 45 (NF45) and regulatory pathways are important in understanding reparative processes in the myocardium. NF45 is a multifunctional regulator of gene expression that participates in the regulation of DNA break repair. Recently, NF45 has been proved to be associated with tumor cell apoptosis in various human malignancies. However, the underlying mechanism of NF45 regulating myocardial ischemia-reperfusion (I/R) injury remains unclear. In this study, western blot showed that NF45 expression decreased after myocardial I/R in vivo. Double immunofluorescent staining revealed that NF45, located in the nucleus of cardiomyocyes, was correlated with cardiomyocyte apoptosis. Furthermore, NF45 expression decreased in H9c2 cells after hypoxia-reoxygenation (H/R) treatment in vitro, which was in line with the results in vivo. Overexpression of NF45 in H9c2 cells reduced cell apoptosis, as evidenced by increased Bcl-2 level, as well as decreased cleaved caspase-3, p53 and p21 expression. The expression of NF45 was reduced by LY294002 (a PI3K/Akt inhibitor), but not SB203580 (a p38 inhibitor), suggesting that NF45 prevented H/R-induced H9c2 cell apoptosis via PI3K/Akt pathway. Our data may supply a novel molecular target for acute myocardial infarction (AMI) therapy. Copyright © 2015 Elsevier GmbH. All rights reserved.

Hyperglycemia and advanced glycation end products (AGEs) suppress the differentiation of 3T3-L1 preadipocytes.

PubMed

Chang, Chia-Chu; Chen, Chen-Yu; Chang, Geen-Dong; Chen, Ting-Huan; Chen, Woan-Ling; Wen, Hui-Chin; Huang, Chih-Yang; Chang, Chung-Ho

2017-08-15

Aging is characterized by mild hyperglycemia and accumulation of advanced glycation end products (AGEs). Effects of chronic exposure to hyperglycemia or AGEs on the adipogenic differentiation of 3T3-L1 preadipocytes remain unclear. We examined the chronic effect of AGEs and high glucose on the differentiation of 3T3-L1 cells by culturing 3T3-L1 cells in the presence of AGEs or 25 mM glucose for 1 month. Chronic incubation of 3T3-L1 cells with AGEs or high glucose blocked their differentiation into mature adipocytes as evidenced by reduced levels of adipocyte markers such as accumulated oil droplets, GPDH, aP2, adiponectin and of adipogenesis regulators PPARγ and C/EBPα. Levels or activities of Src, PDK1, Akt, and NF-κB were higher in AGEs- and high glucose-treated cells than those in 3T3-L1 cells. Levels of Bcl-2 were elevated in AGEs- and high glucose-treated cells, and were attenuated by inhibitors of PI3-kinase, Akt and NF-κB. Moreover, adipogenesis was attenuated in 3T3-L1 cells stably expressing Bcl-2 or YAP. These results suggest that chronic AGEs and high glucose treatments up-regulate Bcl-2 and YAP via the Akt-NF-κB pathway and impair adipogenesis.

Hyperglycemia and advanced glycation end products (AGEs) suppress the differentiation of 3T3-L1 preadipocytes

PubMed Central

Chang, Geen-Dong; Chen, Ting-Huan; Chen, Woan-Ling; Wen, Hui-Chin; Huang, Chih-Yang; Chang, Chung-Ho

2017-01-01

Aging is characterized by mild hyperglycemia and accumulation of advanced glycation end products (AGEs). Effects of chronic exposure to hyperglycemia or AGEs on the adipogenic differentiation of 3T3-L1 preadipocytes remain unclear. We examined the chronic effect of AGEs and high glucose on the differentiation of 3T3-L1 cells by culturing 3T3-L1 cells in the presence of AGEs or 25 mM glucose for 1 month. Chronic incubation of 3T3-L1 cells with AGEs or high glucose blocked their differentiation into mature adipocytes as evidenced by reduced levels of adipocyte markers such as accumulated oil droplets, GPDH, aP2, adiponectin and of adipogenesis regulators PPARγ and C/EBPα. Levels or activities of Src, PDK1, Akt, and NF-κB were higher in AGEs- and high glucose-treated cells than those in 3T3-L1 cells. Levels of Bcl-2 were elevated in AGEs- and high glucose-treated cells, and were attenuated by inhibitors of PI3-kinase, Akt and NF-κB. Moreover, adipogenesis was attenuated in 3T3-L1 cells stably expressing Bcl-2 or YAP. These results suggest that chronic AGEs and high glucose treatments up-regulate Bcl-2 and YAP via the Akt-NF-κB pathway and impair adipogenesis. PMID:28903400

Nuclear factor-κB modulates osteogenesis of periodontal ligament stem cells through competition with β-catenin signaling in inflammatory microenvironments

PubMed Central

Chen, X; Hu, C; Wang, G; Li, L; Kong, X; Ding, Y; Jin, Y

2013-01-01

Inflammation can influence multipotency and self-renewal of mesenchymal stem cells (MSCs), resulting in their awakened bone-regeneration ability. Human periodontal ligament tissue-derived MSCs (PDLSCs) have been isolated, and their differentiation potential was found to be defective due to β-catenin signaling indirectly regulated by inflammatory microenvironments. Nuclear factor-κB (NF-κB) is well studied in inflammation by many different groups. The role of NF-κB needs to be studied in PDLSCs, although genetic evidences have recently shown that NF-κB inhibits osteoblastic bone formation in mice. However, the mechanism as to how inflammation leads to the modulation of β-catenin and NF-κB signaling remains unclear. In this study, we investigated β-catenin and NF-κB signaling through regulation of glycogen synthase kinase 3β activity (GSK-3β, which modulates β-catenin and NF-κB signaling) using a specific inhibitor LiCl and a phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002. We identified that NF-κB signaling might be more important for the regulation of osteogenesis in PDLSCs from periodontitis compared with β-catenin. BAY 11-7082 (an inhibitor of NF-κB) could inhibit phosphorylation of p65 and partly rescue the differentiation potential of PDLSCs in inflammation. Our data indicate that NF-κB has a central role in regulating osteogenic differentiation of PDLSCs in inflammatory microenvironments. Given the molecular mechanisms of NF-κB in osteogenic differentiation governed by inflammation, it can be said that NF-κB helps in improving stem cell-mediated inflammatory bone disease therapy. PMID:23449446

Plant extracts of spices and coffee synergistically dampen nuclear factor-κB in U937 cells.

PubMed

Kolberg, Marit; Paur, Ingvild; Balstad, Trude R; Pedersen, Sigrid; Jacobs, David R; Blomhoff, Rune

2013-10-01

A large array of bioactive plant compounds (phytochemicals) has been identified and synergy among these compounds might contribute to the beneficial effects of plant foods. The transcription factor nuclear factor-κB (NF-κB) has been suggested as a target for many phytochemicals. Due to the complexity of mechanisms involved in NF-κB regulation, including numerous feedback loops, and the large number of phytochemicals which regulate NF-κB activity, we hypothesize that synergistic or antagonistic effects are involved. The objectives of our study were to develop a statistical methodology to evaluate the concept of synergy and antagonism and to use this methodology in a monocytic cell line (U937 expressing an NF-κB-luciferase reporter) treated with lipopolysaccharide and phytochemical-rich plant extracts. Both synergistic and antagonistic effects were clearly observed. Observed synergy was most pronounced for the combinations of oregano and coffee, and thyme and oregano. For oregano and coffee the synergistic effect was highest at 5 mg/mL with 13.9% (P < .001), and for thyme and oregano the highest synergistic effects was at 3 mg/mL with 13.7% (P < .001). Dose dependent synergistic and antagonistic effects were observed for all combinations tested. In conclusion, this work presents a methodological tool to define synergy in experimental studies. Our results support the hypothesis that phytochemical-rich plants may exert synergistic and antagonistic effects on NF-κB regulation. Such complex mechanistic interactions between phytochemicals are likely to underlie the protective effects of a plant-based diet on life-style related diseases. © 2013 Elsevier Inc. All rights reserved.

A long noncoding RNA, lincRNA-Tnfaip3, acts as a coregulator of NF-κB to modulate inflammatory gene transcription in mouse macrophages.

PubMed

Ma, Shibin; Ming, Zhenping; Gong, Ai-Yu; Wang, Yang; Chen, Xiqiang; Hu, Guoku; Zhou, Rui; Shibata, Annemarie; Swanson, Patrick C; Chen, Xian-Ming

2017-03-01

Long intergenic noncoding RNAs (lincRNAs) are long noncoding transcripts (>200 nt) from the intergenic regions of annotated protein-coding genes. We report here that the lincRNA gene lincRNA-Tnfaip3 , located at mouse chromosome 10 proximal to the tumor necrosis factor α-induced protein 3 ( Tnfaip3 ) gene, is an early-primary response gene controlled by nuclear factor-κB (NF-κB) signaling in murine macrophages. Functionally, lincRNA- Tnfaip3 appears to mediate both the activation and repression of distinct classes of inflammatory genes in macrophages. Specifically, induction of lincRNA-Tnfaip3 is required for the transactivation of NF-κB-regulated inflammatory genes in response to bacterial LPSs stimulation. LincRNA-Tnfaip3 physically interacts with the high-mobility group box 1 (Hmgb1), assembling a NF-κB/Hmgb1/lincRNA-Tnfaip3 complex in macrophages after LPS stimulation. This resultant NF-κB/Hmgb1/lincRNA-Tnfaip3 complex can modulate Hmgb1-associated histone modifications and, ultimately, transactivation of inflammatory genes in mouse macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role of NF-κB-induced lincRNA-Tnfaip3 to act as a coactivator of NF-κB for the transcription of inflammatory genes in innate immune cells through modulation of epigenetic chromatin remodeling.-Ma, S., Ming, Z., Gong, A.-Y., Wang, Y., Chen, X., Hu, G., Zhou, R., Shibata, A., Swanson, P. C., Chen, X.-M. A long noncoding RNA, LincRNA-Tnfaip3, acts as a coregulator of NF-κB to modulate inflammatory gene transcription in mouse macrophages. © FASEB.

Macrophages Modulate Migration and Invasion of Human Tongue Squamous Cell Carcinoma

PubMed Central

Pirilä, Emma; Väyrynen, Otto; Sundquist, Elias; Päkkilä, Kaisa; Nyberg, Pia; Nurmenniemi, Sini; Pääkkönen, Virve; Pesonen, Paula; Dayan, Dan; Vered, Marilena; Uhlin-Hansen, Lars; Salo, Tuula

2015-01-01

Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity. PMID:25811194

A contralateral repeated bout effect attenuates induction of NF-κB DNA binding following eccentric exercise.

PubMed

Xin, Ling; Hyldahl, Robert D; Chipkin, Stuart R; Clarkson, Priscilla M

2014-06-01

We investigated the existence of contralateral repeated bout effect and tested if the attenuation of nuclear factor-kappa B (NF-κB; an important regulator of muscle inflammation) induction following eccentric exercise is a potential mechanism. Thirty-one healthy men performed two bouts of knee extension eccentric exercise, initially with one leg and then with the opposite leg 4 wk later. Vastus lateralis muscle biopsies of both exercised and control legs were taken 3 h postexercise. Knee extension isometric and isokinetic strength (60°/sec and 180°/sec) were measured at baseline, pre-exercise, immediately postexercise, and 1/day for 5 days postexercise. Serum creatine kinase (CK) activity and muscle soreness were assessed at baseline and 1/day for 5 days postexercise. NF-κB (p65) DNA-binding activity was measured in the muscle biopsies. Isometric strength loss was lower in bout 2 than in bout 1 at 24, 72, and 96 h postexercise (P < 0.05). Isokinetic strength (60°/s and 180°/s) was reduced less in bout 2 than in bout 1 at 72 h postexercise (P < 0.01). There were no significant differences between bouts for postexercise CK activity or muscle soreness. p65 DNA-binding activity was increased following eccentric exercise (compared with the control leg) in bout 1 (122.9% ± 2.6%; P < 0.001) and bout 2 (109.1% ± 3.0%; P < 0.05). Compared with bout 1, the increase in NF-κB DNA-binding activity postexercise was attenuated after bout 2 (P = 0.0008). Repeated eccentric exercise results in a contralateral repeated bout effect, which could be due to the attenuated increase in NF-κB activity postexercise. Copyright © 2014 the American Physiological Society.

A synthetic diosgenin primary amine derivative attenuates LPS-stimulated inflammation via inhibition of NF-κB and JNK MAPK signaling in microglial BV2 cells.

PubMed

Cai, Bangrong; Seong, Kyung-Joo; Bae, Sun-Woong; Chun, Changju; Kim, Won-Jae; Jung, Ji-Yeon

2018-06-08

Diosgenin, a precursor of steroid hormones in plants, is known to exhibit diverse pharmacological activities including anti-inflammatory properties. In this study, (3β, 25R)‑spirost‑5‑en‑3‑oxyl (2‑((2((2‑aminoethyl)amino)ethyl)amino)ethyl) carbamate (DGP), a new synthetic diosgenin derivative incorporating primary amine was used to investigate its anti-inflammatory effects and underlying mechanisms of action in lipopolysaccharide (LPS)-stimulated microglial BV2 cells. Pretreatment with DGP resulted in significant inhibition of nitric oxide (NO) synthesis, and down-regulation of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated microglial BV2 cells. In addition, DGP decreased the production of reactive oxygen species (ROS) and pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α). The inhibitory effects of DGP on these inflammatory mediators in LPS-stimulated microglial BV2 cells were regulated by NF-κB signaling through blocking p65 nuclear translocation and NF-κB p65/DNA binding activity. DGP also blocked the phosphorylation of c-Jun amino-terminal kinase (JNK), but not p38 kinase or extracellular signal-regulated kinases (ERK). The NF-κB inhibitor JSH-23 and JNK-specific inhibitor SP600125 significantly decreased NO production and IL-6 release in LPS-stimulated BV2 cells, respectively. The overall results demonstrate that DGP has anti-inflammatory effects on LPS-stimulated BV2 cells via inhibition of NF-κB and JNK activation, suggesting that DGP is a potential prophylactic agent in various neurodegenerative disorders. Copyright © 2018. Published by Elsevier B.V.

Nuclear Factor-κB Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling.

PubMed

Inoue, Satoshi; Ide, Hiroki; Mizushima, Taichi; Jiang, Guiyang; Netto, George J; Gotoh, Momokazu; Miyamoto, Hiroshi

2018-06-01

We investigated the role of NF-κB in the development and progression of urothelial cancer as well as cross-talk between NF-κB and androgen receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-κB/p65 ( P = 0.015)/phospho-NF-κB/p65 ( P < 0.001) were significantly elevated in bladder tumors, compared with those in nonneoplastic urothelial tissues. The rates of phospho-NF-κB/p65 positivity were also significantly higher in high-grade ( P = 0.015)/muscle-invasive ( P = 0.033) tumors than in lower grade/non-muscle-invasive tumors. Additionally, patients with phospho-NF-κB/p65-positive muscle-invasive bladder cancer had significantly higher risks of disease progression ( P < 0.001) and cancer-specific mortality ( P = 0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-κB activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N -butyl- N -(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-κB activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both nonneoplastic and neoplastic urothelial cells, NF-κB activators/inhibitors upregulated/downregulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-κB/p65 and phospho-NF-κB/p65. Thus, NF-κB appeared to be activated in bladder cancer, which was associated with tumor progression. NF-κB activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma. Mol Cancer Ther; 17(6); 1303-14. ©2018 AACR . ©2018 American Association for Cancer Research.

Inhibition by antioxidants of nitric oxide synthase expression in murine macrophages: role of nuclear factor kappa B and interferon regulatory factor 1.

PubMed Central

Hecker, M.; Preiss, C.; Klemm, P.; Busse, R.

1996-01-01

1. In view of the potential deleterious effects of high amounts of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS) in inflammation, the prevention of the expression of this enzyme represents an important therapeutic goal. In cytokine-stimulated cells, activation of nuclear factor kappa B (NF-kappa B) is crucial for the increase in iNOS gene expression. Since NF-kappa B activation appears to involve a redox-sensitive step, we have investigated whether three structurally unrelated antioxidants, 5,7-dihydroxyflavone (chrysin), 3,4-dichloroisocoumarin (DCI) and N-acetyl 5-hydroxytryptamine (N-acetylserotonin, NAS), affect iNOS expression in cultured RAW 264.7 monocyte/macrophages stimulated with bacterial lipopolysaccharide (LPS, 140 ng ml-1) and interferon-gamma (IFN gamma, 5 u ml-1). 2. During a 6 h incubation period neither LPS nor IFN gamma alone exerted a significant effect but when combined, caused a prominent increase in nitrite formation, iNOS mRNA and protein abundance. Co-incubation with chrysin (50 microM), DCI (50 microM) or NAS (1 mM) markedly attenuated this increase in iNOS gene expression. 3. DCI, but not chrysin or NAS, prevented the activation of NF-kappa B in cells exposed to LPS plus IFN gamma for 30 min. In contrast, all three antioxidants significantly blunted the DNA-binding activity of interferon regulatory factor 1 (IRF-1), which mediates the synergistic effect of IFN gamma on iNOS gene expression in cells treated for 2 h with LPS plus IFN gamma. 4. DCI thus appears to inhibit iNOS gene expression at the transcriptional level by preventing the activation of both NF-kappa B and IRF-1. The inhibitory effect of DCI on NF-kappa B activation, however, does not seem to be related to its antioxidative properties, since DCI, unlike chrysin or NAS, is a potent serine protease inhibitor which stabilizes the inactive NF-kappa B complex by protecting the inhibitory I kappa B-alpha subunit from proteolytic degradation. 5. The virtually identical inhibitory effect of chrysin, DCI and NAS on the activation of IRF-1 points to a redox-sensitive step in the activation of this transcription factor, which in contrast to NF-kappa B requires de novo protein synthesis. 6. Since iNOS gene expression in human cells and tissues usually requires the combination of several cytokines, antioxidants such as chrysin and NAS which do not interfere with the activation of NF-kappa B may be of therapeutic value for selectively inhibiting the enhanced expression of this enzyme in inflammation. Images Figure 4 Figure 6 Figure 7 PMID:8864559

Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors.

PubMed

Peacock, Jacqueline D; Pridgeon, Matthew G; Tovar, Elizabeth A; Essenburg, Curt J; Bowman, Megan J; Madaj, Zachary B; Koeman, Julie; Boguslawski, Elissa A; Grit, Jamie; Dodd, Rebecca D; Khachaturov, Vadim; Cardona, Diana M; Chen, Mark; Kirsch, David G; Maina, Flavio; Dono, Rosanna; Winn, Mary E; Graveel, Carrie R; Steensma, Matthew R

2018-05-02

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1 MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1KO/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1KO/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs. Copyright ©2018, American Association for Cancer Research.

HMBA Enhances Prostratin-Induced Activation of Latent HIV-1 via Suppressing the Expression of Negative Feedback Regulator A20/TNFAIP3 in NF-κB Signaling.

PubMed

Chen, Duchu; Wang, Huiping; Aweya, Jude Juventus; Chen, Yanheng; Chen, Meihua; Wu, Xiaomeng; Chen, Xiaonan; Lu, Jing; Chen, Ruichuan; Liu, Min

2016-01-01

In the past decade, much emphasis has been put on the transcriptional activation of HIV-1, which is proposed as a promised strategy for eradicating latent HIV-1 provirus. Two drugs, prostratin and hexamethylene bisacetamide (HMBA), have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination, although their cellular target(s) are currently not well understood, especially under drug combination. Here, we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms. While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation, HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20, a negative feedback regulator in the NF-κB signaling pathway. In addition, HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα, thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB, a prerequisite for stimulation of transcription initiation. Thus, by blocking the negative feedback circuit, HMBA functions as a signaling enhancer of the NF-κB signaling pathway.

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases.

PubMed

Lin, T-H; Pajarinen, J; Lu, L; Nabeshima, A; Cordova, L A; Yao, Z; Goodman, S B

Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system. © 2017 Elsevier Inc. All rights reserved.

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases

PubMed Central

Lin, T.-h.; Pajarinen, J.; Lu, L.; Nabeshima, A.; Cordova, L.A.; Yao, Z.; Goodman, S.B.

2017-01-01

Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system. PMID:28215222

Role of TGR-B1-Mediated Down Regulation of NF-kB/Rel Activity During Growth Arrest of Breast Cancer Cells

DTIC Science & Technology

2001-05-01

gallate ( EGCG ), which has been shown to inhibit the induction of NF-KB and growth of breast cancer cell lines in vitro. EGCG reduced NF-KB levels in the...demonstrated activation of NF-KB is induced upon over-expression of Her-2/neu. Thus, studies were initiated with green tea pholyphenol, epigallocatechin -3...NF639 cell line derived from an MMTV-Her-2/neu mouse tumor. NF639 clonal isolates resistant to EGCG appear to display elevated levels of NF-KB. Overall

Lignocellulose nanofibers prepared by ionic liquid pretreatment and subsequent mechanical nanofibrillation of bagasse powder: Application to esterified bagasse/polypropylene composites.

PubMed

Ninomiya, Kazuaki; Abe, Megumi; Tsukegi, Takayuki; Kuroda, Kosuke; Tsuge, Yota; Ogino, Chiaki; Taki, Kentaro; Taima, Tetsuya; Saito, Joji; Kimizu, Mitsugu; Uzawa, Kiyoshi; Takahashi, Kenji

2018-02-15

In the present study, we examined the efficacy of choline acetate (ChOAc, a cholinium ionic liquid))-assisted pretreatment of bagasse powder for subsequent mechanical nanofibrillation to produce lignocellulose nanofibers. Bagasse sample with ChOAc pretreatment and subsequent nanofibrillation (ChOAc/NF-bagasse) was prepared and compared to untreated control bagasse sample (control bagasse), bagasse sample with nanofibrillation only (NF-bagasse) and with ChOAc pretreatment only (ChOAc-bagasse). The specific surface area was 0.83m 2 /g, 3.1m 2 /g, 6.3m 2 /g, and 32m 2 /g for the control bagasse, ChOAc-bagasse, NF-bagasse, and the ChOAc/NF-bagasse, respectively. Esterified bagasse/polypropylene composites were prepared using the bagasse samples. ChOAc/NF-bagasse exhibited the best dispersion in the composites. The tensile toughness of the composites was 0.52J/cm 3 , 0.73J/cm 3 , 0.92J/cm 3 , and 1.29J/cm 3 for the composites prepared using control bagasse, ChOAc-bagasse, NF-bagasse, and ChOAc/NF-bagasse, respectively. Therefore, ChOAc pretreatment and subsequent nanofibrillation of bagasse powder resulted in enhanced tensile toughness of esterified bagasse/polypropylene composites. Copyright © 2017 Elsevier Ltd. All rights reserved.

HIV-1 Nef Induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors

NASA Astrophysics Data System (ADS)

Liu, Xun; Shah, Ankit; Gangwani, Mohitkumar R.; Silverstein, Peter S.; Fu, Mingui; Kumar, Anil

2014-03-01

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients infected with HIV-1. The production of pro-inflammatory cytokines by astrocytes/microglia exposed to viral proteins is thought to be one of the mechanisms leading to HIV-1- mediated neurotoxicity. In the present study we examined the effects of Nef on CCL5 induction in astrocytes. The results demonstrate that CCL5 is significantly induced in Nef-transfected SVGA astrocytes. To determine the mechanisms responsible for the increased CCL5 caused by Nef, we employed siRNA and chemical antagonists. Antagonists of NF-κB, PI3K, and p38 significantly reduced the expression levels of CCL5 induced by Nef transfection. Furthermore, specific siRNAs demonstrated that the Akt, p38MAPK, NF-κB, CEBP, and AP-1 pathways play a role in Nef-mediated CCL5 expression. The results demonstrated that the PI3K/Akt and p38 MAPK pathways, along with the transcription factors NF-κB, CEBP, and AP-1, are involved in Nef-induced CCL5 production in astrocytes.

Cytotoxic activity of the twigs of Cinnamomum cassia through the suppression of cell proliferation and the induction of apoptosis in human colorectal cancer cells.

PubMed

Park, Gwang Hun; Song, Hun Min; Park, Su Bin; Son, Ho-Jun; Um, Yurry; Kim, Hyun-Seok; Jeong, Jin Boo

2018-01-25

Because twigs of Cinnamomum cassia (TC) have been reported to exert anti-cancer activity, the mechanistic study for TC's anti-cancer activity is required. Thus, we elucidated the potential molecular mechanism of TC's anti-proliferative effect and the induction of apoptosis in human colorectal cancer cells. How water extracts form TC (TC-HW) was used in this study. Anti-cell proliferative effect of TC-HW was evaluated by MTT assay. The change of protein or mRNA level by TC-HW was evaluated by Western blot and RT-RCR, respectively. The promoter construct for ATF3, NF-κB, TOP-FLASH or FOP-FLASH was used for the investigation of the transcriptional activity for ATF3, NF-κB or Wnt. siRNA for ATF3 or p65 was used for the knockdown of ATF3 and p65. TC-HW reduced the cell viability in human colorectal cancer cells. TC-HW decreased cyclin D1 protein level through cyclin D1 degradation via GSK3β-dependent threonine-286 (T286) phosphorylation of cyclin D1, indicating that cyclin D1 degradation may contribute to TC-HW-mediated decrease of cyclin D1 protein level. TC-HW downregulated the expression of cyclin D1 mRNA level and inhibited Wnt activation through the downregulation of β-catenin and TCF4 expression, indicating that inhibition of cyclin D1 transcription may also result in TC-HW-mediated decrease of cyclin D1 protein level. In addition, TC-HW was observed to induce apoptosis through ROS-dependent DNA damage. TC-HW-induced ROS increased NF-κB and ATF3 activation, and inhibition of NF-κB and ATF3 activation attenuated TC-HW-mediated apoptosis. Our results suggest that TC-HW may suppress cell proliferation through the downregulation of cyclin D1 via proteasomal degradation and transcriptional inhibition, and may induce apoptosis through ROS-dependent NF-κB and ATF3 activation. These effects of TC-HW may contribute to the reduction of cell viability in human colorectal cancer cells. From these findings, TC-HW has potential to be a candidate for the development of chemoprevention or therapeutic agents for human colorectal cancer.

Lithospermum erythrorhizon extract inhibits Der p2-induced inflammatory response through alleviation of thymic stromal lymphopoietin, nuclear factor Kappa B, and inflammasome expression in human bronchial epithelial cells.

PubMed

Yen, Chung-Yang; Chiang, Wen-Dee; Liu, Shang-Yong; Wang, Kun-Teng; Liao, En-Chih; Hsieh, Ching-Liang

2017-04-06

Lithospermum erythrorhizon (LE) and Angelica sinensis (AS), widely used in several folk medicine for wound, pus discharge and dermatitis for the history of several hundred years in Asian countries. To investigate the therapeutic effect of LE and AS on Der p2-induced inflammatory response in human bronchial epithelial (BEAS-2B) cells. The effects of Der p2 stimulation on thymic stromal lymphopoietin (TSLP), the nuclear factor kappa B (NF-κB) pathway, the inflammasome (specifically, the apoptosis speck-like protein [ASC] and nod-like receptor 3 [NLRP3]), Caspase-1 and the signal transducer and activator of transcription (STAT) 3 pathway were evaluated in the human bronchial epithelial (BEAS-2B) cells. The results indicated that LE, AS, and LE+AS reduced TSLP, I kappa B kinase-α, and NLRP3 levels; LE and AS reduced Caspase-1; LE and LE+AS also reduced NF-κB p50, NF-κB p65, ASC, and STAT3 levels. Both LE and AS aqueous extracts exert anti-inflammatory effects in Der p2-stimulated BEAS-2B cells. These effects may involve multiple mechanisms, including the inhibition of TSLP production as well as the suppression of IKKα, Caspase-1 and NLRP3; however, additional studies are warranted to elucidate the underlying mechanisms. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

The Nuclear Signaling of NF-κB – Current Knowledge, New Insights, and Future Perspectives

PubMed Central

Wan, Fengyi; Lenardo, Michael J.

2011-01-01

The nuclear factor-kappa B (NF-κB) transcription factor plays a critical role in diverse cellular processes associated with proliferation, cell death, development, as well as innate and adaptive immune responses. NF-κB is normally sequestered in the cytoplasm by a family of inhibitory proteins known as IκBs. The signal pathways leading to the liberation and nuclear accumulation of NF-κB, which can be activated by a wide variety of stimuli, have been extensively studied in the past two decades. After gaining access to the nucleus, NF-κB must be actively regulated to execute its fundamental function as a transcription factor. Recent studies have highlighted the importance of nuclear signaling in the regulation of NF-κB transcriptional activity. A non-Rel subunit of NF-κB, ribosomal protein S3 (RPS3), and numerous other nuclear regulators of NF-κB including Akirin, Nurr1, SIRT6, and others, have recently been identified, unveiling novel and exciting layers of regulatory specificity for NF-κB in the nucleus. Further insights into the nuclear events that govern NF-κB function will deepen our understanding of the elegant control of its transcriptional activity and better inform the potential rational design of therapeutics for NF-κB-associated diseases. PMID:19997086

Targeting TNF-α and NF-κB Activation by Bee Venom: Role in Suppressing Adjuvant Induced Arthritis and Methotrexate Hepatotoxicity in Rats

PubMed Central

Darwish, Samar F.; El-Bakly, Wesam M.; Arafa, Hossam M.; El-Demerdash, Ebtehal

2013-01-01

Low dose methotrexate is the cornerstone for the treatment of rheumatoid arthritis. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Dissatisfied arthritis patients are likely to seek the option of complementary and alternative medicine such as bee venom. The combination of natural products with modern medicine poses the possibility of potential interaction between the two groups and needs investigation. The present study was aimed to investigate the modulatory effect of bee venom acupuncture on efficacy, toxicity, and pharmacokinetics and tissue disposition of methotrexate. Complete Freund's adjuvant induced arthritic rats were treated for 3 weeks with methotrexate and/or bee venom. Arthritic score, ankle diameter, paw volume and tissue expression of NF-κB and TNF-α were determined to assess anti-arthritic effects, while anti-nociceptive effects were assessed by gait score and thermal hyperalgesia. Methotrexate toxicity was assessed by measuring serum TNF-α, liver enzymes and expression of NF-κB in liver. Combination therapy of bee venom with methotrexate significantly improved arthritic parameters and analgesic effect as compared to methotrexate alone. Bee venom ameliorated serum TNF-α and liver enzymes elevations as well as over expression of NF-κB in liver induced by methotrexate. Histological examination supported the results. And for the first time bee venom acupuncture was approved to increase methotrexate bioavailability with a significant decrease in its elimination. Conclusion: bee venom potentiates the anti-arthritic effects of methotrexate, possibly by increasing its bioavailability. Also, it provides a potent anti-nociceptive effect. Furthermore, bee venom protects against methotrexate induced hepatotoxicity mostly due to its inhibitory effect on TNF-α and NF-κB. PMID:24278124

Protective effect and molecular mechanism of liquiritin on oxybuprocaine-induced apoptosis of human corneal endothelial cells

PubMed Central

Li, Dan; Zhang, Peng

2018-01-01

This study was designed to investigate the protective effect and possible molecular mechanism of liquiritin on oxybuprocaine-induced apoptosis of human corneal endothelial cells (HCECs). In this study, the effect of oxybuprocaine on the proliferation of HCEC-12 was detected using cell counting kit-8 (CCK-8). The inductive effect of oxybuprocaine on HCEC-12 apoptosis and protective effect of liquiritin against oxybuprocaine-induced HCEC-12 apoptosis were tested by Annexin V/propidium iodide (PI) staining and flow cytometry. The production of reactive oxygen species (ROS) was analyzed by 2,7-dichlorodi-hydrofluorescein diacetate (DCFH-DA) staining and fluorescent-activated cell sorting (FACS), and the expression of nuclear factor-κB (NF-κB) p65 and apoptosis-related proteins, caspase-3 and Bax, was determined by western blot analysis. Our results show that liquiritin resisted the inhibitory effect of oxybuprocaine on the proliferation of HCEC-12, and cell activity had the most significant increase in pretreatment with liquiritin group in the concentration of 8 mg/ml; compared with that in oxybuprocaine group. Apoptosis in pretreatment with liquiritin was distinctly decreased and liquiritin resisted the production of ROS in HCEC-12 induced by oxybuprocaine. Investigation of molecular mechanism revealed that the pretreatment with liquiritin and pyrrolidinedithiocarbamic acid (PDTC) obviously blocked the expression of NF-κB p65 in nuclear protein increased by oxybuprocaine and the expression levels of total proteins, caspase-3 and Bax.Moreover, tumor necrosis factor-α (TNF-α) blocked the inhibitory effect of liquiritin on the expression of NF-κB p65 in nuclear protein and total proteins, caspase-3 and Bax, thus obstructing the protective effect of liquiritin on corneal epithelial cells. The results of this study indicated that liquiritin reduces the expression of apoptosis protein and increases the expression of anti-apoptotic protein through inhibiting NF-κB signal pathway, thus resisting HCEC-12 apoptosis induced by oxybuprocaine. PMID:29545865

Protective effect and molecular mechanism of liquiritin on oxybuprocaine-induced apoptosis of human corneal endothelial cells.

PubMed

Li, Dan; Zhang, Peng

2018-04-01

This study was designed to investigate the protective effect and possible molecular mechanism of liquiritin on oxybuprocaine-induced apoptosis of human corneal endothelial cells (HCECs). In this study, the effect of oxybuprocaine on the proliferation of HCEC-12 was detected using cell counting kit-8 (CCK-8). The inductive effect of oxybuprocaine on HCEC-12 apoptosis and protective effect of liquiritin against oxybuprocaine-induced HCEC-12 apoptosis were tested by Annexin V/propidium iodide (PI) staining and flow cytometry. The production of reactive oxygen species (ROS) was analyzed by 2,7-dichlorodi-hydrofluorescein diacetate (DCFH-DA) staining and fluorescent-activated cell sorting (FACS), and the expression of nuclear factor-κB (NF-κB) p65 and apoptosis-related proteins, caspase-3 and Bax, was determined by western blot analysis. Our results show that liquiritin resisted the inhibitory effect of oxybuprocaine on the proliferation of HCEC-12, and cell activity had the most significant increase in pretreatment with liquiritin group in the concentration of 8 mg/ml; compared with that in oxybuprocaine group. Apoptosis in pretreatment with liquiritin was distinctly decreased and liquiritin resisted the production of ROS in HCEC-12 induced by oxybuprocaine. Investigation of molecular mechanism revealed that the pretreatment with liquiritin and pyrrolidinedithiocarbamic acid (PDTC) obviously blocked the expression of NF-κB p65 in nuclear protein increased by oxybuprocaine and the expression levels of total proteins, caspase-3 and Bax.Moreover, tumor necrosis factor-α (TNF-α) blocked the inhibitory effect of liquiritin on the expression of NF-κB p65 in nuclear protein and total proteins, caspase-3 and Bax, thus obstructing the protective effect of liquiritin on corneal epithelial cells. The results of this study indicated that liquiritin reduces the expression of apoptosis protein and increases the expression of anti-apoptotic protein through inhibiting NF-κB signal pathway, thus resisting HCEC-12 apoptosis induced by oxybuprocaine.

Vitamin D attenuates pro-inflammatory TNF-α cytokine expression by inhibiting NF-кB/p65 signaling in hypertrophied rat hearts.

PubMed

Al-Rasheed, Nawal M; Al-Rasheed, Nouf M; Bassiouni, Yieldez A; Hasan, Iman H; Al-Amin, Maha A; Al-Ajmi, Hanaa N; Mohamad, Raeesa A

2015-06-01

A growing body of evidence suggests that immune activation and inflammatory mediators may play a key role in the development and progression of left ventricle (LV) hypertrophy. The present study was designed to test the hypothesis that the cardioprotective effect of cholecalciferol (Vit-D3) is mediated via the regulation of messenger RNA (mRNA) expression of pro-inflammatory cytokines. Rats were randomly divided into four groups: control group received normal saline (0.9 % NaCl) i.p. for 14 days; Vit-D3 group received Vit-D3 at a dose of 12 μg/kg/day by gavage for 14 days; ISO group received saline for 7 days, and at day 7, ISO (5 mg/kg/day) was injected i.p. for 7 consecutive days to induce cardiac hypertrophy; and Vit-D3 + ISO group was treated with Vit-D3 for 14 days, and at day 7, ISO was administered for 7 consecutive days. Heart/body weight ratio, troponin-T, creatine kinase-MB, and tumor necrosis factor-α (TNF-α) levels of LV tissue were estimated. Levels of mRNA expression of NF-кB (NF-кB)/p65 and inhibitory kappa B (IкB)-α were determined by real-time PCR. Vit-D3 administration before and during induction of cardiac hypertrophy significantly reduced (P < 0.001) cardiac biomarkers. The histopathological examination further confirmed these results. In addition, Vit-D3 significantly decreased (P < 0.001) NF-кB-p65 mRNA expression and increased (P < 0.01) IкB-α mRNA expression in LV tissues compared to ISO group. Based on these findings, it was concluded that the administration of cholecalciferol markedly attenuated the development of ISO-induced cardiac hypertrophy likely through downregulation of TNF-α /NF-кb/p65 signaling pathways. However, it should be pointed out that other signaling pathways may contribute to the cardioprotective effect of Vit-D3 which requires further investigation.

Antisense Morpholino Oligonucleotides Reduce Neurofilament Synthesis and Inhibit Axon Regeneration in Lamprey Reticulospinal Neurons.

PubMed

Zhang, Guixin; Jin, Li-qing; Hu, Jianli; Rodemer, William; Selzer, Michael E

2015-01-01

The sea lamprey has been used as a model for the study of axonal regeneration after spinal cord injury. Previous studies have suggested that, unlike developing axons in mammal, the tips of regenerating axons in lamprey spinal cord are simple in shape, packed with neurofilaments (NFs), and contain very little F-actin. Thus it has been proposed that regeneration of axons in the central nervous system of mature vertebrates is not based on the canonical actin-dependent pulling mechanism of growth cones, but involves an internal protrusive force, perhaps generated by the transport or assembly of NFs in the distal axon. In order to assess this hypothesis, expression of NFs was manipulated by antisense morpholino oligonucleotides (MO). A standard, company-supplied MO was used as control. Axon retraction and regeneration were assessed at 2, 4 and 9 weeks after MOs were applied to a spinal cord transection (TX) site. Antisense MO inhibited NF180 expression compared to control MO. The effect of inhibiting NF expression on axon retraction and regeneration was studied by measuring the distance of axon tips from the TX site at 2 and 4 weeks post-TX, and counting the number of reticulospinal neurons (RNs) retrogradely labeled by fluorescently-tagged dextran injected caudal to the injury at 9 weeks post-TX. There was no statistically significant effect of MO on axon retraction at 2 weeks post-TX. However, at both 4 and 9 weeks post-TX, inhibition of NF expression inhibited axon regeneration.

Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study

PubMed Central

Seminog, O O; Goldacre, M J

2013-01-01

Background: The neurofibromatoses (NF) are genetic disorders. Increased risks of some cancers in people with NF are well recognised, but there is no comprehensive enumeration of the risks across the whole range of site-specific cancers. Our aim was to provide this. Methods: A linked data set of hospital admissions and deaths in England was used to compare rates of tumours in an NF cohort with rates in a comparison cohort, with results expressed as rate ratios (RR). Results: The RR for all cancers combined, in people with both types of NF combined, was 4.3 (95% confidence interval (CI): 4.0–4.6), based on 769 cases of cancer in 8003 people with NF. Considering only people with presumed NF1 (as defined in the main article), the RR for all cancers excluding nervous system malignancies remained elevated (2.7, 95% CI: 2.4–2.9); and risks were significantly high for cancer of the oesophagus (3.3), stomach (2.8), colon (2.0), liver (3.8), lung (3.0), bone (19.6), thyroid (4.9), malignant melanoma (3.6), non-Hodgkin's lymphoma (3.3), chronic myeloid leukaemia (6.7), female breast (2.3) and ovary (3.7). Conclusion: Neurofibromatosis was associated with an increased risk of many individual cancers. The relationships between NF and cancers may hold clues to mechanisms of carcinogenesis more generally. PMID:23257896

Somatotopical feedback versus non-somatotopical feedback for phantom digit sensation on amputees using electrotactile stimulation.

PubMed

Zhang, Dingguo; Xu, Heng; Shull, Peter B; Liu, Jianrong; Zhu, Xiangyang

2015-05-02

Transcutaneous electrical stimulation can provide amputees with tactile feedback for better manipulating an advanced prosthesis. In general, there are two ways to transfer the stimulus to the skin: somatotopical feedback (SF) that stimulates the phantom digit somatotopy on the stump and non-somatotopical feedback (NF) that stimulates other positions on the human body. To investigate the difference between SF and NF, electrotactile experiments were conducted on seven amputees. Electrical stimulation was applied via a complete phantom map to the residual limb (SF) and to the upper arm (NF) separately. The behavior results of discrimination accuracy and response time were used to examine: 1) performance differences between SF and NF for discriminating position, type and strength of tactile feedback; 2) performance differences between SF and NF for one channel (1C), three channels (3C), and five channels (5C). NASA-TLX standardized testing was used to determine differences in mental workload between SF and NF. The grand-averaged discrimination accuracy for SF was 6% higher than NF, and the average response time for SF was 600 ms faster than NF. SF is better than NF for position, type, strength, and the overall modality regarding both accuracy and response time except for 1C modality (p<0.001). Among the six modalities of stimulation channels, performance of 1C/SF was the best, which was similar to that of 1C/NF and 3C/SF; performance of 3C/NF was similar to that of 5C/SF; performance of 5C/NF was the worst. NASA-TLX scores indicated that mental workload increased as the number of stimulation channels increased. We quantified the difference between SF and NF, and the influence of different number of stimulation channels. SF was better than NF in general, but the practical issues such as the limited area of stumps could constrain the use of SF. We found that more channels increased the amount and richness of information to the amputee while fewer channels resulted in higher performance, and thus the 3C/SF modality was a good compromise. Based on this study, we provide possible solutions to the practical problems involving the implementation of tactile feedback for amputees. These results are expected to promote the application of SF and NF tactile feedback for amputees in the future.

PPARα agonist fenofibrate attenuates TNF-α-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Weirong; Lin, Qinqin; Lin, Rong, E-mail: linrong63@yahoo.com.cn

2013-06-10

The ligand-activated transcription factor peroxisome proliferator-activated receptor-α (PPARα) participates in the regulation of cellular inflammation. More recent studies indicated that sirtuin1 (SIRT1), a NAD{sup +}-dependent deacetylase, regulates the inflammatory response in adipocytes. However, whether the role of PPARα in inflammation is mediated by SIRT1 remains unclear. In this study, we aimed to determine the effect of PPARα agonist fenofibrate on the expressions of SIRT1 and pro-inflammatory cytokine CD40 and underlying mechanisms in 3T3-L1 adipocytes. We found that fenofibrate inhibited CD40 expression and up-regulated SIRT1 expression in tumor necrosis factor-α (TNF-α)-stimulated adipocytes, and these effects of fenofibrate were reversed by PPARαmore » antagonist GW6471. Moreover, SIRT1 inhibitors sirtinol/nicotinamide (NAM) or knockdown of SIRT1 could attenuate the effect of fenofibrate on TNF-α-induced CD40 expression in adipocytes. Importantly, NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) augmented the effect of fenofibrate on CD40 expression in adipocytes. Further study found that fenofibrate decreased the expression of acetylated-NF-κB p65 (Ac-NF-κB p65) in TNF-α-stimulated adipocytes, and the effect of fenofibrate was abolished by SIRT1 inhibition. In addition, fenofibrate up-regulated SIRT1 expression through AMPK in TNF-α-stimulated adipocytes. Taken together, these findings indicate that PPARα agonist fenofibrate inhibits TNF-α-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway. -- Highlights: • Fenofibrate up-regulates SIRT1 expression in TNF-α-stimulated adipocytes. • Fenofibrate inhibits CD40 expression through SIRT1 in adipocytes. • The effects of fenofibrate on CD40 and SIRT1 expressions are dependent on PPARα. • Fenofibrate inhibits CD40 expression via SIRT1-dependent deacetylation of NF-κB. • Fenofibrate increases SIRT1 expression through PPARα and AMPK in adipocytes.« less

Interaction, coalescence, and collapse of localized patterns in a quasi-one-dimensional system of interacting particles

NASA Astrophysics Data System (ADS)

Dessup, Tommy; Coste, Christophe; Saint Jean, Michel

2017-01-01

We study the path toward equilibrium of pairs of solitary wave envelopes (bubbles) that modulate a regular zigzag pattern in an annular channel. We evidence that bubble pairs are metastable states, which spontaneously evolve toward a stable single bubble. We exhibit the concept of topological frustration of a bubble pair. A configuration is frustrated when the particles between the two bubbles are not organized in a modulated staggered row. For a nonfrustrated (NF) bubble pair configuration, the bubbles interaction is attractive, whereas it is repulsive for a frustrated (F) configuration. We describe a model of interacting solitary wave that provides all qualitative characteristics of the interaction force: It is attractive for NF systems and repulsive for F systems and decreases exponentially with the bubbles distance. Moreover, for NF systems, the bubbles come closer and eventually merge as a single bubble, in a coalescence process. We also evidence a collapse process, in which one bubble shrinks in favor of the other one, overcoming an energetic barrier in phase space. This process is relevant for both NF systems and F systems. In NF systems, the coalescence prevails at low temperature, whereas thermally activated jumps make the collapse prevail at high temperature. In F systems, the path toward equilibrium involves a collapse process regardless of the temperature.

Mangiferin ameliorates Porphyromonas gingivalis-induced experimental periodontitis by inhibiting phosphorylation of nuclear factor-κB and Janus kinase 1-signal transducer and activator of transcription signaling pathways.

PubMed

Li, H; Wang, Q; Ding, Y; Bao, C; Li, W

2017-02-01

Mangiferin is a natural polyphenol compound with anti-inflammatory properties. However, there have been few reports on the effect of mangiferin on periodontitis. Here, we investigated the anti-inflammatory effects of this compound on experimental periodontitis and the underlying mechanisms. Mice were inoculated with Porphyromonas gingivalis to induce periodontitis, and treated with mangiferin orally (50 mg/kg bodyweight, once a day) for 8 wk. Then, the alveolar bone loss was examined using a scanning electronic microscope. Expression of tumor necrosis factor-α (TNF-α) and the phosphorylation levels of nuclear factor-κB (NF-κB) and Janus kinase 1-signal transducer and activator of adhesion (JAK1-STAT) pathways in the gingival epithelium were detected using western blot analysis and immunohistochemical staining. The results showed that mice with periodontitis exhibited greater alveolar bone loss, stronger expression of TNF-α and higher phosphorylation levels of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia, compared with control mice with no periodontitis. Moreover, treatment with mangiferin could significantly inhibit alveolar bone loss, TNF-α production and phosphorylation of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia. Mangiferin has anti-inflammatory effects on periodontitis, which is associated with its ability to down-regulate the phosphorylation of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Agmatine protects retinal ganglion cells from hypoxia-induced apoptosis in transformed rat retinal ganglion cell line

PubMed Central

Hong, Samin; Lee, Jong Eun; Kim, Chan Yun; Seong, Gong Je

2007-01-01

Background Agmatine is an endogenous polyamine formed by the decarboxylation of L-arginine. We investigated the protective effects of agmatine against hypoxia-induced apoptosis of immortalized rat retinal ganglion cells (RGC-5). RGC-5 cells were cultured in a closed hypoxic chamber (5% O2) with or without agmatine. Cell viability was determined by lactate dehydrogenase (LDH) assay and apoptosis was examined by annexin V and caspase-3 assays. Expression and phosphorylation of mitogen-activated protein kinases (MAPKs; JNK, ERK p44/42, and p38) and nuclear factor-kappa B (NF-κB) were investigated by Western immunoblot analysis. The effects of agmatine were compared to those of brain-derived neurotrophic factor (BDNF), a well-known protective neurotrophin for retinal ganglion cells. Results After 48 hours of hypoxic culture, the LDH assay showed 52.3% cell loss, which was reduced to 25.6% and 30.1% when agmatine and BDNF were administered, respectively. This observed cell loss was due to apoptotic cell death, as established by annexin V and caspase-3 assays. Although total expression of MAPKs and NF-κB was not influenced by hypoxic injury, phosphorylation of these two proteins was increased. Agmatine reduced phosphorylation of JNK and NF-κB, while BDNF suppressed phosphorylation of ERK and p38. Conclusion Our results show that agmatine has neuroprotective effects against hypoxia-induced retinal ganglion cell damage in RGC-5 cells and that its effects may act through the JNK and NF-κB signaling pathways. Our data suggest that agmatine may lead to a novel therapeutic strategy to reduce retinal ganglion cell injury related to hypoxia. PMID:17908330

Low-dose occupational exposure to benzene and signal transduction pathways involved in the regulation of cellular response to oxidative stress.

PubMed

Fenga, Concettina; Gangemi, Silvia; Giambò, Federica; Tsitsimpikou, Christina; Golokhvast, Kirill; Tsatsakis, Aristidis; Costa, Chiara

2016-02-15

Benzene metabolism seems to modulate NF-κB, p38-MAPK (mitogen-activated protein kinase) and signal transducer and activator of transcription 3 (STAT3) signalling pathways via the production of reactive oxygen species. This study aims to evaluate the effects of low-dose, long-term exposure on NF-κB, STAT3, p38-MAPK and stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK) signal transduction pathways in peripheral blood mononuclear cells in gasoline station attendants. The influence of consumption of vegetables and fruits on these pathways has also been evaluated. A total of 91 men, employed in gasoline stations located in eastern Sicily, were enrolled for this study and compared with a control group of 63 male office workers with no history of exposure to benzene. The exposure was assessed by measuring urinary trans,trans-muconic acid (t,t-MA) concentration. Quantitative analyses were performed for proteins NF-κB p65, phospho-NF-κB p65, phospho-IκB-α, phospho-SAPK/JNK, phospho-p38 MAPK and phospho-STAT3 using an immunoenzymatic assay. The results of this study indicate significantly higher t,t-MA levels in gasoline station attendants. With regard to NF-κB, phospho-IκB-α and phospho-STAT3 proteins, statistically significant differences were observed in workers exposed to benzene. However, no differences were observed in SAPK/JNK and p38-MAPK activation. These changes were positively correlated with t,t-MA levels, but only phospho-NF-κB p65 was associated with the intake of food rich in antioxidant active principles. Chronic exposure to low-dose benzene can modulate signal transduction pathways activated by oxidative stress and involved in cell proliferation and apoptosis. This could represent a possible mechanism of carcinogenic action of chronic benzene exposure. Copyright © 2016 Elsevier Inc. All rights reserved.

Anti-proliferative effect of RCE-4 from Reineckia carnea on human cervical cancer HeLa cells by inhibiting the PI3K/Akt/mTOR signaling pathway and NF-κB activation.

PubMed

Bai, Caihong; Yang, Xiaojiao; Zou, Kun; He, Haibo; Wang, Junzhi; Qin, Huilin; Yu, Xiaoqin; Liu, Chengxiong; Zheng, Juyan; Cheng, Fan; Chen, Jianfeng

2016-06-01

Cervical cancer is the second leading cause of cancer deaths in women worldwide. In recent years, the studies find that inflammation is a critical component of tumor progression, and the ideal therapeutic methods should be aimed at the inflammation reaction triggers. (1β,3β,5β,25S)-spirostan-1,3-diol1-[α-L-rhamnopyranosyl-(1 → 2)-β-D-xylopyranoside] (RCE-4) was the main active composition of Reineckia carnea (Andr.) Kunth. It significantly induced apoptosis in cervical cancer Caski cells through the mitochondrial pathway in our previous studies; however, its underlying mechanism remains poorly understood. This study aimed to further evaluate the effect of RCE-4 on human cervical cancer HeLa cells. Based on this observation, we investigated the anti-cervical cancer effect of RCE-4 by modulating phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway, nuclear factor-kappa B (NF-κB) activation, and inflammation-related key factors in HeLa cells. The results indicated that the HeLa cell was the most sensitive with an IC50 of 7.01 μM; RCE-4 significantly promoted the release of cellular lactate dehydrogenase (LDH); increased DNA fragmentation and apoptosis; reduced PI3K, Akt, mTOR, and NF-κBp65 phosphorylation levels; increased the Bax and cleaved poly (ADP-ribose) polymerase (PARP) protein levels; suppressed Bcl-2 protein expression; elevated the Bax/Bcl-2 expression ratio; and decreased the interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) mRNA expressions in HeLa cells in a concentration-dependent manner. These findings suggest that RCE-4 exerted beneficially anti-cervical cancer effect on HeLa cells, mainly inhibiting PI3K/Akt/mTOR signaling pathway phosphorylation and NF-κB activation, promoting HeLa cell apoptosis. Graphical abstract Anti-tumor effect of RCE-4 on HeLa cells.

Lethality of Bacillus Anthracis Spores Due to Short Duration Heating Measured Using Infrared Spectroscopy

DTIC Science & Technology

2005-03-01

images the light onto the detector at the focal plane (FP). 32 FP L5 HG L4 SH SL L3 NF L2 Figure 10. Spectrograph Stage of Raman Base Unit...the precise intensity at any given time. There was a small red light on the front of the instrument, as indicated in Figure 13, which would glow...Force Base , Ohio APPROVED FOR PUBLIC RELEASE; DISTRIBUTION UNLIMITED. The views expressed in this thesis are those of the author and do not

Evaluation of US Air Force Survival/Armor Vest in US Army OH-58 Helicopters

DTIC Science & Technology

1976-02-01

Camera D. EVALUATION RESULTS: In releasing the cyclic friction, figures 3 £ 4, the left top *.Ige -f the armor insert and carrier hit the pilot’s chits ...ow4 -4 40 N) .44 .4 T- ek N . f. f0 r- 0 4 0 %nf𔃾 1035 -4 m) ko OD 4 m , ~ N0 4 4 -4 r4 -4 + 4 % 9 1 9 1 , 1 9 9 9 at ’ 4 . 4 0 a 0 0 ’I + 9 C a 94 9

Dual effects of ouabain on the regulation of proliferation and apoptosis in human umbilical vein endothelial cells: involvement of Na(+)-K(+)-ATPase α-subunits and NF-κB.

PubMed

Ren, Yan-Ping; Zhang, Ming-Juan; Zhang, Ting; Huang, Ruo-Wen

2014-01-01

To elucidate the effect of ouabain on the regulation of proliferation and apoptosis of HUVECs and involvement of different Na(+)-K(+)-ATPase α-subunits and NF-κB. HUVECs were isolated by collagenase perfusion, and MTT assays and cell cycle analysis were performed to study proliferation. NF-κB expression and function were examined by immunohistochemical staining and western blotting. Na(+)-K(+)-ATPase activity was determined by measuring released ouabain inhibitable inorganic phosphate (Pi). The expression of different α-subunits was investigated by real RT-PCR, western blotting and cell immunofluorescence. 0.3 nM ouabain treatment for 0.5 h triggered the proliferation of HUVECs, peaking at 1-2 h. At 1.8 nM for 0.5 h, ouabain induced an increase of cell proliferation for a short time, and then triggered a decrease after 1 h. Cell cycle analysis show that 37% of HUVECs were in G2/M phase of the cell cycle following incubation with 1.8 nM ouabain, compared with 18% with 0.3 nM ouabain. NF-κB activity was assessed by western blot analysis of IκB expression, which was significantly reduced with 0.3 nM ouabain treatment; there was no different between 1.8 nM ouabain treatment and untreated cells. Na(+)-K(+)-ATPase activity in HUVECs was markedly reduced after treatment with 0.3 nM and 1.8 nM ouabain. Real RT-PCR and western blotting indicated that Na(+)-K(+)-ATPase α1-subunit mRNA expression levels increased after 0.3 nM ouabain treatment and decreased after 1.8 nM ouabain treatment. However, α2- and α3-subunit mRNA decreased after 0.3 nM ouabain treatment and increased after 1.8 nM ouabain treatment. Ouabain at different concentrations caused dual effects on proliferation and apoptosis in HUVECs.

Hapalindole H Induces Apoptosis as an Inhibitor of NF-ĸB and Affects the Intrinsic Mitochondrial Pathway in PC-3 Androgen-insensitive Prostate Cancer Cells.

PubMed

Acuña, Ulyana Muñoz; Mo, Shunyan; Zi, Jiachen; Orjala, Jimmy; DE Blanco, Esperanza J Carcache

2018-06-01

Prostate cancer presents the highest incidence rates among all cancers in men. Hapalindole H (Hap H), isolated from Fischerella muscicola (UTEX strain number LB1829) as part of our natural product anticancer drug discovery program, was found to be significantly active against prostate cancer cells. In this study, Hap H was tested for nuclear factor-kappa B (NF-ĸB) inhibition and selective cytotoxic activity against different cancer cell lines. The apoptotic effect was assessed on PC-3 prostate cancer cells by fluorescence-activated cell sorting analysis. The underlying mechanism that induced apoptosis was studied and the effect of Hap H on mitochondria was evaluated and characterized using western blot and flow cytometric analysis. Hap H was identified as a potent NF-ĸB inhibitor (0.76 μM) with selective cytotoxicity against the PC-3 prostate cancer cell line (0.02 μM). The apoptotic effect was studied on PC-3 cells. The results showed that treatment of PC-3 cells with Hap H reduced the formation of NAD(P)H, suggesting that the function of the outer mitochondrial membrane was negatively affected. Thus, the mitochondrial transmembrane potential was assessed in Hap H treated cells. The results showed that the outer mitochondrial membrane was disrupted as an increased amount of JC-1 monomers were detected in treated cells (78.3%) when compared to untreated cells (10.1%), also suggesting that a large number of treated cells went into an apoptotic state. Hap H was found to have potent NF-ĸB p65-inhibitory activity and induced apoptosis through the intrinsic mitochondrial pathway in hormone-independent PC-3 prostate cancer cells. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.

PubMed

Yen, Hilo; Ooka, Tadasuke; Iguchi, Atsushi; Hayashi, Tetsuya; Sugimoto, Nakaba; Tobe, Toru

2010-12-16

The NF-κB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen-associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-κB pathway, leading to the production of a wide array of inflammatory cytokines, in attempt to eradicate the invaders. As a countermeasure, pathogens have evolved ways to subvert and manipulate this system to their advantage. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are closely related bacteria responsible for major food-borne diseases worldwide. Via a needle-like protein complex called the type three secretion system (T3SS), these pathogens deliver virulence factors directly to host cells and modify cellular functions, including by suppressing the inflammatory response. Using gain- and loss-of-function screenings, we identified two bacterial effectors, NleC and NleE, that down-regulate the NF-κB signal upon being injected into a host cell via the T3SS. A recent report showed that NleE inhibits NF-κB activation, although an NleE-deficient pathogen was still immune-suppressive, indicating that other anti-inflammatory effectors are involved. In agreement, our present results showed that NleC was also required to inhibit inflammation. We found that NleC is a zinc protease that disrupts NF-κB activation by the direct cleavage of NF-κB's p65 subunit in the cytoplasm, thereby decreasing the available p65 and reducing the total nuclear entry of active p65. More importantly, we showed that a mutant EPEC/EHEC lacking both NleC and NleE (ΔnleC ΔnleE) caused greater inflammatory response than bacteria carrying ΔnleC or ΔnleE alone. This effect was similar to that of a T3SS-defective mutant. In conclusion, we found that NleC is an anti-inflammatory bacterial zinc protease, and that the cooperative function of NleE and NleC disrupts the NF-κB pathway and accounts for most of the immune suppression caused by EHEC/EPEC.

Effectiveness of Neurofeedback Versus Medication in Treatment of ADHD.

PubMed

Sudnawa, Khemika Khemakanok; Chirdkiatgumchai, Vilawan; Ruangdaraganon, Nichara; Khongkhatithum, Chaiyos; Udomsubpayakul, Umaporn; Jirayucharoensak, Suwicha; Israsena, Pasin

2018-06-22

Neurofeedback (NF) is an operant conditioning procedure that trains participants for self-regulation of brain activity. Previous studies have shown that NF is a promising treatment of ADHD. However, there have been only a few RCT studies comparing effectiveness of NF with medication with various NF protocol and results. The aim of this study was to evaluate theeffectiveness of unipolar electrodeneurofeedback (NF) using theta/beta protocol compared with methylphenidate (MPH) in the treatment of ADHD. Children with newly diagnosed ADHD were randomly organised into NF and MPH groups. Each of children in NF group received 30 sessions of NF. Children in MPH group were prescribed methylphenidate for 12 weeks. Vanderbilt ADHD rating scales were completed by parents and teachers to evaluate ADHD symptoms pre- and post-treatment. Student's t-tests and Cohen's dwere used to compare symptoms between groups and evaluate effect size (ES) of each treatment respectively. Forty children participated in the study. No differences in ADHD baseline symptoms between groups were found. Post-treatment, teachers reported significantly lower ADHD symptoms in the MPH group (p = 0.01), but parents reported no differences betweenthe groups (p = 0.55). MPH demonstrated large ES (Cohen's d 1.30 - 1.69), while NF showed moderate ES (Cohen's d 0.49 - 0.68) for treatment of ADHD symptoms. This study supports NF as a promising alternative treatment for ADHD in children who do not respond or experience significant adverse effects to ADHD medications. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Ion chemistry in germane/fluorocompounds gaseous mixtures: a mass spectrometric and theoretical study.

PubMed

Antoniotti, Paola; Rabezzana, Roberto; Turco, Francesca; Borocci, Stefano; Giordani, Maria; Grandinetti, Felice

2008-10-01

The ion-molecule reactions occurring in GeH(4)/NF(3), GeH(4)/SF(6), and GeH(4)/SiF(4) gaseous mixtures have been investigated by ion trap mass spectrometry and ab initio calculations. While the NF(x)(+) (x=1-3) react with GeH(4) mainly by the exothermic charge transfer, the open-shell Ge(+) and GeH(2)(+) undergo the efficient F-atom abstraction from NF(3) and form GeF(+) and F-GeH(2)(+) as the only ionic products. The mechanisms of these two processes are quite similar and involve the formation of the fluorine-coordinated complexes Ge-F-NF(2)(+) and H(2)Ge-F-NF(2)(+), their subsequent crossing to the significantly more stable isomers FGe-NF(2)(+) and F-GeH(2)-NF(2)(+), and the eventual dissociation of these ions into GeF(+) (or F-GeH(2)(+)) and NF(2). The closed-shell GeH(+) and GeH(3)(+) are instead much less reactive towards NF(3), and the only observed process is the less efficient formation of GeF(+) from GeH(+). The theoretical investigation of this unusual H/F exchange reaction suggests the involvement of vibrationally-hot GeH(+). Passing from NF(3) to SF(6) and SiF(4), the average strength of the M-F bond increases from 70 to 79 and 142 kcal mol(-1), and in fact the only process observed by reacting GeH(n)(+) (n=0-3) with SF(6) and SiF(4) is the little efficient F-atom abstraction from SF(6) by Ge(+). Irrespective of the experimental conditions, we did not observe any ionic product of Ge-N, Ge-S, or Ge-Si connectivity. This is in line with the previously observed exclusive formation of GeF(+) from the reaction between Ge(+) and C-F compounds such as CH(3)F. Additionally observed processes include in particular the conceivable formation of the elusive thiohypofluorous acid FSH from the reaction between SF(+) and GeH(4).

Immunosuppressive effects of fisetin in ovalbumin-induced asthma through inhibition of NF-κB activity.

PubMed

Wu, Mei-Yao; Hung, Shih-Kai; Fu, Shu-Ling

2011-10-12

Fisetin, a flavonoid compound commonly present in fruits and vegetables, can exert anti-inflammation activities via inhibition of the NF-κB-signaling pathway. This study aims to evaluate the antiasthma activity of fisetin and investigate its possible molecular mechanisms. We found that fisetin attenuated lung inflammation, goblet cell hyperplasia, and airway hyperresponsiveness in ovalbumin-induced asthma and decreased eosinophils and lymphocytes in bronchoalveolar lavage fluid. Fisetin treatment reduced expression of the key initiators of allergic airway inflammation (eotaxin-1 and TSLP), Th2-associated cytokines (IL-4, IL-5, and IL-13) in lungs, and Th2-predominant transcription factor GATA-3 and cytokines in thoracic lymph node cells and splenocytes. Notably, fisetin treatment impaired NF-κB activation in OVA-stimulated lung tissues and TNF-α-stimulated bronchial epithelial cells. Collectively, this study demonstrated the beneficial effect of fisetin in the amelioration of asthmatic phenotypes. The antiasthma activity of fisetin is associated with reduction of Th2 responses as well as suppression of NF-κB and its downstream chemokines.

Plumbagin, a vitamin K3 analogue, abrogates lipopolysaccharide-induced oxidative stress, inflammation and endotoxic shock via NF-κB suppression.

PubMed

Checker, Rahul; Patwardhan, Raghavendra S; Sharma, Deepak; Menon, Jisha; Thoh, Maikho; Sandur, Santosh K; Sainis, Krishna B; Poduval, T B

2014-04-01

Plumbagin has been reported to modulate cellular redox status and suppress NF-κB. In the present study, we investigated the effect of plumbagin on lipopolysaccharide (LPS)-induced endotoxic shock, oxidative stress and inflammatory parameters in vitro and in vivo. Plumbagin inhibited LPS-induced nitric oxide, TNF-α, IL-6 and prostaglandin-E2 production in a concentration-dependent manner in RAW 264.7 cells without inducing any cell death. Plumbagin modulated cellular redox status in RAW cells. Plumbagin treatment significantly reduced MAPkinase and NF-κB activation in macrophages. Plumbagin prevented mice from endotoxic shock-associated mortality and decreased serum levels of pro-inflammatory markers. Plumbagin administration ameliorated LPS-induced oxidative stress in peritoneal macrophages and splenocytes. Plumbagin also attenuated endotoxic shock-associated changes in liver and lung histopathology and decreased the activation of ERK and NF-κB in liver. These findings demonstrate the efficacy of plumbagin in preventing LPS-induced endotoxemia and also provide mechanistic insights into the anti-inflammatory effects of plumbagin.

Sorption-desorption of indaziflam and its three metabolites in sandy soils.

PubMed

Trigo, Carmen; Koskinen, William C; Kookana, Rai S

2014-01-01

Indaziflam is a relatively new herbicide for which sorption-desorption information is lacking, and nothing is available on its metabolites. Information is needed on the multiple soil and pesticide characteristics known to influence these processes. For four soils, the order of sorption was indaziflam (N-[1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine) (sandy clay loam: Kf = 5.9, 1/nf = 0.7, Kfoc = 447; sandy loam: Kf = 3.9, 1/nf = 0.9, Kfoc = 276) > triazine indanone metabolite (N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-3-oxo-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine) (sandy clay loam: Kf = 2.1, 1/nf = 0.8, Kfoc = 177; sandy loam: Kf = 1.7, 1/nf = 0.9, Kfoc = 118) > fluoroethyldiaminotriazine metabolite (6-[(1R-1-Fluoroethyl]-1,3,5-triazine-2,4-diamine) (sandy clay loam: Kf = 0.3, 1/nf = 0.9, Kfoc = 28; sandy loam: Kf = 0.3, 1/nf = 0.9, Kfoc = 22) = indaziflam carboxylic acid metabolite (2S,3R)-3-[[4-amino-6-[(1R)-1-fluoroethyl]-1,3,5-triazin-2-yl]amino]-2,3-dihydro-2-methyl-1H-indene-5-carboxylic acid) (sandy clay loam: Kf = 0.3, 1/nf = 0.9, Kfoc = 22; sandy loam: Kf = 0.5, 1/nf = 0.8, Kfoc = 32). The metabolites being more polar than the parent compound showed lower sorption. Desorption was hysteretic for indaziflam and triazine indanone metabolite, but not for the other two metabolites. Unsaturated transient flow Kd's were lower than batch Kd's for indaziflam, but similar for fluoroethyldiaminotriazine metabolite. Batch Kd's would overpredict potential offsite transport if desorption hysteresis is not taken into account.

Geraniol produces antidepressant-like effects in a chronic unpredictable mild stress mice model.

PubMed

Deng, Xue-Yang; Xue, Jin-Song; Li, Hong-Yan; Ma, Zhan-Qiang; Fu, Qiang; Qu, Rong; Ma, Shi-Ping

2015-12-01

Geraniol (GE), which has neuroprotection and anti-inflammation activities, is mostly abundant in the essential oils of rose, ginger, lemon, orange, lavender etc. However, its antidepressant-like effect has not been reported before. The present study was designed to investigate whether GE confers an antidepressant effect in mice exposed to a chronic unpredictable mild stress (CUMS) model of depression and to explore its possible mechanisms. The results showed that GE treatments for 3 weeks significantly alleviated the depression-related behaviors of CUMS-exposed mice, as indicated by restored decreased sucrose preference and shortened immobile time in both the forced swimming tests (FST) and tail suspension tests (TST). And these ameliorative effects of GE treatment were involved with regulating CUMS-induced pro-inflammatory cytokine interleukin-1 beta (IL-1β) related neuro-inflammation. We further found that GE treatment reversed CUMS-induced IL-1β elevation, possibly by inhibiting nuclear factor kappa B (NF-κB) pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome expression. Taken together, our findings suggested that GE exerted a potential antidepressant-like effect in CUMS mice model of depression, which may provide an insight into the potential of GE in therapeutic implications for depression. Copyright © 2015 Elsevier Inc. All rights reserved.

NF-κB Activation Protects Oligodendrocytes against Inflammation

PubMed Central

Stone, Sarrabeth; Jamison, Stephanie; Yue, Yuan; Durose, Wilaiwan

2017-01-01

NF-κB is a key player in inflammatory diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the effects of NF-κB activation on oligodendrocytes in MS and EAE remain unknown. We generated a mouse model that expresses IκBαΔN, a super-suppressor of NF-κB, specifically in oligodendrocytes and demonstrated that IκBαΔN expression had no effect on oligodendrocytes under normal conditions (both sexes). Interestingly, we showed that oligodendrocyte-specific expression of IκBαΔN blocked NF-κB activation in oligodendrocytes and resulted in exacerbated oligodendrocyte death and hypomyelination in young, developing mice that express IFN-γ ectopically in the CNS (both sexes). We also showed that NF-κB inactivation in oligodendrocytes aggravated IFN-γ-induced remyelinating oligodendrocyte death and remyelination failure in the cuprizone model (male mice). Moreover, we found that NF-κB inactivation in oligodendrocytes increased the susceptibility of mice to EAE (female mice). These findings imply the cytoprotective effects of NF-κB activation on oligodendrocytes in MS and EAE. SIGNIFICANCE STATEMENT Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. NF-κB is a major player in inflammatory diseases that acts by regulating inflammation and cell viability. Data indicate that NF-κB activation in inflammatory cells facilitates the development of MS. However, to date, attempts to understand the role of NF-κB activation in oligodendrocytes in MS have been unsuccessful. Herein, we generated a mouse model that allows for inactivation of NF-κB specifically in oligodendrocytes and then used this model to determine the precise role of NF-κB activation in oligodendrocytes in models of MS. The results presented in this study represent the first demonstration that NF-κB activation acts cell autonomously to protect oligodendrocytes against inflammation in animal models of MS. PMID:28842413

VS-5584 as a PI3K/mTOR inhibitor enhances apoptotic effects of subtoxic dose arsenic trioxide via inhibition of NF-κB activity in B cell precursor-acute lymphoblastic leukemia.

PubMed

Toosi, Bahareh; Zaker, Farhad; Alikarami, Fatemeh; Kazemi, Ahmad; Teremmahi Ardestanii, Majid

2018-06-01

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway as a survival signaling cascade is a prominent feature of cancers such as acute lymphoblastic leukemia (ALL). In patients with B-cell precursor-ALL (BCP-ALL), the high activity of the pathway correlates with the weak response to anti-leukemic drugs and relapse as a result of downstream prosurvival pathway activation, such as nuclear factor kappa B (NF-κB). Recent targeted therapy (PI3K/mTOR inhibitors) in combination with a multifunctional conventional chemotherapeutic drug may be useful for treatment of BCP-ALL patients. In the current study, the potential of a subtoxic dose (0.2 μM) of arsenic trioxide (ATO) in combination with VS-5584 (a highly potent PI3K/mTOR dual inhibitor) was tested for blocking of the PI3K/Akt/mTOR pathway, inhibition of NF-κB activation and induction of apoptosis and cell-cycle arrest. The data indicate that VS-5584 as a PI3K/mTOR inhibitor inhibited cell proliferation and induced apoptosis in NALM-6 cells by means of NF-κB transcriptional activity suppression. This apoptotic process markedly increased 72 h after administration of the subtoxic dose of ATO. We also showed that concomitant treatment of VS-5584 and the subtoxic dose of ATO significantly inhibited phosphorylation of NF-κB inhibitor alpha (IκBα) and S6 ribosomal protein (S6) as the downstream proteins of the PI3K/Akt/mTOR pathway. Combining VS-5584 and a subtoxic dose of ATO also resulted in down expression of the NF-κB target genes involved in cell proliferation and survival. These results indicate that incorporation of VS-5584/ATO combination into BCP-ALL therapeutic protocols can improve treatment and the survival of patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Targeting Signaling to YAP for the Therapy of NF2

DTIC Science & Technology

2015-10-01

clear mechanism of Merlin’s tumor suppressor function. Our studies have shown that inactivation of Merlin/NF2 de-regulates the E3 ubiquitin ligase...Keywords NF2, E3 ubiquitin ligase, high throughput small molecule screening, targeted therapy. 6 Accomplishment Major goals and objectives

Vinpocetine reduces lipopolysaccharide-induced inflammatory pain and neutrophil recruitment in mice by targeting oxidative stress, cytokines and NF-κB.

PubMed

Ruiz-Miyazawa, Kenji W; Pinho-Ribeiro, Felipe A; Zarpelon, Ana C; Staurengo-Ferrari, Larissa; Silva, Rangel L; Alves-Filho, Jose C; Cunha, Thiago M; Cunha, Fernando Q; Casagrande, Rubia; Verri, Waldiceu A

2015-07-25

In response to lipopolysaccharide (LPS), tissue resident macrophages and recruited neutrophils produce inflammatory mediators through activation of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. These mediators include inflammatory cytokines and reactive oxygen species that, in turn, sensitize nociceptors and lead to inflammatory pain. Vinpocetine is a nootropic drug widely used to treat cognitive and neurovascular disorders, and more recently its anti-inflammatory properties through inhibition of NF-κB activation have been described. In the present study, we used the intraplantar and intraperitoneal LPS stimulus in mice to investigate the effects of vinpocetine pre-treatment (3, 10, or 30mg/kg by gavage) in hyperalgesia, leukocyte recruitment, oxidative stress, and pro-inflammatory cytokine production (TNF-α, IL-1β, and IL-33). LPS-induced NF-κB activation and cytokine production were investigated using RAW 264.7 macrophage cell in vitro. Vinpocetine (30mg/kg) significantly reduces hyperalgesia to mechanical and thermal stimuli, and myeloperoxidase (MPO) activity (a neutrophil marker) in the plantar paw skin, and also inhibits neutrophil and mononuclear cell recruitment, superoxide anion and nitric oxide production, oxidative stress, and cytokine production (TNF-α, IL-1β and IL-33) in the peritoneal cavity. At least in part, these effects seem to be mediated by direct effects of vinpocetine on macrophages, since it inhibited the production of the same cytokines (TNF-α, IL-1β and IL-33) and the NF-κB activation in LPS-stimulated RAW 264.7 macrophages. Our results suggest that vinpocetine represents an important therapeutic approach to treat inflammation and pain induced by a gram-negative bacterial component by targeting NF-κB activation and NF-κB-related cytokine production in macrophages. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Regulation of NF-{kappa}B activity in astrocytes: effects of flavonoids at dietary-relevant concentrations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spilsbury, Alison; Vauzour, David; Spencer, Jeremy P.E.

Highlights: Black-Right-Pointing-Pointer We tested the hypothesis that low concentrations of flavonoids inhibit NF-{kappa}B in astrocytes. Black-Right-Pointing-Pointer Primary cultured astrocytes possess a functional {kappa}B-system, measured using luciferase assays. Black-Right-Pointing-Pointer Seven flavonoids (100 nM-1 {mu}M) failed to reduce NF-{kappa}B activity in astrocytes. Black-Right-Pointing-Pointer Four flavonoids (100 nM-1 {mu}M) failed to reduce TNFa-stimulated NF-{kappa}B activity in astrocytes. Black-Right-Pointing-Pointer (-)-Epicatechin did not regulate nuclear translocation of the NF-{kappa}B subunit, p65. -- Abstract: Neuroinflammation plays an important role in the progression of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Sustained activation of nuclear transcription factor {kappa}B (NF-{kappa}B) is thought to play an importantmore » role in the pathogenesis of neurodegenerative disorders. Flavonoids have been shown to possess antioxidant and anti-inflammatory properties and we investigated whether flavonoids, at submicromolar concentrations relevant to their bioavailability from the diet, were able to modulate NF-{kappa}B signalling in astrocytes. Using luciferase reporter assays, we found that tumour necrosis factor (TNF{alpha}, 150 ng/ml) increased NF-{kappa}B-mediated transcription in primary cultures of mouse cortical astrocytes, which was abolished on co-transfection of a dominant-negative I{kappa}B{alpha} construct. In addition, TNF{alpha} increased nuclear localisation of p65 as shown by immunocytochemistry. To investigate potential flavonoid modulation of NF-{kappa}B activity, astrocytes were treated with flavonoids from different classes; flavan-3-ols ((-)-epicatechin and (+)-catechin), flavones (luteolin and chrysin), a flavonol (kaempferol) or the flavanones (naringenin and hesperetin) at dietary-relevant concentrations (0.1-1 {mu}M) for 18 h. None of the flavonoids modulated constitutive or TNF{alpha}-induced NF-{kappa}B activity. Therefore, we conclude that NF-{kappa}B signalling in astrocytes is not a major target for flavonoids.« less

Evidence of functional cross talk between the Notch and NF-κB pathways in nonneoplastic hyperproliferating colonic epithelium.

PubMed

Ahmed, Ishfaq; Roy, Badal; Chandrakesan, Parthasarathy; Venugopal, Anand; Xia, Lijun; Jensen, Roy; Anant, Shrikant; Umar, Shahid

2013-02-15

The Notch and NF-κB signaling pathways regulate stem cell function and inflammation in the gut, respectively. We investigate whether a functional cross talk exists between the two pathways during transmissible murine colonic hyperplasia (TMCH) caused by Citrobacter rodentium (CR). During TMCH, NF-κB activity and subunit phosphorylation in colonic crypts of NIH Swiss mice at days 6 and 12 were associated with increases in downstream target CXC chemokine ligand (CXCL)-1/keratinocyte-derived chemokine (KC) expression. Blocking Notch signaling acutely for 5 days with the Notch blocker dibenzazepine (DBZ) failed to inhibit crypt NF-κB activity or CXCL-1/KC expression. Chronic DBZ administration for 10 days, however, blocked Notch and NF-κB signaling in the crypts and abrogated hyperplasia. Intriguingly, chronic Notch inhibition was associated with significant increases in IL-1α, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 2, and KC in the crypt-denuded lamina propria or whole distal colon, with concomitant increases in myeloperoxidase activity. In core-3(-/-) mice, which are defective in intestinal mucin, DBZ administration replicated the results of NIH Swiss mice; in Apc(Min/+) mice, which are associated with CR-induced elevation of NF-κB-p65(276) expression, DBZ reversed the increase in NF-κB-p65(276), which may have blocked rapid proliferation of the mutated crypts. DBZ further blocked reporter activities involving the NF-κB-luciferase reporter plasmid or the Toll-like receptor 4/NF-κB/SEAPorter HEK-293 reporter cell line, while ectopic expression of Notch-N(ICD) reversed the inhibitory effect. Dietary bael (Aegle marmelos) extract (4%) and curcumin (4%) restored Notch and NF-κB cross talk in NIH Swiss mice, inhibited CR/DBZ-induced apoptosis in the crypts, and promoted crypt regeneration. Thus functional cross talk between the Notch and NF-κB pathways during TMCH regulates hyperplasia and/or inflammation in response to CR infection.

Trichomonas vaginalis Induces SiHa Cell Apoptosis by NF-κB Inactivation via Reactive Oxygen Species

PubMed Central

Quan, Juan-Hua; Kang, Byung-Hun; Yang, Jung-Bo; Rhee, Yun-Ee; Noh, Heung-Tae; Choi, In-Wook; Cha, Guang-Ho; Yuk, Jae-Min

2017-01-01

Trichomonas vaginalis induces apoptosis in host cells through various mechanisms; however, little is known about the relationship between apoptosis, reactive oxygen species (ROS), and NF-κB signaling pathways in the cervical mucosal epithelium. Here, we evaluated apoptotic events, ROS production, and NF-κB activity in T. vaginalis-treated cervical mucosal epithelial SiHa cells, with or without specific inhibitors, using fluorescence microscopy, DNA fragmentation assays, subcellular fractionation, western blotting, and luciferase reporter assay. SiHa cells treated with live T. vaginalis at a multiplicity of infection of 5 (MOI 5) for 4 h produced intracellular and mitochondrial ROS in a parasite-load-dependent manner. Incubation with T. vaginalis caused DNA fragmentation, cleavage of caspase 3 and PARP, and release of cytochrome c into the cytoplasm. T. vaginalis-treated SiHa cells showed transient early NF-κB p65 nuclear translocation, which dramatically dropped at 4 h after treatment. Suppression of NF-κB activity was dependent on parasite burden. However, treatment with the ROS scavenger, N-acetyl-C-cysteine (NAC), reversed the effect of T. vaginalis on apoptosis and NF-κB inactivation in SiHa cells. Taken together, T. vaginalis induces apoptosis in human cervical mucosal epithelial cells by parasite-dose-dependent ROS production through an NF-κB-regulated, mitochondria-mediated pathway. PMID:29410962

Quercetin ameliorates imiquimod-induced psoriasis-like skin inflammation in mice via the NF-κB pathway.

PubMed

Chen, Haiming; Lu, Chuanjian; Liu, Huazhen; Wang, Maojie; Zhao, Hui; Yan, Yuhong; Han, Ling

2017-07-01

Quercetin (QC) is a dietary flavonoid abundant in many natural plants. A series of studies have shown that it has been shown to exhibit several biological properties, including anti-inflammatory, anti-oxidant, cardio-protective, vasodilatory, liver-protective and anti-cancer activities. However, so far the possible therapeutic effect of QC on psoriasis has not been reported. The present study was undertaken to evaluate the potential beneficial effect of QC in psoriasis using a generated imiquimod (IMQ)-induced psoriasis-like mouse model, and to further elucidate its underlying mechanisms of action. Effects of QC on PASI scores, back temperature, histopathological changes, oxidative/anti-oxidative indexes, pro-inflammatory cytokines and NF-κB pathway in IMQ-induced mice were investigated. Our results showed that QC could significantly reduce the PASI scores, decrease the temperature of the psoriasis-like lesions, and ameliorate the deteriorating histopathology in IMQ-induced mice. Moreover, QC effectively attenuated levels of TNF-α, IL-6 and IL-17 in serum, increased activities of GSH, CAT and SOD, and decreased the accumulation of MDA in skin tissue induced by IMQ in mice. The mechanism may be associated with the down-regulation of NF-κB, IKKα, NIK and RelB expression and up-regulation of TRAF3, which were critically involved in the non-canonical NF-κB pathway. In conclusion, our present study demonstrated that QC had appreciable anti-psoriasis effects in IMQ-induced mice, and the underlying mechanism may involve the improvement of antioxidant and anti-inflammatory status and inhibition on the activation of the NF-κB signaling. Hence, QC, a naturally occurring flavone with potent anti-psoriatic effects, has the potential for further development as a candidate for psoriasis treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Cocoa consumption reduces NF-κB activation in peripheral blood mononuclear cells in humans.

PubMed

Vázquez-Agell, M; Urpi-Sarda, M; Sacanella, E; Camino-López, S; Chiva-Blanch, G; Llorente-Cortés, V; Tobias, E; Roura, E; Andres-Lacueva, C; Lamuela-Raventós, R M; Badimon, L; Estruch, R

2013-03-01

Epidemiological studies have demonstrated an association between high-polyphenol intake and reduced incidence of atherosclerosis. The healthy effects of cocoa-polyphenols may be due to their antioxidant and anti-inflammatory actions, although the exact mechanisms are unknown and depend on the matrix in which cocoa-polyphenols are delivered. Nuclear factor κB (NF-κB) is a key molecule in the pathophysiology of atherosclerosis involved in the regulation of adhesion molecules(AM) and cytokine expression and its activation is the first step in triggering the inflammatory process. The aim of this study was to evaluate the effect of acute cocoa consumption in different matrices related to the bioavailability of cocoa-polyphenols in NF-κB activation and the expression of AM. Eighteen healthy volunteers randomly received 3 interventions: 40g of cocoa powder with milk (CM), with water (CW), and only milk (M). NF-κB activation in leukocytes and AM (sICAM, sVCAM, E-selectin) were measured before and 6h after each intervention. Consumption of CW significantly decreased NF-κB activation compared to baseline and to CM (P < 0.05, both), did not change after CM intervention, and significantly increased after M intervention (P = 0.014). sICAM-1 concentrations significantly decreased after 6h of CW and CM interventions (P ≤ 0.026; both) and E-selectin only decreased after CW intervention (P = 0.028). No significant changes were observed in sVCAM-1 concentrations. The anti-inflammatory effect of cocoa intake may depend on the bioavailability of bioactive compounds and may be mediated at least in part by the modulation of NF-κB activation and downstream molecules reinforcing the link between cocoa intake and health. Copyright © 2011 Elsevier B.V. All rights reserved.

The C-terminal domains of NF-H and NF-M subunits maintain axonal neurofilament content by blocking turnover of the stationary neurofilament network.

PubMed

Rao, Mala V; Yuan, Aidong; Campbell, Jabbar; Kumar, Asok; Nixon, Ralph A

2012-01-01

Newly synthesized neurofilaments or protofilaments are incorporated into a highly stable stationary cytoskeleton network as they are transported along axons. Although the heavily phosphorylated carboxyl-terminal tail domains of the heavy and medium neurofilament (NF) subunits have been proposed to contribute to this process and particularly to stability of this structure, their function is still obscure. Here we show in NF-H/M tail deletion [NF-(H/M)(tailΔ)] mice that the deletion of both of these domains selectively lowers NF levels 3-6 fold along optic axons without altering either rates of subunit synthesis or the rate of slow axonal transport of NF. Pulse labeling studies carried out over 90 days revealed a significantly faster rate of disappearance of NF from the stationary NF network of optic axons in NF-(H/M)(tailΔ) mice. Faster NF disappearance was accompanied by elevated levels of NF-L proteolytic fragments in NF-(H/M)(tailΔ) axons. We conclude that NF-H and NF-M C-terminal domains do not normally regulate NF transport rates as previously proposed, but instead increase the proteolytic resistance of NF, thereby stabilizing the stationary neurofilament cytoskeleton along axons.

The C-Terminal Domains of NF-H and NF-M Subunits Maintain Axonal Neurofilament Content by Blocking Turnover of the Stationary Neurofilament Network

PubMed Central

Rao, Mala V.; Yuan, Aidong; Campbell, Jabbar; Kumar, Asok; Nixon, Ralph A.

2012-01-01

Newly synthesized neurofilaments or protofilaments are incorporated into a highly stable stationary cytoskeleton network as they are transported along axons. Although the heavily phosphorylated carboxyl-terminal tail domains of the heavy and medium neurofilament (NF) subunits have been proposed to contribute to this process and particularly to stability of this structure, their function is still obscure. Here we show in NF-H/M tail deletion [NF-(H/M)tailΔ] mice that the deletion of both of these domains selectively lowers NF levels 3–6 fold along optic axons without altering either rates of subunit synthesis or the rate of slow axonal transport of NF. Pulse labeling studies carried out over 90 days revealed a significantly faster rate of disappearance of NF from the stationary NF network of optic axons in NF-(H/M)tailΔ mice. Faster NF disappearance was accompanied by elevated levels of NF-L proteolytic fragments in NF-(H/M)tailΔ axons. We conclude that NF-H and NF-M C-terminal domains do not normally regulate NF transport rates as previously proposed, but instead increase the proteolytic resistance of NF, thereby stabilizing the stationary neurofilament cytoskeleton along axons. PMID:23028520

An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3 beta and NF-kappa B.

PubMed

Fishman, Pnina; Bar-Yehuda, Sara; Ohana, Gil; Barer, Faina; Ochaion, Avivit; Erlanger, Abigail; Madi, Lea

2004-04-01

A(3) adenosine receptor (A(3)AR) activation with the specific agonist CF101 has been shown to inhibit the development of colon carcinoma growth in syngeneic and xenograft murine models. In the present study, we looked into the effect of CF101 on the molecular mechanisms involved in the inhibition of HCT-116 colon carcinoma in mice. In tumor lesions derived from CF101-treated mice, a decrease in the expression level of protein kinase A (PKA) and an increase in glycogen synthase kinase-3 beta (GSK-3 beta) was observed. This gave rise to downregulation of beta-catenin and its transcriptional gene products cyclin D1 and c-Myc. Further mechanistic studies in vitro revealed that these responses were counteracted by the selective A(3)AR antagonist MRS 1523 and by the GSK-3 beta inhibitors lithium and SB216763, confirming that the observed effects were A(3)AR and GSK-3 beta mediated. CF101 downregulated PKB/Akt expression level, resulting in a decrease in the level and DNA-binding capacity of NF-kappa B, both in vivo and in vitro. Furthermore, the PKA and PKB/Akt inhibitors H89 and Worthmannin mimicked the effect of CF101, supporting their involvement in mediating the response to the agonist. This is the first demonstration that A(3)AR activation induces colon carcinoma growth inhibition via the modulation of the key proteins GSK-3 beta and NF-kappa B.

The biophysical and physiological basis for mitigated elevations in heart rate with electric fan use in extreme heat and humidity

NASA Astrophysics Data System (ADS)

Ravanelli, Nicholas M.; Gagnon, Daniel; Hodder, Simon G.; Havenith, George; Jay, Ollie

2017-02-01

Electric fan use in extreme heat wave conditions has been thought to be disadvantageous because it might accelerate heat gain to the body via convection. However, it has been recently shown that fan use delays increases in heart rate even at high temperatures (42 °C) in young adults. We here assess the biophysical and physiological mechanisms underlying the apparently beneficial effects of fan use. Eight males (24 ± 3 y; 80.7 ± 11.7 kg; 2.0 ± 0.1 m2) rested at either 36 °C or 42 °C, with (F) or without (NF) electric fan use (4.2 m/s) for 120 min while humidity increased every 7.5 min by 0.3 kPa from a baseline value of 1.6 kPa. Heart rate (HR), local sweat rate (LSR), cutaneous vascular conductance (CVC), core and mean skin temperatures, and the combined convective/radiative heat loss (C+R), evaporative heat balance requirements (Ereq) and maximum evaporative potential (Emax) were assessed. C+R was greater with fan use at 36 °C (F 8 ± 6, NF 2 ± 2 W/m2; P = 0.04) and more negative (greater dry heat gain) with fan use at 42 °C (F -78 ± 4, NF -27 ± 2 W/m2; P < 0.01). Consequently, Ereq was lower at 36 °C (F 38 ± 16, NF 45 ± 3 W/m2; P = 0.04) and greater at 42 °C (F 125 ± 1, NF 74 ± 3 W/m2; P < 0.01) with fan use. However, fan use resulted in a greater Emax at baseline humidity at both 36 °C (F 343 ± 10, NF 153 ± 5 W/m2; P < 0.01) and 42 °C (F 376 ± 13, NF 161 ± 4 W/m2; P < 0.01) and throughout the incremental increases in humidity. Within the humidity range that a rise in HR was prevented by fan use but not without a fan, LSR was higher in NF at both 36 °C ( P = 0.04) and 42 °C ( P = 0.05), and skin temperature was higher in NF at 42 °C ( P = 0.05), but no differences in CVC or core temperatures were observed (all P > 0.05). These results suggest that the delayed increase in heart rate with fan use during extreme heat and humidity is associated with improved evaporative efficiency.

Quantum chemical calculations of anion complex [B12Hx(NF2)12-x]2-, x = 9 - 12

NASA Astrophysics Data System (ADS)

Koblova, E. A.; Saldin, V. I.; Ustinov, A. Yu

2017-01-01

The geometric, energetic, spectral and electronic properties of various isomers of B12Hх(NF2)12-х 2- anion complex with x = 9 - 12 have been studied using Density Functional Theory (B3LYP/6-311++G**). It was shown that the most stable isomers are characterized by the preference to form the most symmetric structures with uniformly distributed charge densities. However, when replacing a hydrogen atom with difluoramino group, an inductive effect occurs. NF2 group pulls a part of electron density that leads to the polarization of the boron core. Blue shifts in the IR spectrum compared to the vibrations of the free radical NF2 ranging from 5 to 69 cm-1 for the most stable isomers with the minimum total energy are characteristic and points to the stability of B12Hх(NF2)12-х 2- anions. The obtained results broaden the idea of aromaticity of B12H12 2- anion and will be useful in synthesis of new B12H12 2- derivatives.

A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gan, Fei-Fei; Ling, Hui; Ang, Xiaohui

Natural compounds containing vanilloid and Michael acceptor moieties appear to possess anti-cancer and chemopreventive properties. The ginger constituent shogaol represents one such compound. In this study, the anti-cancer potential of a synthetic novel shogaol analog 3-phenyl-3-shogaol (3-Ph-3-SG) was assessed by evaluating its effects on signaling pathways. At non-toxic concentrations, 3-Ph-3-SG suppressed cancer cell invasion in MDA-MB-231 and MCF-7 breast carcinoma cells through inhibition of PMA-activated MMP-9 expression. At similar concentrations, 3-Ph-3-SG reduced expression of the inflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanglandin-E{sub 2} (PGE{sub 2}) in RAW 264.7 macrophage-like cells. Inhibition of cancermore » cell invasion and inflammation by 3-Ph-3-SG were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway. The 3-Ph-3-SG also demonstrated cytoprotective effects by inducing the antioxidant response element (ARE)-driven genes NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Cytoprotection by 3-Ph-3-SG was achieved at least partly through modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (Keap1), which resulted in accumulation of transcription factor NF-E2 p45-related factor 2 (Nrf2). The activities of 3-Ph-3-SG were comparable to those of 6-shogaol, the most abundant naturally-occurring shogaol, and stronger than those of 4-hydroxyl-null deshydroxy-3-phenyl-3-shogaol, which attested the importance of the 4-hydroxy substituent in the vanilloid moiety for bioactivity. In summary, 3-Ph-3-SG is shown to possess activities that modulate stress-associated pathways relevant to multiple steps in carcinogenesis. Therefore, it warrants further investigation of this compound as a promising candidate for use in chemotherapeutic and chemopreventive strategies. - Highlights: • Novel shogaol 3-phenyl-3-shogaol suppressed cancer cell invasion and inflammation. • Anti-invasive and anti-inflammatory effects were NF-κB-dependent. • 3-Phenyl-3-shogaol induced ARE-driven genes to achieve cytoprotection. • Cytoprotective effects were brought about by modification of cysteines in Keap1. • Chemopreventive activities of 3-phenyl-3-shogaol and 6-shogaol were comparable.« less

Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia.

PubMed

Boudry-Labis, Elise; Roche-Lestienne, Catherine; Nibourel, Olivier; Boissel, Nicolas; Terre, Christine; Perot, Christine; Eclache, Virginie; Gachard, Nathalie; Tigaud, Isabelle; Plessis, Ghislaine; Cuccuini, Wendy; Geffroy, Sandrine; Villenet, Céline; Figeac, Martin; Leprêtre, Frederic; Renneville, Aline; Cheok, Meyling; Soulier, Jean; Dombret, Hervé; Preudhomme, Claude

2013-04-01

Germline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small ∼0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression. Copyright © 2013 Wiley Periodicals, Inc.

Long noncoding RNA HAGLROS regulates cell apoptosis and autophagy in lipopolysaccharides-induced WI-38 cells via modulating miR-100/NF-κB axis.

PubMed

Liu, Meihan; Han, Tao; Shi, Shaomin; Chen, Enqi

2018-06-07

Pneumonia is a lower respiratory disease caused by pathogens or other factors. This study aimed to explore the roles and mechanism of long noncoding RNA HAGLROS in lipopolysaccharides (LPS)-induced inflammatory injury in pneumonia. The HAGLROS expression in serum of patients with acute stage pneumonia was detected. To induce pulmonary injury, WI-38 human lung fibroblasts were stimulated with lipopolysaccharides (LPS). The HAGLROS expressions in LPS-treated WI-38 cells and the effects of HAGLROS knockdown on the viability, apoptosis, and autophagy of LPS-induced cells were detected. Moreover, the regulatory relationship between HAGLROS and miR-100 was explored as well as the functional targets of miR-100 were identified. Furthermore, the regulatory relationship between miR-100 and PI3K/AKT/NF-κB pathway was elucidated. LncRNA HAGLROS was higher expressed in serum of patients with acute stage pneumonia compared with that in serum of healthy control. LPS caused WI-38 cell injury and increased HAGLROS levels. Downregulation of HAGLROS alleviated LPS-induced cell injury via increasing cell viability, and inhibiting apoptosis and autophagy. Moreover, there was a negative correlation between HAGLROS and miR-100, and the effects of HAGLROS downregulation on LPS-induced apoptosis and autophagy in WI-38 cells were by regulation of miR-100. Furthermore, NFΚB3 was verified as a functional target of miR-100 and effects of miR-100 inhibition on LPS-induced WI-38 cell injury were alleviated by knockdown of NFΚB3. Besides, Knockdown of HAGLROS inhibited the activation of PI3K/AKT/NF-κB pathway. Our findings reveal that downregulation of HAGLROS may alleviate LPS-induced inflammatory injury in WI-38 cells via modulating miR-100/NF-κB axis. HAGLROS/miR-100/NF-κB axis may provide a new strategy for treating acute stage of pneumonia. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Protective protein/cathepsin A down-regulates osteoclastogenesis by associating with and degrading NF-kappaB p50/p65.

PubMed

Masuhara, Masaaki; Sato, Takuya; Hada, Naoto; Hakeda, Yoshiyuki

2009-01-01

Disruption of the cooperative function balance between osteoblasts and osteoclasts causes various bone disorders, some of which are attributed to abnormal osteoclast recruitment. Osteoclast differentiation is dependent on the receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) as well as the macrophage colony-stimulating factor. The osteoclast formation induced by cytokines requires activation of NF-kappaB, AP-1 and nuclear factor of activated T cells c1. However, osteoclasts are not the only cell types that express these transcription factors, suggesting that some unknown molecules specific for osteoclasts may associate with the transcription factors. Here, we explored the possibility of molecules binding directly to NF-kappaB and cloned protective protein/cathepsin A (PPCA) by yeast two-hybrid screening using a cDNA library of osteoclast precursors. Forced expression of PPCA with p50/p65 in HEK293 cells decreased both the level of p50/p65 proteins and the transcriptional activity. Abundant PPCA was detected in the lysosomes of the transfected HEK293 cells, but a small amount of this enzyme was also present in the cytosolic fraction. In addition, over-expression of PPCA caused the disappearance of p50/p65 in both the lysosomal and cytosolic fractions. PPCA was expressed throughout osteoclastogenesis, and the expression was slightly up-regulated by RANKL signaling. Knockdown of PPCA in osteoclast precursors with PPCA siRNA stimulated binding of nuclear proteins to oligonucleotides containing an NF-kappaB binding motif and increased osteoclastogenesis. Our present results indicate a novel role for PPCA in osteoclastogenesis via down-regulation of NF-kappaB activity and suggest a new function for PPCA as an NF-kappaB-degrading enzyme in addition to its known multifunctional properties.

Heats of NF(sub n) (n= 1-3) and NF(sub n)(+)(n = 1-3)

NASA Technical Reports Server (NTRS)

Ricca, Alessandra; Arnold, James (Technical Monitor)

1998-01-01

Accurate heats of formation are computed for NF(sub n) and NF(sub n)(+), for n = 1-3. The geometries and the vibrational frequencies are determined at the B3LYP level of theory. The energetics are determined at the CCSD(T) level of theory. Basis set limit values are obtained by extrapolation. In those cases where the CCSD(T) calculations become prohibitively large, the basis set extrapolation is performed at the MP2 level. The temperature dependence of the heat of formation, heat capacity, and entropy are computed for the temperature range 300 to 4000 K and fit to a polynomial.

Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice

PubMed Central

McKenna, Sarah; Michaelis, Katherine A.; Agboke, Fadeke; Liu, Thanh; Han, Kristie; Yang, Guang; Dennery, Phyllis A.

2014-01-01

Oxygen toxicity contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Neonatal mice exposed to hyperoxia develop a simplified lung structure that resembles BPD. Sustained activation of the transcription factor NF-κB and increased expression of protective target genes attenuate hyperoxia-induced mortality in adults. However, the effect of enhancing hyperoxia-induced NF-κB activity on lung injury and development in neonatal animals is unknown. We performed this study to determine whether sustained NF-κB activation, mediated through IκBβ overexpression, preserves lung development in neonatal animals exposed to hyperoxia. Newborn wild-type (WT) and IκBβ-overexpressing (AKBI) mice were exposed to hyperoxia (>95%) or room air from day of life (DOL) 0–14, after which all animals were kept in room air. Survival curves were generated through DOL 14. Lung development was assessed using radial alveolar count (RAC) and mean linear intercept (MLI) at DOL 3 and 28 and pulmonary vessel density at DOL 28. Lung tissue was collected, and NF-κB activity was assessed using Western blot for IκB degradation and NF-κB nuclear translocation. WT mice demonstrated 80% mortality through 14 days of exposure. In contrast, AKBI mice demonstrated 60% survival. Decreased RAC, increased MLI, and pulmonary vessel density caused by hyperoxia in WT mice were significantly attenuated in AKBI mice. These findings were associated with early and sustained NF-κB activation and expression of cytoprotective target genes, including vascular endothelial growth factor receptor 2. We conclude that sustained hyperoxia-induced NF-κB activation improves neonatal survival and preserves lung development. Potentiating early NF-κB activity after hyperoxic exposure may represent a therapeutic intervention to prevent BPD. PMID:24748603

Participation of the IKK-α/β complex in the inhibition of the TNF-α/NF-κB pathway by glycine: Possible involvement of a membrane receptor specific to adipocytes.

PubMed

Contreras-Nuñez, Erika; Blancas-Flores, Gerardo; Cruz, Miguel; Almanza-Perez, Julio Cesar; Gomez-Zamudio, Jaime H; Ventura-Gallegosc, Jose Luis; Zentella-Dehesa, Alejandro; Roberto-Lazzarini; Roman-Ramos, Ruben; Alarcon-Aguilar, Francisco Javier

2018-06-01

Glycine modulates inflammatory processes mediated by macrophages and adipocytes through decreasing the secretion of TNF-α, IL-6, and leptin, while increasing adiponectin. These effects have been associated with the inactivation of NF-κB in response to TNF-α, across an increase of its inhibitor IκB-α in adipocytes. However, glycine upstream mainly influences the IκB kinase (IKK) complex, a multi-protein kinase complex considered a critical point in regulation of the NF-κB pathway; whether that is responsible for the TNF-α-induced phosphorylation of IkB has not been explored. Additionally, although previous studies have described glycine interactions with specific receptors (GlyR) in different immune system cell types, it is currently unknown whether adipocytes present GlyR. In this research, participation of the IKK-α/β complex in the inhibition of the TNF-α/NF-κB pathway by glycine was evaluated and associated with the synthesis and secretion of inflammatory cytokines in 3T3-L1 adipocytes. Furthermore, we also explored GlyR expression, its localization on the plasmatic membrane, intracellular calcium concentrations [Ca 2+ ] i and strychnine antagonist action over the GlyR in these cells. Glycine decreased the IKK-α/β complex and the phosphorylation of NF-κB, diminishing the expression and secretion of IL-6 and TNF-α, but increasing that of adiponectin. GlyR expression and its fluorescence in the plasma membrane were increased in the presence of glycine. In addition, glycine decreased [Ca 2+ ] i ; whereas strychnine + glycine treatment inhibited the activation of NF-κB observed with glycine. In conclusion, the reduction of TNF-α and IL-6 and suppression of the TNF-α/NF-κB pathway by glycine may be explained in part by inhibition of the IKK-α/β complex, with a possible participation of GlyR in 3T3-L1 adipocytes. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Spin-Orbit Relaxation Rates of Bi(6p(3) 2D(3/2)) Following Photolysis of Bi(CH3)3 at Lambda = 193 nm

DTIC Science & Technology

1989-07-07

C. E. Gardner, J. Chem. Phys. 80, 1861 and references therein (1981). 12. R. F. Heidner III, H . Helvajian , J. S. Holloway, and J. B. Koffend (to be...observed from the blue BiF(A - X) band system. [1 0] NF(aIA) is conveniently produced by means of the H2/NF2 chain reac- tion[111 F + H2 * HF(v) + H (3... H + NF2 NF(a 1) + F (4) in which reaction 4 produces the (a 1A) state with a branching ratio of >0.9. [7,121 Thus, we have a system capable of

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes

PubMed Central

Song, Zhen-peng; Xiong, Bing-rui; Guan, Xue-hai; Cao, Fei; Manyande, Anne; Zhou, Ya-qun; Zheng, Hua; Tian, Yu-ke

2016-01-01

Aim: To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats. Methods: A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 μg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1β in vitro. Results: BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 μg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1β-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 μmol/L) significantly inhibited the translocation of NF-κB to nucleus. Conclusion: Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes. PMID:27157092

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes.

PubMed

Song, Zhen-Peng; Xiong, Bing-Rui; Guan, Xue-Hai; Cao, Fei; Manyande, Anne; Zhou, Ya-Qun; Zheng, Hua; Tian, Yu-Ke

2016-06-01

To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats. A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 μg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1β in vitro. BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 μg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1β-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 μmol/L) significantly inhibited the translocation of NF-κB to nucleus. Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes.

Immunomodulatory Effects of the Mycosporine-Like Amino Acids Shinorine and Porphyra-334

PubMed Central

Becker, Kathrin; Hartmann, Anja; Ganzera, Markus; Fuchs, Dietmar; Gostner, Johanna M.

2016-01-01

Mycosporine-like amino acids (MAAs) are secondary metabolites, produced by a large variety of microorganisms including algae, cyanobacteria, lichen and fungi. MAAs act as UV-absorbers and photo-protectants. MAAs are suggested to exert pharmaceutical relevant bioactivities in the human system. We particularly focused on their effect on defence and regulatory pathways that are active in inflamed environments. The MAAs shinorine and porphyra-334 were isolated and purified from the red algae Porphyra sp. using chromatographic methods. The effect of MAAs on central signaling cascades, such as transcription factor nuclear factor kappa b (NF-κB) activation, as well as tryptophan metabolism, was investigated in human myelomonocytic THP-1 and THP-1-Blue cells. Cells were exposed to the MAAs in the presence or absence of lipopolysaccharide (LPS). NF-κB activity and the activity of tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO-1) were used as readout. Compounds were tested in the concentration range from 12.5 to 200 µg/mL. Both MAAs were able to induce NF-κB activity in unstimulated THP-1-Blue cells, whereby the increase was dose-dependent and more pronounced with shinorine treatment. While shinorine also slightly superinduced NF-κB in LPS-stimulated cells, porphyra-334 reduced NF-κB activity in this inflammatory background. Modulation of tryptophan metabolism was moderate, suppressive in stimulated cells with the lower treatment concentration of both MAAs and with the unstimulated cells upon porphyra-334 treatment. Inflammatory pathways are affected by MAAs, but despite the structural similarity, diverse effects were observed. PMID:27338421

Downregulation of STAT3/NF-κB potentiates gemcitabine activity in pancreatic cancer cells.

PubMed

Gong, Jingjing; Muñoz, Amanda R; Pingali, Subramanya; Payton-Stewart, Florastina; Chan, Daniel E; Freeman, James W; Ghosh, Rita; Kumar, Addanki P

2017-02-01

There is an unmet need to develop new agents or strategies against therapy resistant pancreatic cancer (PanCA). Recent studies from our laboratory showed that STAT3 negatively regulates NF-κB and that inhibition of this crosstalk using Nexrutine® (Nx) reduces transcriptional activity of COX-2. Inhibition of these molecular interactions impedes pancreatic cancer cell growth as well as reduces fibrosis in a preclinical animal model. Nx is an extract derived from the bark of Phellodendron amurense and has been utilized in traditional Chinese medicine as antidiarrheal, astringent, and anti-inflammatory agent for centuries. We hypothesized that "Nx-mediated inhibition of survival molecules like STAT3 and NF-κB in pancreatic cancer cells will improve the efficacy of the conventional chemotherapeutic agent, gemcitabine (GEM)." Therefore, we explored the utility of Nx, one of its active constituents berberine and its derivatives, to enhance the effects of GEM. Using multiple human pancreatic cancer cells we found that combination treatment with Nx and GEM resulted in significant alterations of proteins in the STAT3/NF-κB signaling axis culminating in growth inhibition in a synergistic manner. Furthermore, GEM resistant cells were more sensitive to Nx treatment than their parental GEM-sensitive cells. Interestingly, although berberine, the Nx active component used, and its derivatives were biologically active in GEM sensitive cells they did not potentiate GEM activity when used in combination. Taken together, these results suggest that the natural extract, Nx, but not its active component, berberine, has the potential to improve GEM sensitivity, perhaps by down regulating STAT3/NF-κB signaling. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Effects of canonical NF-κB signaling pathway on the proliferation and odonto/osteogenic differentiation of human stem cells from apical papilla.

PubMed

Li, Junjun; Yan, Ming; Wang, Zilu; Jing, Shuanglin; Li, Yao; Liu, Genxia; Yu, Jinhua; Fan, Zhipeng

2014-01-01

NF-κB signaling pathway plays a complicated role in the biological functions of mesenchymal stem cells. However, the effects of NF-κB pathway on the odonto/osteogenic differentiation of stem cells from apical papilla (SCAPs) remain unclear. The present study was designed to evaluate the effects of canonical NF-κB pathway on the osteo/odontogenic capacity of SCAPs in vitro. Western blot results demonstrated that NF-κB pathway in SCAPs was successfully activated by TNF-α or blocked by BMS-345541. NF-κB pathway-activated SCAPs presented a higher proliferation activity compared with control groups, as indicated by dimethyl-thiazol-diphenyl tetrazolium bromide assay (MTT) and flow cytometry assay (FCM). Wound scratch assay revealed that NF-κB pathway-activated SCAPs presented an improved migration capacity, enhanced alkaline phosphatase (ALP) activity, and upregulated mineralization capacity of SCAPs, as compared with control groups. Meanwhile, the odonto/osteogenic markers (ALP/ALP, RUNX2/RUNX2, OSX/OSX, OCN/OCN, OPN/OPN, BSP/BSP, DSPP/DSP, and DMP-1/DMP-1) in NF-κB pathway-activated SCAPs were also significantly upregulated as compared with control groups at both protein and mRNA levels. However, NF-κB pathway-inhibited SCAPs exhibited a lower proliferation/migration capacity, and decreased odonto/osteogenic ability in comparison with control groups. Our findings suggest that classical NF-κB pathway plays a paramount role in the proliferation and committed differentiation of SCAPs.

The effect of charge on the renal distribution of ferritin.

PubMed

Cohen, S; Vernier, R L; Michael, A F

1983-02-01

The effect of charge on the tissue distribution of ferritin was evaluated in rats following intravenous administration of 3 monomeric species preparatively separated by molecular sieve chromatography from aggregated ferritin and having the same molecular weight but differing only in electrostatic charge: native ferritin, with a isoelectric point (pI) of 4.5 (NF); cationized ferritin, with a pI of 6.4-7.4 (CF 7.0); and cationized ferritin, with a pI of 8.25-8.75 (CF 8.5). At varying time intervals (30 minutes to 72 hours) after the administration of these ferritins in a dose of 10 mg/100 g, the levels in the blood were determined, the tissue (kidney, liver, spleen) distribution semiquantitatively evaluated by immunofluorescence (IF), and electron microscopic examination (EM) of the kidney carried out. The following results were obtained: 1) The plasma levels of CF (8.5) and CF (7.0) were significantly higher than NF after 6 hours. NF was not detected after 24 hours, whereas CF continued to circulate at 72 hours. 2) There was a striking decrease in the uptake of CF (7.0) and CF (8.5), when compared with NF, by Kupffer cells and splenic phagocytes in the red pulp at all time periods. 3) In the glomerulus, NF was found primarily in the mesangium and gradually disappeared over a period of 72 hours, whereas CF was present in greater amounts and persisted for longer periods of time in the mesangium and in the peripheral capillary wall. By electron microscopy, CF (8.5) could be seen in th lamina rara and within the mesangium in small aggregates aligned parallel to mesangial cell processes, whereas NF and CF (7.0) were distributed homogeneously throughout the mesangial matrix. 4) NF, but not CF, was also observed surrounding blood vessels and in interstitial phagocytes. These in vivo studies demonstrate that the electrostatic charge of ferritin affects its uptake in vivo by components of the mononuclear phagocytic system (MPS). The persistence and distribution of CF in glomeruli is a consequence of higher blood levels associated with impaired phagocytic uptake as well as charge-related binding to sites within the glomeruli.

Protective effect of geraniol inhibits inflammatory response, oxidative stress and apoptosis in traumatic injury of the spinal cord through modulation of NF-κB and p38 MAPK

PubMed Central

Wang, Jiansheng; Su, Baishan; Zhu, Hongbin; Chen, Chao; Zhao, Gang

2016-01-01

Geraniol is a type of monoterpenoid with a rose scent and a slightly sweet flavor. It is found in the volatile oil of various plants, and has anti-inflammatory and anti-oxidant effects. The present study aimed to investigate the protective effect of geraniol in inhibiting the inflammatory response, oxidative stress and apoptosis in traumatic spinal cord injury (SCI), as well as to analyze the mechanism underlying its effect. Adult male Sprague-Dawley rats were induced to traumatic SCI through a surgical procedure and were defined as the SCI model group. SCI or normal rats were then administered 250 mg/kg/day geraniol for 4 weeks. The Basso, Beattie and Bresnahan (BBB) test and the spinal cord water content were used to analyze the effect of geraniol against traumatic SCI in rats. The inflammatory response, oxidative stress, and caspase-9 and −3 activities were measured using commercial ELISA kits. In addition, the associated mechanism was analyzed, using western blot analysis to determine the protein expression levels of nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK). The results of the present study demonstrated that BBB scores were significantly increased and the spinal cord water content was significantly inhibited in SCI rats after 3 weeks of geraniol treatment. Furthermore, the inflammatory response, oxidative stress, and the caspase-9 and −3 activities were significantly suppressed upon treatment with geraniol. Finally, the mechanism of geraniol against traumatic SCI downregulated the NF-κB and p38 MAPK pathways in SCI rats. Therefore, the protective effect of geraniol is suggested to inhibit the inflammatory response, oxidative stress and apoptosis in traumatic SCI through the modulation of NF-κB and p38 MAPK. PMID:28105094

A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia.

PubMed

Shanmugam, Rajasubramaniam; Gade, Padmaja; Wilson-Weekes, Annique; Sayar, Hamid; Suvannasankha, Attaya; Goswami, Chirayu; Li, Lang; Gupta, Sushil; Cardoso, Angelo A; Baghdadi, Tareq Al; Sargent, Katie J; Cripe, Larry D; Kalvakolanu, Dhananjaya V; Boswell, H Scott

2012-01-15

Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB-and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD(+) cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD(+) AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD(+) human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NF-κB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD(+) AMLs had selective nuclear activation of p52NF-κB. Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD(+) AML. ©2011 AACR.

Marked potentiation of cell swelling by cytokines in ammonia-sensitized cultured astrocytes

PubMed Central

2010-01-01

Background Brain edema leading to high intracranial pressure is a lethal complication of acute liver failure (ALF), which is believed to be cytotoxic due to swelling of astrocytes. In addition to the traditional view that elevated levels of blood and brain ammonia are involved in the mechanism of brain edema in ALF, emerging evidence suggests that inflammatory cytokines also contribute to this process. We earlier reported that treatment of astrocyte cultures with a pathophysiological concentration of ammonia (5 mM NH4Cl) resulted in the activation of nuclear factor-kappaB (NF-κB) and that inhibition of such activation diminished astrocyte swelling, suggesting a key role of NF-κB in the mechanism of ammonia-induced astrocyte swelling. Since cytokines are also well-known to activate NF-κB, this study examined for additive/synergistic effects of ammonia and cytokines in the activation of NF-κB and their role in astrocyte swelling. Methods Primary cultures of astrocytes were treated with ammonia and cytokines (TNF-α, IL-1, IL-6, IFN-γ, each at 10 ng/ml), individually or in combination, and cell volume was determined by the [3H]-O-methylglucose equilibration method. The effect of ammonia and cytokines on the activation of NF-κB was determined by immunoblots. Results Cell swelling was increased by ammonia (43%) and by cytokines (37%) at 24 h. Simultaneous co-treatment with cytokines and ammonia showed no additional swelling. By contrast, cultures pretreated with ammonia for 24 h and then exposed to cytokines for an additional 24 h, showed a marked increase in astrocyte swelling (129%). Treatment of cultures with ammonia or cytokines alone also activated NF-κB (80-130%), while co-treatment had no additive effect. However, in cultures pre-treated with ammonia for 24 h, cytokines induced a marked activation of NF-κB (428%). BAY 11-7082, an inhibitor of NF-κB, completely blocked the astrocyte swelling in cultures pre-treated with ammonia and followed by the addition of a mixture of cytokines. Conclusion Our results indicate that ammonia and a mixture of cytokines each cause astrocyte swelling but when these agents are added simultaneously, no additive effects were found. On the other hand, when cells were initially treated with ammonia and 24 h later given a mixture of cytokines, a marked potentiation in cell swelling and NF-κB activation occurred. These data suggest that the potentiation in cell swelling is a consequence of the initial activation of NF-κB by ammonia. These findings provide a likely mechanism for the exacerbation of brain edema in patients with ALF in the setting of sepsis/inflammation. PMID:20942959

Naringin attenuates the development of carrageenan-induced acute lung inflammation through inhibition of NF-κb, STAT3 and pro-inflammatory mediators and enhancement of IκBα and anti-inflammatory cytokines.

PubMed

Ahmad, Sheikh Fayaz; Attia, Sabry M; Bakheet, Saleh A; Zoheir, Khairy M A; Ansari, Mushtaq Ahmad; Korashy, Hesham M; Abdel-Hamied, Hala E; Ashour, Abdelkader E; Abd-Allah, Adel R A

2015-04-01

Naringin has been reported to possess diverse pharmacological properties, including anti-arthritic and anti-inflammatory activities. The aim of the present study was to determine the potential anti-inflammatory effect of naringin in a mouse model of carrageenan-induced pleurisy. A single dose of naringin (40 and 80 mg/kg) was administered per oral (p.o.) 1 h before carrageenan (Cg) administration. Pro- and anti-inflammatory cytokines were analysed in pleural fluid. We also assessed the effects of naringin on the expression levels of iNOS, inducible cyclooxygenase isoform (COX-2), ICAM-1, MIP-2, PGE2, STAT3, TGF-β1, nuclear factor kappa B (NF-κB) and inhibitor of kappa B (IκBα) in lung tissue. The histological examinations revealed anti-inflammatory effect of naringin while Cg group deteriorated. Naringin downregulated Th1 and upregulated Th2 cytokines. Western blot analyses revealed increased protein expression of NF-κB, STAT3 and COX-2 and decreased IκBα in response to Cg treatment, which were reversed by the treatment with naringin. In the Cg group, mRNA expression levels of pro-inflammatory mediators upregulated and anti-inflammatory mediators downregulated. Naringin reversed these actions.

Ectromelia virus encodes a BTB/kelch protein, EVM150, that inhibits NF-κB signaling.

PubMed

Wang, Qian; Burles, Kristin; Couturier, Brianne; Randall, Crystal M H; Shisler, Joanna; Barry, Michele

2014-05-01

The NF-κB signaling pathway plays a critical role in inflammation and innate immunity. Consequently, many viruses have evolved strategies to inhibit NF-κB in order to facilitate replication and evasion of the host immune response. Recently, we determined that ectromelia virus, the causative agent of mousepox, contains a family of four BTB/kelch proteins that interact with cullin-3-based ubiquitin ligases. We demonstrate here that expression of EVM150, one of the four BTB/kelch proteins, inhibited NF-κB activation induced by tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Although EVM150 inhibited NF-κB p65 nuclear translocation, IκBα degradation was observed, indicating that EVM150 functioned downstream of IκBα degradation. Significantly, expression of the BTB-only domain of EVM150 blocked NF-κB activation, demonstrating that EVM150 functioned independently of the kelch domain and its role as an adapter for cullin-3-based ubiquitin ligases. Furthermore, cullin-3 knockdown by small interfering RNA demonstrated that cullin-3-based ubiquitin ligases are dispensable for TNF-α-induced NF-κB activation. Interestingly, nuclear translocation of IRF3 and STAT1 still occurred in the presence of EVM150, indicating that EVM150 prevented NF-κB nuclear translocation specifically. In addition to identifying EVM150 as an inhibitor of the NF-κB pathway, this study provides new insights into the role of BTB/kelch proteins during virus infection. With the exception of virulence studies, little work has been done to determine the role of poxviral BTB/kelch proteins during infection. This study, for the first time, has identified a mechanism for the ectromelia virus BTB/kelch protein EVM150. Here, we show that EVM150 is a novel inhibitor of the cellular NF-κB pathway, an important component of the antiviral response. This study adds EVM150 to the growing list of NF-κB inhibitors in poxviruses and provides new insights into the role of BTB/kelch proteins during virus infection.

Tunable UV Laser Photolysis of NF2: Quantum Yield for NF(a1 delta) Production.

DTIC Science & Technology

1988-05-25

UV Laser Photolysis of NF2: Quantum Yield for NF(a A) Production ’v0 LR. F. HEIDNER, H . HELVAJIAN , 4and J. B. KOFFEND Aerophysics Laboratory...experiments, the chemistry of NF2 with various hydrocarbons has been studied. It has also been shown that the addition-elimination reaction between H and NF2...COMPLI R LEN SP, 3 ,HAND L BE AM~ H O [ I , , i 1 CAIHOC IAM COOLED GaAs CAPACITANCE PHOTOTUIBE MANOMETER _ LENS /’~ ~L + . ANMEE _.... BANDPASS FILTER

Overexpression of cellular repressor of E1A-stimulated genes inhibits TNF-{alpha}-induced apoptosis via NF-{kappa}B in mesenchymal stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, Cheng-Fei; Cardiovascular Research Institute and Department of Cardiology, Shenyang Northern Hospital, Shenyang; Han, Ya-Ling, E-mail: hanyaling53@gmail.com

2011-03-25

Research highlights: {yields} CREG protected MSCs from tumor necrosis factor-{alpha} (TNF-{alpha}) induced apoptosis. {yields} CREG inhibits the phosphorylation of I{kappa}B{alpha} and prevents the activation of NF-{kappa}B. {yields} CREG inhibits NF-{kappa}B nuclear translocation and pro-apoptosis protein transcription. {yields} CREG anti-apoptotic effect involves inhibition of the death receptor pathway. {yields} p53 is downregulated by CREG via NF-{kappa}B pathway under TNF-{alpha} stimulation. -- Abstract: Bone marrow-derived mesenchymal stem cells (MSCs) show great potential for therapeutic repair after myocardial infarction. However, poor viability of transplanted MSCs in the ischemic heart has limited their use. Cellular repressor of E1A-stimulated genes (CREG) has been identified asmore » a potent inhibitor of apoptosis. This study therefore aimed to determine if rat bone marrow MSCs transfected with CREG-were able to effectively resist apoptosis induced by inflammatory mediators, and to demonstrate the mechanism of CREG action. Apoptosis was determined by flow cytometric and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays. The pathways mediating these apoptotic effects were investigated by Western blotting. Overexpression of CREG markedly protected MSCs from tumor necrosis factor-{alpha} (TNF-{alpha}) induced apoptosis by 50% after 10 h, through inhibition of the death-receptor-mediated apoptotic pathway, leading to attenuation of caspase-8 and caspase-3. Moreover, CREG resisted the serine phosphorylation of I{kappa}B{alpha} and prevented the nuclear translocation of the transcription factor nuclear factor-{kappa}B (NF-{kappa}B) under TNF-{alpha} stimulation. Treatment of cells with the NF-{kappa}B inhibitor pyrrolidine dithiocarbamate (PDTC) significantly increased the transcription of pro-apoptosis proteins (p53 and Fas) by NF-{kappa}B, and attenuated the anti-apoptotic effects of CREG on MSCs. The results of this study indicate that CREG acts as a novel and potent survival factor in MSCs, and may therefore be a useful therapeutic adjunct for transplanting MSCs into the damaged heart after myocardial infarction.« less

Current status and recommendations for biomarkers and biobanking in neurofibromatosis.

PubMed

Hanemann, C Oliver; Blakeley, Jaishri O; Nunes, Fabio P; Robertson, Kent; Stemmer-Rachamimov, Anat; Mautner, Victor; Kurtz, Andreas; Ferguson, Michael; Widemann, Brigitte C; Evans, D Gareth; Ferner, Rosalie; Carroll, Steven L; Korf, Bruce; Wolkenstein, Pierre; Knight, Pamela; Plotkin, Scott R

2016-08-16

Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks. These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN. © 2016 American Academy of Neurology.

Current status and recommendations for biomarkers and biobanking in neurofibromatosis

PubMed Central

Blakeley, Jaishri O.; Nunes, Fabio P.; Robertson, Kent; Stemmer-Rachamimov, Anat; Mautner, Victor; Kurtz, Andreas; Ferguson, Michael; Widemann, Brigitte C.; Evans, D. Gareth; Ferner, Rosalie; Carroll, Steven L.; Korf, Bruce; Wolkenstein, Pierre; Knight, Pamela; Plotkin, Scott R.

2016-01-01

Objective: Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). Methods: The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. Results: We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks. Conclusions: These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN. PMID:27527649

Ultrafast surface modification of Ni3S2 nanosheet arrays with Ni-Mn bimetallic hydroxides for high-performance supercapacitors.

PubMed

Zou, Xu; Sun, Qing; Zhang, Yuxin; Li, Guo-Dong; Liu, Yipu; Wu, Yuanyuan; Yang, Lan; Zou, Xiaoxin

2018-03-14

Amorphous Ni-Mn bimetallic hydroxide film on the three-dimensional nickle foam (NF)-supported conductive Ni 3 S 2 nanosheets (denoted as Ni-Mn-OH@Ni 3 S 2 /NF) is successfully synthesized by an ultrafast process (5 s). The fascinating structural characteristic endows Ni-Mn-OH@Ni 3 S 2 /NF electrodes better electrochemical performance. The specific capacitance of 2233.3 F g -1 at a current density of 15 A g -1 can achieve high current density charge and discharge at 20/30 A g -1 that the corresponding capacitance is 1529.16 and 1350 F g -1 , respectively. As well as good cycling performance after 1000 cycles can maintain 72% at 15 A g -1 . The excellent performance can be attributed to unique surface modification nanostructures and the synergistic effect of the bimetallic hydroxide film. The impressive results provide new opportunity to produce advanced electrode materials by simple and green route and this material is expected to apply in high energy density storage systems.

Andrographolide Sensitizes Ras-Transformed Cells to Radiation in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hung, Shih-Kai; Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan; Tzu Chi University School of Medicine, Hualian, Taiwan

2010-07-15

Purpose: Increasing the sensitivity of tumor cells to radiation is a major goal of radiotherapy. The present study investigated the radiosensitizing effects of andrographolide and examined the molecular mechanisms of andrographolide-mediated radiosensitization. Methods and Materials: An H-ras-transformed rat kidney epithelial (RK3E) cell line was used to measure the radiosensitizing effects of andrographolide in clonogenic assays, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assays, and a xenograft tumor growth model. The mechanism of andrographolide-sensitized cell death was analyzed using annexin V staining, caspase 3 activity assays, and terminal transferase uridyl nick end labeling assays. The roles of nuclear factor kappa B (NF-{kappa}B) and Akt inmore » andrographolide-mediated sensitization were examined using reporter assays, electrophoretic mobility shift assays, and Western blotting. Results: Concurrent andrographolide treatment (10 {mu}M, 3 h) sensitized Ras-transformed cells to radiation in vitro (sensitizer enhancement ratio, 1.73). Andrographolide plus radiation (one dose of 300 mg/kg peritumor andrographolide and one dose of 6 Gy radiation) resulted in significant tumor growth delay (27 {+-} 2.5 days) compared with radiation alone (22 {+-} 1.5 days; p <.05). Radiation induced apoptotic markers (e.g., caspase-3, membrane reversion, DNA fragmentation), and andrographolide treatment did not promote radiation-induced apoptosis. However, the protein level of activated Akt was significantly reduced by andrographolide. NF-{kappa}B activity was elevated in irradiated Ras-transformed cells, and andrographolide treatment significantly reduced radiation-induced NF-{kappa}B activity. Conclusion: Andrographolide sensitized Ras-transformed cells to radiation both in vitro and in vivo. Andrographolide-mediated radiosensitization was associated with downregulation of Akt and NF-{kappa}B activity. These observations indicate that andrographolide is a novel radiosensitizing agent with potential application in cancer radiotherapy.« less

An IκB Kinase-regulated feed-forward circuit prolongs inflammation

PubMed Central

Perez, Jessica M.; Chirieleison, Steven M.; Abbott, Derek W.

2015-01-01

Summary Loss of NF-κB signaling causes immunodeficiency while inhibition of NF-κB can be efficacious in treating chronic inflammatory disease. Inflammatory NF-κB signaling must therefore be tightly regulated, and while many mechanisms to downregulate NF-κB have been elucidated, there have only been limited studies demonstrating positive feed-forward regulation of NF-κB signaling. In this work, we use a bioinformatic and proteomic approach to discover that the IKK family of proteins can phosphorylate the E3 ubiquitin ligase, ITCH, a critical downregulator of TNF-mediated NF-κB activation. Phosphorylation of ITCH by IKKs leads to impaired ITCH E3 ubiquitin ligase activity and prolongs NF-κB signaling and pro-inflammatory cytokine release. Since genetic loss of ITCH mirrors IKK-induced ITCH phosphorylation, we further show that the ITCH−/− mouse’s spontaneous lung inflammation and subsequent death can be delayed when TNF signaling is genetically deleted. This work thus identifies a new positive feed-forward regulation of NF-kB activation that drives inflammatory disease. PMID:26190110

Differential effect of predictors of bone mineral density and hip geometry in postmenopausal women: a cross-sectional study.

PubMed

Singh, Rekha; Gupta, Sushil; Awasthi, Ashish

2015-01-01

Osteoporosis is an important health problem in postmenopausal women. Lactation duration (LD), parity, menopause duration (MD), and body mass index (BMI) are important predictors of bone mineral density (BMD) and osteoporotic fractures in them. In addition, they have site-specific effects on BMD. Osteoporosis is especially prevalent in postmenopausal women. The aim of the study was to determine the effects of age, parity, LD, MD, and BMI on BMD at different sites and hip geometry in postmenopausal women. In this cross-sectional study, 87 women (45 years and above and at least 5 years postmenopausal) were enrolled. Subjects were divided into three parity groups (group 1: ≤ 2 children, group: 3-4 children, and group 3: > 4 children) and three LD groups (group 1: < 4 years, group 2: 4-8 years, and group 3: > 8 years). BMD was measured at neck of femur (BMD-NF), trochanter (BMD-TR), inter-trochanter (BMD-IT), spine (BMD-LS), and forearm (BMD-FA). Hip geometry was analyzed based on dual energy X-ray absorptiometry. One way ANOVA was used for comparisons of groups, and Bonferroni correction was used as post-hoc test. p value < 0.05 was considered significant. A significant difference in mean BMD was found between parity groups 1 and 3 at BMD-NF, BMD-TR, and BMD-LS, and between LD groups 1 and 3 at BMD-NF, BMD-TR, BMD-IT, and BMD-LS. Mean buckling ratio (BR) at IT was significantly different between parity groups 1 and 3, and LD groups 1 and 3. In multivariate regression analysis, BMI, age, and parity were significant predictors for BMD-NF; parity, BMI, and MD for BMD-TR; BMI, MD, and LD for BMD-IT; BMI and LD for BMD-LS; and age, LD, and BMI for BMD-FA. BMI and LD were significant predictors of IT-BR, while MD and BMI of narrow neck BR. MD, LD, parity, BMI, and age are important factors influencing BMD at hip and spine in postmenopausal women, and have site-specific effects on BMD.

Simultaneous imaging of temporal changes of NF-κB activity and viable tumor cells in Huh7/NF-κB-tk-luc2/rfp tumor-bearing mice.

PubMed

Wang, Wei-Hsun; Chiang, I-Tsang; Liu, Yu-Chang; Hsu, Fei-Ting; Chen, Hong-Wen; Chen, Chuan-Lin; Lee, Yi-Jang; Lin, Wuu-Jyh; Hwang, Jeng-Jong

2013-01-01

Few studies have reported that the effect of sorafenib on advanced human hepatocellular carcinoma (HCC) is taking place via the inhibition of NF-κB signal transduction. Here we constructed a human HCC Huh7 stable clone with NF-κB-responsive element to drive dual reporter genes, herpes simplex virus thymidine kinase (tk) and firefly luciferase (luc2), and co-transfected with a third red fluorescent protein (rfp) gene, renamed as Huh7/NF-κB-tk-luc2/rfp cells, and combined with bioluminescent imaging (BLI) and red fluorescent protein imaging (RFPI) to monitor the effect of sorafenib on NF-κB activation and tumor inhibition. The results show that sorafenib could suppress the NF-κB-DNA binding activity, and the expression of downstream effector proteins. Notably, the relative photon fluxes obtained from RFPI and BLI, which represent the viable tumor cells and cells with NF-κB activation, decreased after sorafenib treatment by 50 to 65%, and 87.5 to >90%, respectively, suggesting that NF-κB activation is suppressed in viable HCC cells by sorafenib. Simultaneous molecular imaging of the temporal change of NF-κB activity and of viable cells in the same Huh7/NF-κB-tk-luc2/rfp tumors of the animal may reflect the real status of NF-κB activity and the viable tumor cells at the time of imaging.

Genistein Promotes Proliferation of Human Cervical Cancer Cells Through Estrogen Receptor-Mediated PI3K/Akt-NF-κB Pathway

PubMed Central

Chen, Hai-Hong; Chen, Shu-Ping; Zheng, Qiu-Ling; Nie, Shao-Ping; Li, Wen-Juan; Hu, Xiao-Juan; Xie, Ming-Yong

2018-01-01

Phytoestrogens are polyphenol compounds which have similar structure to 17β-estradiol (E2), a kind of main estrogen in women. Thus, phytoestrogens may affect the reproductive and endocrine systems, leading to the development of estrogen-related cancers. The effect of genistein (Gen), one of the most studied phytoestrogens, on human cervical cancer cells (HeLa) was investigated in this study. It was found that Gen at concentrations of 0.001, 0.01, 0.1 and 1 µmol·L-1 promoted the proliferation of HeLa cells in a dose-dependent manner. Gen increased the portion of HeLa cells in S phase and decreased the portion of the cells in G1 phase. Besides, apoptosis rate of the cells was significantly lower when treated with Gen compared with the control group. It was also found that the expression of ERα, Akt or nuclear NF-κB p65 protein was activated by Gen. The correlation between these three proteins may be as following: ERα was the upstream, followed by Akt, and then nuclear NF-κB p65 protein. In addition, the downstream genes of activated nuclear NF-κB p65 were found to be associated with cell cycle and apoptosis of cancer cells. Our results suggested that Gen may stimulate cell proliferation partially through the estrogen receptor-mediated PI3K/Akt-NF-κB pathway and the further activation of the downstream genes of nuclear NF-κB p65. PMID:29344275

Effect of Simvastatin on Cognitive Functioning in Children With Neurofibromatosis Type 1

PubMed Central

Krab, Lianne C.; de Goede-Bolder, Arja; Aarsen, Femke K.; Pluijm, Saskia M. F.; Bouman, Marlies J.; van der Geest, Jos N.; Lequin, Maarten; Catsman, Coriene E.; Arts, Willem Frans M.; Kushner, Steven A.; Silva, Alcino J.; de Zeeuw, Chris I.; Moll, Henriëtte A.; Elgersma, Ype

2009-01-01

Context Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. Objective To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. Design, Setting, and Participants Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. Intervention Simvastatin or placebo treatment once daily for 12 weeks. Main Outcome Measures Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. Results No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (β=0.10; 95% confidence interval [CI], −0.36 to 0.56); cancellation test (β=−0.19; 95% CI, −0.67 to 0.29); prism adaptation (odds ratio=2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (β=0.06; 95% CI, −0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (β=0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β =0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment. Conclusion In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. PMID:18632543

The Role of SDF-1alpha and CXCR4 in Metastatic Breast Cancer

DTIC Science & Technology

2006-08-01

vegetables of the genus Brassica can inhibit NF-κB in breast cancer cells. Therefore, we hypothesize that I3C may be able to inhibit the bone metastasis...and NF-κB. We have previously shown that Indole-3-carbinol (I3C), a natural compound present in vegetables of the genus Brassica , can inhibit NF-κB

The anti-inflammatory effect of Andrographis paniculata (Burm. f.) Nees on pelvic inflammatory disease in rats through down-regulation of the NF-κB pathway.

PubMed

Zou, Wei; Xiao, Zuoqi; Wen, Xiaoke; Luo, Jieying; Chen, Shuqiong; Cheng, Zeneng; Xiang, Daxiong; Hu, Jian; He, Jingyu

2016-11-25

Andrographis paniculata (Burm. f.) Nees (APN), a principal constituent of a famous traditional Chinese medicine Fukeqianjin tablet which is used for the treatment of pelvic inflammatory disease (PID), has been reported to have anti-inflammatory effect in vitro. However, whether it has pharmacological effect on PID in vivo is unclear. Therefore, the aim of this study is to test the anti-inflammatory effect of APN and illuminate a potential mechanism. Thirty-six female specific pathogen-free SD rats were randomly divided into control group, PID group, APN1 group, APN2 group, APN3 group and prednisone group. Pathogen-induced PID rats were constructed. The APN1, APN2 and APN3 group rats were orally administrated with APN extract at different levels. The prednisone group rats were administrated with prednisone. Eight days after the first infection, the histological examination of upper genital tract was carried out, and enzyme-linked immunosorbent assay (ELISA) was carried out using homogenate of the uterus and fallopian tube. Furthermore, immunohistochemical evaluations of NF-κB p65 and IκB-α in uterus was conducted. APN obviously suppressed the infiltrations of neutrophils and lymphocytes, and it could significantly reduce the excessive production of cytokines and chemokines including IL-1β, IL-6, CXCL-1, MCP-1 and RANTES in a dose-dependent manner. Furthermore, APN could block the pathogen-induced activation of NF-κB pathway. APN showed potent anti-inflammatory effect on pathogen-induced PID in rats, with a potential mechanism of inhibiting the NF-κB signal pathway.

Oleoylethanolamide exerts anti-inflammatory effects on LPS-induced THP-1 cells by enhancing PPARα signaling and inhibiting the NF-κB and ERK1/2/AP-1/STAT3 pathways.

PubMed

Yang, Lichao; Guo, Han; Li, Ying; Meng, Xianglan; Yan, Lu; Dan Zhang; Wu, Sangang; Zhou, Hao; Peng, Lu; Xie, Qiang; Jin, Xin

2016-10-10

The present study aimed to examine the anti-inflammatory actions of oleoylethanolamide (OEA) in lipopolysaccharide (LPS)-induced THP-1 cells. The cells were stimulated with LPS (1 μg/ml) in the presence or absence of OEA (10, 20 and 40 μM). The pro-inflammatory cytokines were evaluated by qRT-PCR and ELISA. The THP-1 cells were transiently transfected with PPARα small-interfering RNA, and TLR4 activity was determined with a blocking test using anti-TLR4 antibody. Additionally, a special inhibitor was used to analyse the intracellular signaling pathway. OEA exerted a potent anti-inflammatory effect by reducing the production of pro-inflammatory cytokines and TLR4 expression, and by enhancing PPARα expression. The modulatory effects of OEA on LPS-induced inflammation depended on PPARα and TLR4. Importantly, OEA inhibited LPS-induced NF-κB activation, IκBα degradation, expression of AP-1, and the phosphorylation of ERK1/2 and STAT3. In summary, our results demonstrated that OEA exerts anti-inflammatory effects by enhancing PPARα signaling, inhibiting the TLR4-mediated NF-κB signaling pathway, and interfering with the ERK1/2-dependent signaling cascade (TLR4/ERK1/2/AP-1/STAT3), which suggests that OEA may be a therapeutic agent for inflammatory diseases.

Quercetin protects rat dorsal root ganglion neurons against high glucose-induced injury in vitro through Nrf-2/HO-1 activation and NF-κB inhibition.

PubMed

Shi, Yue; Liang, Xiao-chun; Zhang, Hong; Wu, Qun-li; Qu, Ling; Sun, Qing

2013-09-01

To examine the effects of quercetin, a natural antioxidant, on high glucose (HG)-induced apoptosis of cultured dorsal root ganglion (DRG) neurons of rats. DRG neurons exposed to HG (45 mmol/L) for 24 h were employed as an in vitro model of diabetic neuropathy. Cell viability, reactive oxygen species (ROS) level and apoptosis were determined. The expression of NF-кB, IкBα, phosphorylated IкBα and Nrf2 was examined using RT PCR and Western blot assay. The expression of hemeoxygenase-1 (HO-1), IL-6, TNF-α, iNOS, COX-2, and caspase-3 were also examined. HG treatment markedly increased DRG neuron apoptosis via increasing intracellular ROS level and activating the NF-κB signaling pathway. Co-treatment with quercetin (2.5, 5, and 10 mmol/L) dose-dependently decreased HG-induced caspase-3 activation and apoptosis. Quercetin could directly scavenge ROS and significantly increased the expression of Nrf-2 and HO-1 in DRG neurons. Quercetin also dose-dependently inhibited the NF-κB signaling pathway and suppressed the expression of iNOS, COX-2, and proinflammatory cytokines IL-6 and TNF-α. Quercetin protects rat DRG neurons against HG-induced injury in vitro through Nrf-2/HO-1 activation and NF-κB inhibition, thus may be beneficial for the treatment of diabetic neuropathy.

HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice

PubMed Central

Leus, Niek G. J.; van den Bosch, Thea; van der Wouden, Petra E.; Krist, Kim; Ourailidou, Maria E.; Eleftheriadis, Nikolaos; Kistemaker, Loes E. M.; Bos, Sophie; Gjaltema, Rutger A. F.; Mekonnen, Solomon A.; Bischoff, Rainer; Gosens, Reinoud; Haisma, Hidde J.; Dekker, Frank J.

2017-01-01

Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-κB, among others. NF-κB is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-κB could attenuate inflammatory responses in COPD via modulation of the NF-κB signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro- and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-κB activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke-exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD. PMID:28344354

Detonation Characteristics of Mixtures of HMX and Emulsion Explosives

DTIC Science & Technology

1989-04-01

and an aqueous emulsion explo- sive have been determined. The emulsion explosive consisted of amonium - nitrate , sodium- nitrate and water in the...1989 D Cb ID A Final Report C14 Approved for public release; distribution unlimited. AIR FORCE WEAPONS LABORATORY Air Force Systems Command Kirtland...TERMS (ContInue on nvwn Nf ocosury and idsŘ by block number) FIELD GROUP SUB-GROUP Explosives; Ammonium Nitrate ;- 19 01Emulsion Explosives; ( 07 04

Revisiting overexpression of a heterologous β-glucosidase in Trichoderma reesei: fusion expression of the Neosartorya fischeri Bgl3A to cbh1 enhances the overall as well as individual cellulase activities.

PubMed

Xue, Xianli; Wu, Yilan; Qin, Xing; Ma, Rui; Luo, Huiying; Su, Xiaoyun; Yao, Bin

2016-07-11

The filamentous fungus Trichoderma reesei has the capacity to secret large amounts of cellulase and is widely used in a variety of industries. However, the T. reesei cellulase is weak in β-glucosidase activity, which results in accumulation of cellobiose inhibiting the endo- and exo-cellulases. By expressing an exogenous β-glucosidase gene, the recombinant T. reesei cellulase is expected to degrade cellulose into glucose more efficiently. The thermophilic β-glucosidase NfBgl3A from Neosartorya fischeri is chosen for overexpression in T. reesei due to its robust activity. In vitro, the Pichia pastoris-expressed NfBgl3A aided the T. reesei cellulase in releasing much more glucose with significantly lower amounts of cellobiose from crystalline cellulose. The NfBgl3A gene was hence fused to the cbh1 structural gene and assembled between the strong cbh1 promoter and cbh1 terminator to obtain pRS-NfBgl3A by using the DNA assembler method. pRS-NfBgl3A was transformed into the T. reesei uridine auxotroph strain TU-6. Six positive transformants showed β-glucosidase activities of 2.3-69.7 U/mL (up to 175-fold higher than that of wild-type). The largely different β-glucosidase activities in the transformants may be ascribed to the gene copy numbers of NfBgl3A or its integration loci. The T. reesei-expressed NfBgl3A showed highly similar biochemical properties to that expressed in P. pastoris. As expected, overexpression of NfBgl3A enhanced the overall cellulase activity of T. reesei. The CBHI activity in all transformants increased, possibly due to the extra copies of cbh1 gene introduced, while the endoglucanase activity in three transformants also largely increased, which was not observed in any other studies overexpressing a β-glucosidase. NfBgl3A had significant transglycosylation activity, generating sophorose, a potent cellulase inducer, and other oligosaccharides from glucose and cellobiose. We report herein the successful overexpression of a thermophilic N. fischeri β-glucosidase in T. reesei. In the same time, the fusion of NfBgl3A to the cbh1 gene introduced extra copies of the cellobiohydrolase 1 gene. As a result, we observed improved β-glucosidase and cellobiohydrolase activity as well as the overall cellulase activity. In addition, the endoglucanase activity also increased in some of the transformants. Our results may shed light on design of more robust T. reesei cellulases.

Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response

PubMed Central

Burgess, Joshua T; Bolderson, Emma; Adams, Mark N; Baird, Anne-Marie; Zhang, Shu-Dong; Gately, Kathy A; Umezawa, Kazuo; O'Byrne, Kenneth J; Richard, Derek J

2016-01-01

Apoptosis is a highly regulated cellular process that functions to remove undesired cells from multicellular organisms. This pathway is often disrupted in cancer, providing tumours with a mechanism to avoid cell death and promote growth and survival. The putative tumour suppressor, SASH1 (SAM and SH3 domain containing protein 1), has been previously implicated in the regulation of apoptosis; however, the molecular role of SASH1 in this process is still unclear. In this study, we demonstrate that SASH1 is cleaved by caspase-3 following UVC-induced apoptosis. Proteolysis of SASH1 enables the C-terminal fragment to translocate from the cytoplasm to the nucleus where it associates with chromatin. The overexpression of wild-type SASH1 or a cleaved form of SASH1 representing amino acids 231–1247 leads to an increase in apoptosis. Conversely, mutation of the SASH1 cleavage site inhibits nuclear translocation and prevents the initiation of apoptosis. SASH1 cleavage is also required for the efficient translocation of the transcription factor nuclear factor-κB (NF-κB) to the nucleus. The use of the NF-κB inhibitor DHMEQ demonstrated that the effect of SASH1 on apoptosis was dependent on NF-κB, indicating a codependence between SASH1 and NF-κB for this process. PMID:27831555

Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response.

PubMed

Burgess, Joshua T; Bolderson, Emma; Adams, Mark N; Baird, Anne-Marie; Zhang, Shu-Dong; Gately, Kathy A; Umezawa, Kazuo; O'Byrne, Kenneth J; Richard, Derek J

2016-11-10

Apoptosis is a highly regulated cellular process that functions to remove undesired cells from multicellular organisms. This pathway is often disrupted in cancer, providing tumours with a mechanism to avoid cell death and promote growth and survival. The putative tumour suppressor, SASH1 (SAM and SH3 domain containing protein 1), has been previously implicated in the regulation of apoptosis; however, the molecular role of SASH1 in this process is still unclear. In this study, we demonstrate that SASH1 is cleaved by caspase-3 following UVC-induced apoptosis. Proteolysis of SASH1 enables the C-terminal fragment to translocate from the cytoplasm to the nucleus where it associates with chromatin. The overexpression of wild-type SASH1 or a cleaved form of SASH1 representing amino acids 231-1247 leads to an increase in apoptosis. Conversely, mutation of the SASH1 cleavage site inhibits nuclear translocation and prevents the initiation of apoptosis. SASH1 cleavage is also required for the efficient translocation of the transcription factor nuclear factor-κB (NF-κB) to the nucleus. The use of the NF-κB inhibitor DHMEQ demonstrated that the effect of SASH1 on apoptosis was dependent on NF-κB, indicating a codependence between SASH1 and NF-κB for this process.

Chokeberry (Aronia melanocarpa (Michx.) Elliot) concentrate inhibits NF-κB and synergizes with selenium to inhibit the release of pro-inflammatory mediators in macrophages.

PubMed

Appel, Kurt; Meiser, Peter; Millán, Estrella; Collado, Juan Antonio; Rose, Thorsten; Gras, Claudia C; Carle, Reinhold; Muñoz, Eduardo

2015-09-01

Black chokeberry has been known to play a protective role in human health due to its high polyphenolic content including anthocyanins and caffeic acid derivatives. In the present study, we first characterized the polyphenolic content of a commercial chokeberry concentrate and investigated its effect on LPS-induced NF-κB activation and release of pro-inflammatory mediators in macrophages in the presence or the absence of sodium selenite. Examination of the phytochemical profile of the juice concentrate revealed high content of polyphenols (3.3%), including anthocyanins, proanthocyanidins, phenolic acids, and flavonoids. Among them, cyanidin-3-O-galactoside and caffeoylquinic acids were identified as the major compounds. Data indicated that chokeberry concentrate inhibited both the release of TNFα, IL-6 and IL-8 in human peripheral monocytes and the activation of the NF-κB pathway in RAW 264.7 macrophage cells. Furthermore, chokeberry synergizes with sodium selenite to inhibit NF-κB activation, cytokine release and PGE2 synthesis. These findings suggest that selenium added to chokeberry juice enhances significantly its anti-inflammatory activity, thus revealing a sound approach in order to tune the use of traditional herbals by combining them with micronutrients. Copyright © 2015 Elsevier B.V. All rights reserved.

Ursolic acid mediates photosensitization by initiating mitochondrial-dependent apoptosis

NASA Astrophysics Data System (ADS)

Lee, Yuan-Hao; Wang, Exing; Kumar, Neeru; Glickman, Randolph D.

2013-02-01

The signaling pathways PI3K/Akt and MAPK play key roles in transcription, translation and carcinogenesis, and may be activated by light exposure. These pathways may be modulated or inhibited by naturally-occurring compounds, such as the triterpenoid, ursolic acid (UA). Previously, the transcription factors p53 and NF-kB, which transactivate mitochondrial apoptosis-related genes, were shown to be differentially modulated by UA. Our current work indicates that UA causes these effects via the mTOR and insulin-mediated pathways. UA-modulated apoptosis, following exposure to UV radiation, is observed to correspond to differential levels of oxidative stress in retinal pigment epithelial (RPE) and skin melanoma (SM) cells. Flow cytometry analysis, DHE (dihydroethidium) staining and membrane permeability assay showed that UA pretreatment potentiated cell cycle arrest and radiation-induced apoptosis selectively on SM cells while DNA photo-oxidative damage (i.e. strand breakage) was reduced, presumably by some antioxidant activity of UA in RPE cells. The UA-mediated NF-κB activation in SM cells was reduced by rapamycin pretreatment, which indicates that these agents exert inter-antagonistic effects in the PI3K/Akt/mTOR pathway. In contrast, the antagonistic effect of UA on the PI3K/Akt pathway was reversed by insulin leading to greater NF-κB and p53 activation in RPE cells. MitoTracker, a mitochondrial functional assay, indicated that mitochondria in RPE cells experienced reduced oxidative stress while those in SM cells exhibited increased oxidative stress upon UA pretreatment. When rapamycin administration was followed by UA, mitochondrial oxidative stress was increased in RPE cells but decreased in SM cells. These results indicate that UA modulates p53 and NF-κB, initiating a mitogenic response to radiation that triggers mitochondria-dependent apoptosis.

A randomized controlled trial into the effects of neurofeedback, methylphenidate, and physical activity on EEG power spectra in children with ADHD.

PubMed

Janssen, Tieme W P; Bink, Marleen; Geladé, Katleen; van Mourik, Rosa; Maras, Athanasios; Oosterlaan, Jaap

2016-05-01

The clinical and neurophysiological effects of neurofeedback (NF) as treatment for children with ADHD are still unclear. This randomized controlled trial (RCT) examined electroencephalogram (EEG) power spectra before and after NF compared to methylphenidate (MPH) treatment and physical activity (PA) - as semi-active control group - during resting and active (effortful) task conditions to determine whether NF can induce sustained alterations in brain function. Using a multicentre three-way parallel group RCT design, 112 children with a DSM-IV diagnosis of ADHD, aged between 7 and 13 years, were initially included. NF training consisted of 30 sessions of theta/beta training at Cz over a 10-week period. PA training was a semi-active control group, matched in frequency and duration. Methylphenidate was titrated using a double-blind placebo controlled procedure in 6 weeks, followed by a stable dose for 4 weeks. EEG power spectra measures during eyes open (EO), eyes closed (EC) and task (effortful) conditions were available for 81 children at pre- and postintervention (n = 29 NF, n = 25 MPH, n = 27 PA). Train Your Brain? Exercise and Neurofeedback Intervention for ADHD, https://clinicaltrials.gov/show/;NCT01363544, Ref. No. NCT01363544. Both NF and MPH resulted in comparable reductions in theta power from pre- to postintervention during the EO condition compared to PA (ηp (2)  = .08 and .12). For NF, greater reductions in theta were related to greater reductions in ADHD symptoms. During the task condition, only MPH showed reductions in theta and alpha power compared to PA (ηp (2)  = .10 and .12). This study provides evidence for specific neurophysiological effects after theta/beta NF and MPH treatment in children with ADHD. However, for NF these effects did not generalize to an active task condition, potentially explaining reduced behavioural effects of NF in the classroom. © 2016 Association for Child and Adolescent Mental Health.

Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy.

PubMed

Gupta, Sudhiranjan; Maitra, Ratan; Young, Dave; Gupta, Anasuya; Sen, Subha

2009-08-01

Myotrophin-induced activation of NF-kappaB has been shown to be associated with cardiac hypertrophy (CH) that progresses to heart failure (HF). In the present study, we examined the cause-and-effect relationship between myotrophin and NF-kappaB activation using small hairpin RNA (shRNA) against myotrophin both in vitro (using neonatal rat myocytes) and in vivo [using myotrophin transgenic (Myo-Tg) mice, which overexpress myotrophin in the heart, develop CH, and gradually progress to HF]. Among several lentiviral vectors expressing myotrophin shRNAs, L-sh-109 showed the best silencing effect at both the mRNA (155.3 +/- 5.9 vs. 32.5 +/- 5.5, P < 0.001) and protein levels associated with a significant reduction of atrial natriuretic factor (ANF) and NF-kappaB. In vivo, when L-sh-109 was delivered directly into the hearts of 10-wk-old Myo-Tg mice, we observed a significant regression of cardiac mass (8.0 vs. 5.7 mg/g, P < 0.001) and myotrophin gene expression (54.5% over untreated Myo-Tg mice, P < 0.001) associated with a reduction in ANF and NF-kappaB signaling components. Our data suggest that using RNA interference to silence the myotrophin gene prevents NF-kappaB activation, associated with an attenuation of CH. This strategy could be an excellent therapeutic means for the treatment of CH and HF.

Cyanidin-3-glucoside attenuates angiotensin II-induced oxidative stress and inflammation in vascular endothelial cells.

PubMed

Sivasinprasasn, Sivanan; Pantan, Rungusa; Thummayot, Sarinthorn; Tocharus, Jiraporn; Suksamrarn, Apichart; Tocharus, Chainarong

2016-10-28

Angiotensin II (Ang II) causes oxidative stress and vascular inflammation, leading to vascular endothelial cell dysfunction, and is associated with the development of inflammatory cardiovascular diseases such as atherosclerosis. Therefore, interventions of oxidative stress and inflammation may contribute to the reduction of cardiovascular diseases. Cyanidin-3-glucoside (C3G) plays a role in the prevention of oxidative damage in several diseases. Here, we investigated the effect of C3G on Ang II-induced oxidative stress and vascular inflammation in human endothelial cells (EA.hy926). C3G dose-dependently suppressed the free radicals and inhibited the nuclear factor-kappa B (NF-κB) signaling pathway by protecting the degradation of inhibitor of kappa B-alpha (IκB-α), inhibiting the expression and translocation of NF-κB into the nucleus through the down-regulation of NF-κB p65 and reducing the expression of inducible nitric oxide synthase (iNOS). Pretreatment with C3G not only prohibited the NF-κB signaling pathway but also promoted the activity of the nuclear erythroid-related factor 2 (Nrf2) signaling pathway through the upregulation of endogenous antioxidant enzymes. Particularly, we observed that C3G significantly enhanced the production of superoxide dismutase (SOD) and induced the expression of heme oxygenase (HO-1). Our findings confirm that C3G can protect against vascular endothelial cell inflammation induced by AngII. C3G may represent a promising dietary supplement for the prevention of inflammation, thereby decreasing the risk for the development of atherosclerosis. Copyright © 2016. Published by Elsevier Ireland Ltd.

NF-κB1, NF-κB2 and c-Rel differentially regulate susceptibility to colitis-associated adenoma development in C57BL/6 mice.

PubMed

Burkitt, Michael D; Hanedi, Abdalla F; Duckworth, Carrie A; Williams, Jonathan M; Tang, Joseph M; O'Reilly, Lorraine A; Putoczki, Tracy L; Gerondakis, Steve; Dimaline, Rod; Caamano, Jorge H; Pritchard, D Mark

2015-07-01

NF-κB signalling is an important factor in the development of inflammation-associated cancers. Mouse models of Helicobacter-induced gastric cancer and colitis-associated colorectal cancer have demonstrated that classical NF-κB signalling is an important regulator of these processes. In the stomach, it has also been demonstrated that signalling involving specific NF-κB proteins, including NF-κB1/p50, NF-κB2/p52, and c-Rel, differentially regulate the development of gastric pre-neoplasia. To investigate the effect of NF-κB subunit loss on colitis-associated carcinogenesis, we administered azoxymethane followed by pulsed dextran sodium sulphate to C57BL/6, Nfkb1(-/-), Nfkb2(-/-), and c-Rel(-/-) mice. Animals lacking the c-Rel subunit were more susceptible to colitis-associated cancer than wild-type mice, developing 3.5 times more colonic polyps per animal than wild-type mice. Nfkb2(-/-) mice were resistant to colitis-associated cancer, developing fewer polyps per colon than wild-type mice (median 1 compared to 4). To investigate the mechanisms underlying these trends, azoxymethane and dextran sodium sulphate were administered separately to mice of each genotype. Nfkb2(-/-) mice developed fewer clinical signs of colitis and exhibited less severe colitis and an attenuated cytokine response compared with all other groups following DSS administration. Azoxymethane administration did not fully suppress colonic epithelial mitosis in c-Rel(-/-) mice and less colonic epithelial apoptosis was also observed in this genotype compared to wild-type counterparts. These observations demonstrate different functions of specific NF-κB subunits in this model of colitis-associated carcinogenesis. NF-κB2/p52 is necessary for the development of colitis, whilst c-Rel-mediated signalling regulates colonic epithelial cell turnover following DNA damage. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB/STAT3/ERK and mitochondria-mediated apoptosis pathway.

PubMed

Park, Ji-Hyun; Seo, Young Ho; Jang, Jung-Hee; Jeong, Chul-Ho; Lee, Sooyeun; Park, Byoungduck

2017-12-11

Methamphetamine (METH) is a commonly abused drug that may result in neurotoxic effects. Recent studies have suggested that involvement of neuroinflammatory processes in brain dysfunction is induced by misuse of this drug. However, the mechanism underlying METH-induced inflammation and neurotoxicity in neurons is still unclear. In this study, we investigated whether asiatic acid (AA) effected METH-mediated neuroinflammation and neurotoxicity in dopaminergic neuronal cells. And we further determined whether the effect involved in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK) pathway. We used the human dopaminergic neuroblastoma SH-SY5Y cell line, murine microglial BV2 cell line, and primary culture of rat embryo mesencephalic neurons. Pro-inflammatory cytokine production was monitored by ELISA and RT/real-time PCR. The cell cycle distribution and mitochondrial membrane integrity was analyzed by flow cytometry. We used immunoblotting, DNA-binding activity, and immunofluorescence staining to analyze the effect of AA on activation of the NF-κB, STAT3, MAPK-ERK, and apoptosis signaling pathways. METH induced TNF receptor (TNFR) expression and led to morphological changes of cells. Additionally, this drug increased pro-inflammatory cytokine (TNFα and IL-6) expression. AA significantly suppressed METH-induced TNFR expression in concentration dependent. Increased secretion of TNFα and IL-6 was inhibited in METH-stimulated neuronal cells by AA administration. AA showed significant protection against METH-induced translocation of NF-κB/STAT3 and ERK phosphorylation. AA inhibited METH-induced proteolytic fragmentation of caspase-3 and PARP. The pro-apoptotic protein Bax was significantly decreased, while the anti-apoptotic protein Bcl-xL was increased by AA treatment in METH-stimulated cells. A similar protective effect of AA on mitochondrial membrane integrity was also confirmed by flow cytometry and immunofluorescence staining. Based on the literatures and our findings, AA is a promising candidate for an anti-neurotoxic agent, and it can potentially be used for the prevention and treatment of various neurological disorders.

A novel polyester composite nanofiltration membrane formed by interfacial polymerization of pentaerythritol (PE) and trimesoyl chloride (TMC)

NASA Astrophysics Data System (ADS)

Cheng, Jun; Shi, Wenxin; Zhang, Lanhe; Zhang, Ruijun

2017-09-01

A novel polyester thin film composite nanofiltration (NF) membrane was prepared by interfacial polymerization of pentaerythritol (PE) and trimesoyl chloride (TMC) on polyethersulfone (PES) supporting membrane. The performance of the polyester composite NF membrane was optimized by regulating the preparation parameters, including reaction time, pH of the aqueous phase solution, pentaerythritol concentration and TMC concentration. A series of characterization, including permeation experiments, attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscope (SEM), atomic force microscopy (AFM), zeta potential analyzer and chlorine resistance experiments, were employed to study the properties of the optimized membrane. The results showed that the optimized polyester composite NF membrane exhibited very high rejection of Na2SO4 (98.1%), but the water flux is relatively low (6.1 L/m2 h, 0.5 MPa, 25 °C). The order of salt rejections is Na2SO4 > MgSO4 > MgCl2 > NaCl, which indicated the membrane was negatively charged, just consistent with the membrane zeta potential results. After treating by NaClO solutions with different concentrations (100 ppm, 500 ppm, 1000 ppm, 2000 ppm, 3000 ppm) for 48 h, the results demonstrated that the polyester NF membrane had good chlorine resistance. Additionally, the polyester TFC NF membrane exhibits good long-term stability.

Effects of Canonical NF-κB Signaling Pathway on the Proliferation and Odonto/Osteogenic Differentiation of Human Stem Cells from Apical Papilla

PubMed Central

Li, Junjun; Yan, Ming; Wang, Zilu; Jing, Shuanglin; Li, Yao; Liu, Genxia; Yu, Jinhua; Fan, Zhipeng

2014-01-01

Background Information. NF-κB signaling pathway plays a complicated role in the biological functions of mesenchymal stem cells. However, the effects of NF-κB pathway on the odonto/osteogenic differentiation of stem cells from apical papilla (SCAPs) remain unclear. The present study was designed to evaluate the effects of canonical NF-κB pathway on the osteo/odontogenic capacity of SCAPs in vitro. Results. Western blot results demonstrated that NF-κB pathway in SCAPs was successfully activated by TNF-α or blocked by BMS-345541. NF-κB pathway-activated SCAPs presented a higher proliferation activity compared with control groups, as indicated by dimethyl-thiazol-diphenyl tetrazolium bromide assay (MTT) and flow cytometry assay (FCM). Wound scratch assay revealed that NF-κB pathway-activated SCAPs presented an improved migration capacity, enhanced alkaline phosphatase (ALP) activity, and upregulated mineralization capacity of SCAPs, as compared with control groups. Meanwhile, the odonto/osteogenic markers (ALP/ALP, RUNX2/RUNX2, OSX/OSX, OCN/OCN, OPN/OPN, BSP/BSP, DSPP/DSP, and DMP-1/DMP-1) in NF-κB pathway-activated SCAPs were also significantly upregulated as compared with control groups at both protein and mRNA levels. However, NF-κB pathway-inhibited SCAPs exhibited a lower proliferation/migration capacity, and decreased odonto/osteogenic ability in comparison with control groups. Conclusion. Our findings suggest that classical NF-κB pathway plays a paramount role in the proliferation and committed differentiation of SCAPs. PMID:24864235

Antiinflammatory effects of glucocorticoids in brain cells, independent of NF-kappa B.

PubMed

Bourke, E; Moynagh, P N

1999-08-15

Glucocorticoids are potent antiinflammatory drugs. They inhibit the expression of proinflammatory cytokines and adhesion molecules. It has recently been proposed that the underlying basis to such inhibition is the induction of the protein I kappa B, which inhibits the transcription factor NF-kappa B. The latter is a key activator of the genes encoding cytokines and adhesion molecules. The present study shows that the synthetic glucocorticoid, dexamethasone, inhibits the induction of the proinflammatory cytokine IL-8 and the adhesion molecules VCAM-1 and ICAM-1 in human 1321N1 astrocytoma and SK.N.SH neuroblastoma cells. However, dexamethasone failed to induce I kappa B or inhibit activation of NF-kappa B by IL-1 in the two cell types. EMSA confirmed the identity of the activated NF-kappa B by demonstrating that an oligonucleotide, containing the wild-type NF-kappa B-binding motif, inhibited formation of the NF-kappa B-DNA complexes whereas a mutated form of the NF-kappa B-binding motif was ineffective. In addition, supershift analysis showed that the protein subunits p50 and p65 were prevalent components in the activated NF-kappa B complexes. The lack of effect of dexamethasone on the capacity of IL-1 to activate NF-kappa B correlated with its inability to induce I kappa B and the ability of IL-1 to cause degradation of I kappa B, even in the presence of dexamethasone. The results presented in this paper strongly suggest that glucocorticoids may exert antiinflammatory effects in cells of neural origin by a mechanism(s) independent of NF-kappa B.

Oleamide suppresses lipopolysaccharide-induced expression of iNOS and COX-2 through inhibition of NF-kappaB activation in BV2 murine microglial cells.

PubMed

Oh, Young Taek; Lee, Jung Yeon; Lee, Jinhwa; Lee, Ju Hie; Kim, Ja-Eun; Ha, Joohun; Kang, Insug

2010-05-03

Oleamide (cis-9-octadecenamide) is an endogenous sleep-inducing fatty acid amide that accumulates in the cerebrospinal fluid of the sleep-deprived animals. Microglia are the major immune cells involved in neuroinflammation causing brain damage during infection, ischemia, and neurodegenerative disease. In this study, we examined the effects of oleamide on LPS-induced production of proinflammatory mediators and the mechanisms involved in BV2 microglia. Oleamide inhibited LPS-induced production of NO and prostaglandin E2 as well as expression of iNOS and COX-2. We showed that oleamide blocked LPS-induced NF-kappaB activation and phosphorylation of inhibitor kappaB kinase (IKK). We also showed that oleamide inhibited LPS-induced phosphorylation of Akt, p38 MAPK, and ERK, activation of PI 3-kinase, and accumulation of reactive oxygen species (ROS). Finally, we showed that a specific antagonist of the CB2 receptor, AM630, blocked the inhibitory effects of oleamide on LPS-induced production of proinflammatory mediators and activation of NF-kappaB. Taken together, our results suggest that oleamide shows an anti-inflammatory effect through inhibition of NF-kappaB activation in LPS-stimulated BV2 microglia. 2010 Elsevier Ireland Ltd. All rights reserved.

Surface morphology, optical, and electrochromic properties of nanostructured nickel ferrite (NiFe2O4) prepared by sol-gel method: effects of Ni/Fe molar ratios

NASA Astrophysics Data System (ADS)

Bazhan, Z.; Ghodsi, F. E.; Mazloom, J.

2016-05-01

Nanostructured nickel ferrite (NF) was prepared by the sol-gel method and calcined at 500 °C for 2 h. The effect of Ni/Fe molar ratios (0, 10, 30, 50 %) on structural, morphological, compositional, optical, and magnetic properties of samples was investigated using analytical tools. XRD patterns indicated the presence of hematite phase in the pure and 10 % NF samples. The samples of 30 and 50 % Ni/Fe molar ratios showed the formation of nickel ferrite structure. Using AFM images, power spectrum density analysis were performed for Ni/Fe with different molar ratio. Also the effect of thickness on morphology of 30 % sample was studied. The fractal dimension increases by increasing the Ni/Fe molar ratio. Optical parameters were evaluated by theoretical approach, and compositional dependence of these parameters was discussed comprehensively. Band gap narrowing was observed in nickel ferrite thin films by increasing the nickel contents from 10 to 50 %. Magnetic analysis revealed that increasing nickel content improved the saturation magnetization. Electrochemical measurements indicated that NF thin films have higher total charge density rather than Fe2O3 thin films and the ion storage capacitance of NF thin films increased by increasing the Ni/Fe content.

Electron transport parameters in NF3

NASA Astrophysics Data System (ADS)

Lisovskiy, V.; Yegorenkov, V.; Ogloblina, P.; Booth, J.-P.; Martins, S.; Landry, K.; Douai, D.; Cassagne, V.

2014-03-01

We present electron transport parameters (the first Townsend coefficient, the dissociative attachment coefficient, the fraction of electron energy lost by collisions with NF3 molecules, the average and characteristic electron energy, the electron mobility and the drift velocity) in NF3 gas calculated from published elastic and inelastic electron-NF3 collision cross-sections using the BOLSIG+ code. Calculations were performed for the combined RB (Rescigno 1995 Phys. Rev. E 52 329, Boesten et al 1996 J. Phys. B: At. Mol. Opt. Phys. 29 5475) momentum-transfer cross-section, as well as for the JB (Joucoski and Bettega 2002 J. Phys. B: At. Mol. Opt. Phys. 35 783) momentum-transfer cross-section. In addition, we have measured the radio frequency (rf) breakdown curves for various inter-electrode gaps and rfs, and from these we have determined the electron drift velocity in NF3 from the location of the turning point in these curves. These drift velocity values are in satisfactory agreement with those calculated by the BOLSIG+ code employing the JB momentum-transfer cross-section.

Houttuynia cordata blocks HSV infection through inhibition of NF-κB activation.

PubMed

Chen, Xiaoqing; Wang, Zhongxia; Yang, Ziying; Wang, Jingjing; Xu, Yunxia; Tan, Ren-Xiang; Li, Erguang

2011-11-01

Houttuynia cordata Thunb. is a medicinal plant widely used in folk medicine in several Asian countries. It has been reported that a water extract of H. cordata exhibits activity against herpes simplex virus (HSV) and the virus of severe acute respiratory syndrome (SARS), although the mechanisms are not fully understood yet. Previous studies have demonstrated absolute requirement of NF-κB activation for efficient replication of HSV-1 and HSV-2 and inhibition of NF-κB activation has been shown to suppress HSV infection. Here we show that a hot water extract of H. cordata (HCWE) inhibits HSV-2 infection through inhibition of NF-κB activation. The IC(50) was estimated at 50 μg/ml of lyophilized HCWE powder. At 150 and 450 μg/ml, HCWE blocked infectious HSV-2 production by more than 3 and 4 logs, respectively. The inhibitory activity was concomitant with an inhibition of NF-κB activation by HSV-2 infection. Although activation of NF-κB and Erk MAPK has been implicated for HSV replication and growth, HCWE showed no effect on HSV-2-induced Erk activation. Furthermore, we show that treatment with quercetin, quercitrin or isoquercitrin, major water extractable flavonoids from H. cordata, significantly blocked HSV-2 infection. These results together demonstrated that H. cordata blocks HSV-2 infection through inhibition of NF-κB activation. Copyright © 2011 Elsevier B.V. All rights reserved.

Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-κB activation

PubMed Central

Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

2010-01-01

Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-α-evoked translocation of nuclear factor (NF)-κB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-κB and production of TNF-α in mouse macrophage RAW264·7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-α level and inhibited the LPS-evoked nuclear translocation of NF-κB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS. PMID:20030669

Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappaB activation.

PubMed

Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

2010-05-01

Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-alpha-evoked translocation of nuclear factor (NF)-kappaB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-kappaB and production of TNF-alpha in mouse macrophage RAW264.7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-alpha level and inhibited the LPS-evoked nuclear translocation of NF-kappaB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS.

Novel β-TCP Coated Titanium Nanofiber Surface for Enhanced Bone Growth.

PubMed

Lim, Hyun-Pil; Park, Sang-Won; Yun, Kwi-Dug; Park, Chan; Ji, Min-Kyung; Oh, Gye-Jeong; Lee, Jong-Tak; Lee, Kwangmin

2018-02-01

In this study, we examined the effect of β-tricalcium phosphate (β-TCP) coating on alkali-treated CP Grade II titanium surface via RF magnetron sputtering on osteoblast like cell (MC3T3-E1) viability and bone formation in rat tibia. The specimens were divided into three groups; commercially pure titanium (control group), alkali-treated titanium with nanofiber structure (NF group) and β-TCP coating on alkali-treated titanium with nanofiber structure (TNF group). The surface characteristics of specimens were observed under a field emission scanning electron microscope (FE-SEM), and contact angle was measured. The cell viability was assessed in vitro after 1 day, 3 days and 7 days. Implants of 2.0 mm diameter and 5.0 mm length were inserted into the tibia of rats. After 4 wks, the histomorphometric analysis was performed. Group NF and group TNF showed improved hydrophilicity of Ti. Group TNF showed significantly higher cell viability (P < 0.05) after 7 days. The bone to implant contact (BIC) ratio of the control group, NF group, and TNF group were 32.3%, 35.5%, and 63.9%, respectively. The study results suggested that β-TCP coated alkali-treated titanium surface via RF magnetron sputtering might be effective in implant dentistry due to enhanced hydrophilicity, improved cell response, and better osseointegration.

Finite Element Analysis of the Endodontically-treated Maxillary Premolars restored with Composite Resin along with Glass Fiber Insertion in Various Positions.

PubMed

Navimipour, Elmira Jafari; Firouzmandi, Maryam; Mirhashemi, Fatemeh Sadat

2015-04-01

This study evaluated the effect of three methods of glass fiber insertion on stress distribution pattern and cusp movement of the root-filled maxillary premolars using finite element method (FEM) analysis. A three-dimensional (3 D) FEM model of a sound upper premolar tooth and four models of root-filled upper premolars with mesiocclusodistal (MOD) cavities were molded and restored with: (1) Composite resin only (NF); (2) Composite resin along with a ribbon of glass fiber placed in the occlusal third (OF); (3) Composite resin along with a ribbon of glass fiber placed circumferentially in the cervical third (CF), and (4) Composite resin along with occlusal and circumferential fibers (OCF). A static vertical load was applied to calculate the stress distributions. Structural analysis program by Solidworks were used for FEM analysis. Von-Mises stress values and cusp movements induced by occlusal loading were evaluated. Maximum Von-Mises stress of enamel occurred in sound tooth, followed by NF, CF, OF and OCF. Maximum Von-Mises stress of dentin occurred in sound tooth, followed by OF, OCF, CF and NF. Stress distribution patterns of OF and OCF were similar. Maximum overall stress values were concentrated in NF. Although stress distribution patterns of NF and CF were found as similar, CF showed lower stress values. Palatal cusp movement was more than buccal cusp in all of the models. The results of our study indicated that while the circumferential fiber had little effect on overall stress concentration, it provided a more favorable stress distribution pattern in cervical region. The occlusal fiber reduced the average stress in the entire structure but did not reduce cuspal movement. Incorporating glass fiber in composite restorations may alter the stress state within the structure depending on fiber position.

6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages.

PubMed

Pan, Min-Hsiung; Hsieh, Min-Chi; Hsu, Ping-Chi; Ho, Sheng-Yow; Lai, Ching-Shu; Wu, Hou; Sang, Shengmin; Ho, Chi-Tang

2008-12-01

Ginger, the rhizome of Zingiber officinale, is a traditional medicine with carminative effect, antinausea, anti-inflammatory, and anticarcinogenic properties. In this study, we investigated the inhibitory effects of 6-shogaol and a related compound, 6-gingerol, on the induction of nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with LPS. Western blotting and reverse transcription-PCR analyses demonstrated that 6-shogaol significantly blocked protein and mRNA expression of inducible NOS (iNOS) and COX-2 in LPS-induced macrophages. The in vivo anti-inflammatory activity was evaluated by a topical 12-O-tetradecanoylphorbol 13-acetate (TPA) application to mouse skin. When applied topically onto the shaven backs of mice prior to TPA, 6-shogaol markedly inhibited the expression of iNOS and COX-2 proteins. Treatment with 6-shogaol resulted in the reduction of LPS-induced nuclear translocation of nuclear factor-kappaB (NF kappaB) subunit and the dependent transcriptional activity of NF kappaB by blocking phosphorylation of inhibitor kappaB (I kappaB)alpha and p65 and subsequent degradation of I kappaB alpha. Transient transfection experiments using NF kappaB reporter constructs indicated that 6-shogaol inhibits the transcriptional activity of NF kappaB in LPS-stimulated mouse macrophages. We found that 6-shogaol also inhibited LPS-induced activation of PI3K/Akt and extracellular signal-regulated kinase 1/2, but not p38 mitogen-activated protein kinase (MAPK). Taken together, these results show that 6-shogaol downregulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NF kappaB by interfering with the activation PI3K/Akt/I kappaB kinases IKK and MAPK.

Sedanolide induces autophagy through the PI3K, p53 and NF-κB signaling pathways in human liver cancer cells.

PubMed

Hsieh, Shu-Ling; Chen, Chi-Tsai; Wang, Jyh-Jye; Kuo, Yu-Hao; Li, Chien-Chun; Hsieh, Lan-Chi; Wu, Chih-Chung

2015-12-01

Sedanolide (SN), a phthalide-like compound from celery seed oil, possesses antioxidant effects. However, the effect of SN on cell death in human liver cancer cells has yet to be determined. In this study, cell viability determination, monodansylcadaverine (MDC) fluorescent staining and immunoblot analysis were performed to determine autophagy induction and autophagy-induced protein expression changes via molecular examination after human liver cancer (J5) cells were treated with SN. Our studies demonstrate that SN suppressed J5 cell viability by inducing autophagy. Phosphoinositide 3-kinase (PI3K)-I, mammalian target of rapamycin (mTOR) and Akt protein levels decreased, whereas PI3K-III, LC3-II and Beclin-1 protein levels increased following SN treatment in J5 cells. In addition, SN treatment upregulated nuclear p53 and damage-regulated autophagy modulator (DRAM) and downregulated cytosolic p53 and Tp53-induced glycolysis and apoptosis regulator (TIGAR) expression in J5 cells. Furthermore, the cytosolic phosphorylation of inhibitor of kappa B (IκB) and nuclear p65 and the DNA-binding activity of NF-κB increased after SN treatment. These results suggest that SN induces J5 cell autophagy by regulating PI3K, p53 and NF-κB autophagy-associated signaling pathways in J5 cells.

Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-κB-mediated inflammation

PubMed Central

Leus, Niek G.J.; Zwinderman, Martijn R.H.; Dekker, Frank J.

2016-01-01

Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications are lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing (inflammatory) gene expression. Intriguingly, apart from histones, HDACs also target non-histone proteins. The nuclear factor κB (NF-κB) pathway is an important regulator in the expression of numerous inflammatory genes, and acetylation plays a crucial role in regulating its responses. Several studies have shed more light on the role of HDAC 1-3 in inflammation with a particular pro-inflammatory role for HDAC 3. Nevertheless, the HDAC-NF-κB interactions in inflammatory signalling have not been fully understood. An important challenge in targeting the regulatory role of HDACs in the NF-κB pathway is the development of highly potent small molecules that selectively target HDAC iso-enzymes. This review focuses on the role of HDAC 3 in (NF-κB-mediated) inflammation and NF-κB lysine acetylation. In addition, we address the application of frequently used small molecule HDAC inhibitors as an approach to attenuate inflammatory responses, and their potential as novel therapeutics. Finally, recent progress and future directions in medicinal chemistry efforts aimed at HDAC 3-selective inhibitors are discussed. PMID:27371876

Ursolic acid inhibits breast cancer growth by inhibiting proliferation, inducing autophagy and apoptosis, and suppressing inflammatory responses via the PI3K/AKT and NF-κB signaling pathways in vitro

PubMed Central

Luo, Juan; Hu, Yan-Ling; Wang, Hong

2017-01-01

Breast cancer, which is the second leading cause of cancer-associated mortality in women worldwide, develops from breast tissue. Chemotherapy is the most commonly used therapy to treat breast cancer. However, a number of natural plant-derived products have been suggested as alternative therapies to treat different types of cancer, such as breast cancer. The aim of the present study was to determine the anti-tumor effects of ursolic acid and its effect on apoptosis and inflammation in breast cancer cells. The anti-cancer effects of ursolic acid were evaluated in vitro using flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction. The results suggest that ursolic acid inhibits the viability of breast cancer cells by inducing autophagy and apoptosis without inducing cell death. Cellular migration assays demonstrated that ursolic acid was able to suppress the invasive ability of breast cancer cells (P<0.05). In addition, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was downregulated following ursolic acid administration (P<0.05), leading to an upregulation of glycogen synthase kinase activity (P<0.05) and downregulation of B-cell lymphoma 2 (P<0.05), subsequently causing autophagy and apoptosis via cyclin-D1 inhibition and caspase-3 stimulation (P<0.05). Furthermore, the inflammatory response of breast cancer cells was assessed by measuring levels of nuclear factor (NF)-κB. Ursolic acid was found to downregulate NF-κB in breast cancer cells, thus inhibiting inflammation and preventing the progression of breast cancer (P<0.05). To the best of our knowledge, the present study is the first to assess the effect of ursolic acid on breast cancer cells through PI3K/AKT-regulated GSK and caspase-3 accompanied by NF-κB signaling pathways. The results of the present study regarding the potential underlying molecular mechanisms of ursolic acid may be used to develop novel therapeutic strategies for breast cancer treatment. PMID:29042957

PPARbeta/delta agonist stimulates human lung carcinoma cell growth through inhibition of PTEN expression: the involvement of PI3K and NF-kappaB signals.

PubMed

Han, ShouWei; Ritzenthaler, Jeffrey D; Zheng, Ying; Roman, Jesse

2008-06-01

Recent studies suggest that activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) promotes cancer cell survival. We previously demonstrated that a selective PPARbeta/delta agonist, GW501516, stimulated human non-small cell lung carcinoma (NSCLC) cell growth. Here, we explore the mechanisms responsible for this effect. We show that GW501516 decreased phosphate and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor known to decrease cell growth and induce apoptosis. Activation of PPARbeta/delta and phosphatidylinositol 3-kinase (PI3K)/Akt signaling was associated with inhibition of PTEN. GW501516 increased NF-kappaB DNA binding activity and p65 protein expression through activation of PPARbeta/delta and PI3K/Akt signals and enhanced the physical interactions between PPARbeta/delta and p65 protein. Conversely, inhibition of PI3K and silencing of p65 by small RNA interference (siRNA) blocked the effect of GW501516 on PTEN expression and on NSCLC cell proliferation. GW501516 also inhibited IKBalpha protein expression. Silencing of IKBalpha enhanced the effect of GW501516 on PTEN protein expression and on cell proliferation. It also augmented the GW501516-induced complex formation of PPARbeta/delta and p65 proteins. Overexpression of PTEN suppressed NSCLC cell growth and eliminated the effect of GW501516 on phosphorylation of Akt. Together, our observations suggest that GW501516 induces the proliferation of NSCLC cells by inhibiting the expression of PTEN through activation of PPARbeta/delta, which stimulates PI3K/Akt and NF-kappaB signaling. Overexpression of PTEN overcomes this effect and unveils PPARbeta/delta and PTEN as potential therapeutic targets in NSCLC.

S632A3, a new glutarimide antibiotic, suppresses lipopolysaccharide-induced pro-inflammatory responses via inhibiting the activation of glycogen synthase kinase 3β.

PubMed

Deng, Hongbin; Zhang, Na; Wang, Yan; Chen, Jinjing; Shen, Jiajia; Wang, Zhen; Xu, Rong; Zhang, Jingpu; Song, Danqing; Li, Diandong

2012-12-10

Inflammatory mediators including inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) contribute to the course of a variety of inflammatory diseases. S632A3 is a new member of the glutarimide antibiotics isolated from a cultured broth of Streptomyces hygroscopicus S632 with a potent NF-κB inhibitory activity. In the present study, we investigated the anti-inflammatory effects and the underlying molecular mechanism of S632A3 on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. S632A3 concentration-dependently inhibited LPS-induced NO and prostaglandin E(2) (PGE(2)) production through the suppression of iNOS and COX-2 at gene transcription levels. In addition, S632A3 suppressed NF-κB-dependent inflammatory responses by inhibiting the activation of glycogen synthase kinase 3β (GSK-3β), while the activation of IκB kinase (IKK) complex was unaffected. S632A3 suppressed NF-κB activity by differentially affecting the CREB (cAMP response element-binding protein) and NF-κB p65 interacting with the coactivator CBP (CREB binding protein). S632A3 also inhibited GSK-3β-elicited iNOS and COX-2 expression. Moreover, S632A3 was shown to inhibit the activation of ASK1 (Apoptosis-signal regulating kinase 1) and p38 mitogen-activated protein kinase, therefore attenuated the LPS-induced NF-κB activity in macrophages. Furthermore, S632A3 significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 production while increased the anti-inflammatory cytokine IL-10 production in LPS-stimulated RAW264.7 cells. Our study thus provides a molecular mechanism by which S632A3 inhibited LPS-induced pro-inflammatory response in macrophages through interfering with the activation of GSK-3β and ASK1-p38 signaling. Copyright © 2012 Elsevier Inc. All rights reserved.

Curcumin Enhances the Effect of Chemotherapy against Colorectal Cancer Cells by Inhibition of NF-κB and Src Protein Kinase Signaling Pathways

PubMed Central

Shakibaei, Mehdi; Mobasheri, Ali; Lueders, Cora; Busch, Franziska; Shayan, Paviz; Goel, Ajay

2013-01-01

Objective Development of treatment resistance and adverse toxicity associated with classical chemotherapeutic agents highlights the need for safer and effective therapeutic approaches. Herein, we examined the effectiveness of a combination treatment regimen of 5-fluorouracil (5-FU) and curcumin in colorectal cancer (CRC) cells. Methods Wild type HCT116 cells and HCT116+ch3 cells (complemented with chromosome 3) were treated with curcumin and 5-FU in a time- and dose-dependent manner and evaluated by cell proliferation assays, DAPI staining, transmission electron microscopy, cell cycle analysis and immunoblotting for key signaling proteins. Results The individual IC50 of curcumin and 5-FU were approximately 20 µM and 5 µM in HCT116 cells and 5 µM and 1 µM in HCT116+ch3 cells, respectively (p<0.05). Pretreatment with curcumin significantly reduced survival in both cells; HCT116+ch3 cells were considerably more sensitive to treatment with curcumin and/or 5-FU than wild-type HCT116 cells. The IC50 values for combination treatment were approximately 5 µM and 1 µM in HCT116 and 5 µM and 0.1 µM in HCT116+ch3, respectively (p<0.05). Curcumin induced apoptosis in both cells by inducing mitochondrial degeneration and cytochrome c release. Cell cycle analysis revealed that the anti-proliferative effect of curcumin and/or 5-FU was preceded by accumulation of CRC cells in the S cell cycle phase and induction of apoptosis. Curcumin potentiated 5-FU-induced expression or cleavage of pro-apoptotic proteins (caspase-8, -9, -3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins. Although 5-FU activated NF-κB/PI-3K/Src pathway in CRC cells, this was down-regulated by curcumin treatment through inhibition of IκBα kinase activation and IκBα phosphorylation. Conclusions Combining curcumin with conventional chemotherapeutic agents such as 5-FU could provide more effective treatment strategies against chemoresistant colon cancer cells. The mechanisms involved may be mediated via NF-κB/PI-3K/Src pathways and NF-κB regulated gene products. PMID:23451189

5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone inhibits nitric oxide production in lipopolysaccharide-stimulated BV2 microglia via NF-κB suppression and Nrf-2-dependent heme oxygenase-1 induction.

PubMed

Kang, Chang-Hee; Kim, Min Jeong; Seo, Min Jeong; Choi, Yung Hyun; Jo, Wol Soon; Lee, Kyung-Tae; Jeong, Yong Kee; Kim, Gi-Young

2013-07-01

In this study, we found that 5-hydroxy-3,6,7,8,3'4'-hexamethoxyflavone (5HHMF) from Hizikia fusiforme considerably inhibits lipopolysaccharide (LPS)-stimulated NO production by suppressing the expression of inducible NO synthase (iNOS) in BV2 microglia. In addition, 5HHMF blocked LPS-induced phosphorylation of IκB, resulting in suppression of the nuclear translocation of nuclear factor-κB (NF-κB) subunits, namely p65 and p50, which are important molecules involved in the regulation of iNOS expression. Pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor, along with 20S proteasome inhibitor (PSI) significantly inhibited LPS-induced iNOS expression, which indirectly suggested that 5HHMF downregulated iNOS expression by suppressing NF-κB activity. Thus, we found that 5HHMF enhances heme oxygenase-1 (HO-1) expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation. In addition, cobalt protoporphyrin (CoPP), a specific HO-1 inducer, predominantly suppressed LPS-induced NO production. In contrast, zinc protoporphyrin (ZnPP), a specific HO-1 inhibitor, showed a partial suppressive effect of 5HHMF on LPS-induced NO production. Further, 5HHMF increased specific DNA-binding activity of Nrf2, and transient knockdown with Nrf2 siRNA subsequently reversed 5HHMF-induced NO inhibition, which was followed by suppression of HO-1 activity. Taken together, our findings indicate that 5HHMF suppresses NO production through modulation of iNOS, consequently suppressing NF-κB activity and induction of Nrf2-dependent HO-1 activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of baicalin in CD4 + CD29 + T cell subsets of ulcerative colitis patients

PubMed Central

Yu, Feng-Yan; Huang, Shao-Gang; Zhang, Hai-Yan; Ye, Hua; Chi, Hong-Gang; Zou, Ying; Lv, Ru-Xi; Zheng, Xue-Bao

2014-01-01

AIM: To evaluate the role of baicalin in ulcerative colitis (UC) with regard to the CD4+CD29+ T helper cell, its surface markers and serum inflammatory cytokines. METHODS: Flow cytometry was used to detect the percentage of CD4+CD29+ cells in patients with UC. Real time polymerase chain reaction was used to detect expression of GATA-3, forkhead box P3, T-box expressed in T cells (T-bet), and retinoic acid-related orphan nuclear hormone receptor C (RORC). Western blotting was used to analyze expression of nuclear factor-κB (NF-κB) p65, phosphorylation of NF-κB (p-NF-κB) p65, STAT4, p-STAT4, STAT6 and p-STAT6. The concentrations of interferon-γ (IFN-γ), interleukin (IL)-4, IL-5, IL-6, IL-10 and TGF-β in serum were determined by ELISA assay. RESULTS: The percentages of CD4+CD29+ T cells were lower in treatment with 40 and 20 μmol/L baicalin than in the treatment of no baicalin. Treatment with 40 or 20 μmol/L baicalin significantly upregulated expression of IL-4, TGF-β1 and IL-10, increased p-STAT6/STAT6 ratio, but downregulated expression of IFN-γ, IL-5, IL-6, RORC, Foxp3 and T-bet, and decreased ratios of T-bet/GATA-3, p-STAT4/STAT4 and p-NF-κB/NF-κB compared to the treatment of no baicalin. CONCLUSION: The results indicate that baicalin regulates immune balance and relieves the ulcerative colitis-induced inflammation reaction by promoting proliferation of CD4+CD29+ cells and modulating immunosuppressive pathways. PMID:25386078

Activation of NF-kappa B Signaling Promotes Growth of Prostate Cancer Cells in Bone

PubMed Central

Jin, Renjie; Sterling, Julie A.; Edwards, James R.; DeGraff, David J.; Lee, Changki; Park, Serk In; Matusik, Robert J.

2013-01-01

Patients with advanced prostate cancer almost invariably develop osseous metastasis. Although many studies indicate that the activation of NF-κB signaling appears to be correlated with advanced cancer and promotes tumor metastasis by influencing tumor cell migration and angiogenesis, the influence of altered NF-κB signaling in prostate cancer cells within boney metastatic lesions is not clearly understood. While C4-2B and PC3 prostate cancer cells grow well in the bone, LNCaP cells are difficult to grow in murine bone following intraskeletal injection. Our studies show that when compared to LNCaP, NF-κB activity is significantly higher in C4-2B and PC3, and that the activation of NF-κB signaling in prostate cancer cells resulted in the increased expression of the osteoclast inducing genes PTHrP and RANKL. Further, conditioned medium derived from NF-κB activated LNCaP cells induce osteoclast differentiation. In addition, inactivation of NF-κB signaling in prostate cancer cells inhibited tumor formation in the bone, both in the osteolytic PC3 and osteoblastic/osteoclastic mixed C4-2B cells; while the activation of NF-κB signaling in LNCaP cells promoted tumor establishment and proliferation in the bone. The activation of NF-κB in LNCaP cells resulted in the formation of an osteoblastic/osteoclastic mixed tumor with increased osteoclasts surrounding the new formed bone, similar to metastases commonly seen in patients with prostate cancer. These results indicate that osteoclastic reaction is required even in the osteoblastic cancer cells and the activation of NF-κB signaling in prostate cancer cells increases osteoclastogenesis by up-regulating osteoclastogenic genes, thereby contributing to bone metastatic formation. PMID:23577181

Histone Methyltransferase NSD2/MMSET Mediates Constitutive NF-κB Signaling for Cancer Cell Proliferation, Survival, and Tumor Growth via a Feed-Forward Loop

PubMed Central

Yang, Ping; Guo, Linlang; Duan, Zhijian J.; Tepper, Clifford G.; Xue, Ling; Chen, Xinbin; Kung, Hsing-Jien; Gao, Allen C.

2012-01-01

Constitutive NF-κB activation by proinflammatory cytokines plays a major role in cancer progression. However, the underlying mechanism is still unclear. We report here that histone methyltransferase NSD2 (also known as MMSET or WHSC1), a target of bromodomain protein ANCCA/ATAD2, acts as a strong coactivator of NF-κB by directly interacting with NF-κB for activation of target genes, including those for interleukin-6 (IL-6), IL-8, vascular endothelial growth factor A (VEGFA), cyclin D, Bcl-2, and survivin, in castration-resistant prostate cancer (CRPC) cells. NSD2 is recruited to the target gene promoters upon induction and mediates NF-κB activation-associated elevation of histone H3K36me2 and H3K36me3 marks at the promoter, which involves its methylase activity. Interestingly, we found that NSD2 is also critical for cytokine-induced recruitment of NF-κB and acetyltransferase p300 and histone hyperacetylation. Importantly, NSD2 is overexpressed in prostate cancer tumors, and its overexpression correlates with NF-κB activation. Furthermore, NSD2 expression is strongly induced by tumor necrosis factor alpha (TNF-α) and IL-6 via NF-κB and plays a crucial role in tumor growth. These results identify NSD2 to be a key chromatin regulator of NF-κB and mediator of the cytokine autocrine loop for constitutive NF-κB activation and emphasize the important roles played by NSD2 in cancer cell proliferation and survival and tumor growth. PMID:22645312

TRIB3 mediates the expression of Wnt5a and activation of nuclear factor-κB in Porphyromonas endodontalis lipopolysaccharide-treated osteoblasts.

PubMed

Yu, Y; Qiu, L; Guo, J; Yang, D; Qu, L; Yu, J; Zhan, F; Xue, M; Zhong, M

2015-08-01

Porphyromonas endodontalis lipopolysaccharide (LPS) is considered to be correlated with the progression of bone resorption in periodontal and periapical diseases. Wnt5a has recently been implicated in inflammatory processes, but its role is unclear as a P. endodontalis LPS-induced mediator in osteoblasts. Tribbles homolog 3 (TRIB3) encodes a pseudokinase and has been linked to inflammation in certain situations. Here, we found that P. endodontalis LPS induced Wnt5a expression in a dose- and time-dependent manner and it also upregulated translocation, phosphorylation and transcriptional activity of nuclear factor-κB (NF-κB) in MC3T3-E1 cells. Bay 11-7082 blocked the translocation of NF-κB and Wnt5a expression induced by P. endodontalis LPS. Chromatin immunoprecipitation assay further established that induction of Wnt5a by P. endodontalis LPS was mediated through the NF-κB p65 subunit. Additionally, P. endodontalis LPS increased expression of TRIB3 in osteoblasts after 10 h simulated time. Overexpression of TRIB3 enhanced NF-κB phosphorylation and Wnt5a induction, whereas knockdown of TRIB3 inhibited NF-κB phosphorylation and Wnt5a expression in P. endodontalis LPS-stimulated osteoblasts. These results suggest that P. endodontalis LPS has the ability to promote the expression of Wnt5a in mouse osteoblasts, and this induction is mainly mediated by NF-κB pathway. TRIB3 seems to modulate the sustained expression of Wnt5a in osteoblasts stimulated by P. endodontalis LPS, as well as regulating NF-κB phosphorylation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions

PubMed Central

Tantiwong, Puntip; Shanmugasundaram, Karthigayan; Monroy, Adriana; Ghosh, Sangeeta; Li, Mengyao; DeFronzo, Ralph A.; Cersosimo, Eugenio; Sriwijitkamol, Apiradee; Mohan, Sumathy

2010-01-01

NF-κB is a transcription factor that controls the gene expression of several proinflammatory proteins. Cell culture and animal studies have implicated increased NF-κB activity in the pathogenesis of insulin resistance and muscle atrophy. However, it is unclear whether insulin-resistant human subjects have abnormal NF-κB activity in muscle. The effect that exercise has on NF-κB activity/signaling also is not clear. We measured NF-κB DNA-binding activity and the mRNA level of putative NF-κB-regulated myokines interleukin (IL)-6 and monocyte chemotactic protein-1 (MCP-1) in muscle samples from T2DM, obese, and lean subjects immediately before, during (40 min), and after (210 min) a bout of moderate-intensity cycle exercise. At baseline, NF-κB activity was elevated 2.1- and 2.7-fold in obese nondiabetic and T2DM subjects, respectively. NF-κB activity was increased significantly at 210 min following exercise in lean (1.9-fold) and obese (2.6-fold) subjects, but NF-κB activity did not change in T2DM. Exercise increased MCP-1 mRNA levels significantly in the three groups, whereas IL-6 gene expression increased significantly only in lean and obese subjects. MCP-1 and IL-6 gene expression peaked at the 40-min exercise time point. We conclude that insulin-resistant subjects have increased basal NF-κB activity in muscle. Acute exercise stimulates NF-κB in muscle from nondiabetic subjects. In T2DM subjects, exercise had no effect on NF-κB activity, which could be explained by the already elevated NF-κB activity at baseline. Exercise-induced MCP-1 and IL-6 gene expression precedes increases in NF-κB activity, suggesting that other factors promote gene expression of these cytokines during exercise. PMID:20739506

NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions.

PubMed

Tantiwong, Puntip; Shanmugasundaram, Karthigayan; Monroy, Adriana; Ghosh, Sangeeta; Li, Mengyao; DeFronzo, Ralph A; Cersosimo, Eugenio; Sriwijitkamol, Apiradee; Mohan, Sumathy; Musi, Nicolas

2010-11-01

NF-κB is a transcription factor that controls the gene expression of several proinflammatory proteins. Cell culture and animal studies have implicated increased NF-κB activity in the pathogenesis of insulin resistance and muscle atrophy. However, it is unclear whether insulin-resistant human subjects have abnormal NF-κB activity in muscle. The effect that exercise has on NF-κB activity/signaling also is not clear. We measured NF-κB DNA-binding activity and the mRNA level of putative NF-κB-regulated myokines interleukin (IL)-6 and monocyte chemotactic protein-1 (MCP-1) in muscle samples from T2DM, obese, and lean subjects immediately before, during (40 min), and after (210 min) a bout of moderate-intensity cycle exercise. At baseline, NF-κB activity was elevated 2.1- and 2.7-fold in obese nondiabetic and T2DM subjects, respectively. NF-κB activity was increased significantly at 210 min following exercise in lean (1.9-fold) and obese (2.6-fold) subjects, but NF-κB activity did not change in T2DM. Exercise increased MCP-1 mRNA levels significantly in the three groups, whereas IL-6 gene expression increased significantly only in lean and obese subjects. MCP-1 and IL-6 gene expression peaked at the 40-min exercise time point. We conclude that insulin-resistant subjects have increased basal NF-κB activity in muscle. Acute exercise stimulates NF-κB in muscle from nondiabetic subjects. In T2DM subjects, exercise had no effect on NF-κB activity, which could be explained by the already elevated NF-κB activity at baseline. Exercise-induced MCP-1 and IL-6 gene expression precedes increases in NF-κB activity, suggesting that other factors promote gene expression of these cytokines during exercise.

Preparation of graphene oxide modified poly(m-phenylene isophthalamide) nanofiltration membrane with improved water flux and antifouling property

NASA Astrophysics Data System (ADS)

Yang, Mei; Zhao, Changwei; Zhang, Shaofeng; Li, Pei; Hou, Deyin

2017-02-01

Poly (m-phenylene isophthalamide)/graphene oxide (PMIA/GO) composite nanofiltartion (NF) membranes were prepared via a facile phase inversion method. Structures, surface properties and hydrophilicities of the membrane were analyzed using FT-IR, XPS, AFM, SEM, water contact angle and Zeta-potential measurements. FTIR spectra indicated the existence of hydrophilic carboxylic acid and hydroxyl groups in the GO molecules. SEM pictures revealed the large and finger-like micro-voids formed in the sublayer of the NF membranes after adding GO. The zeta-potential and water contact angle results proved that PMIA/GO composite membranes had more negatively charged and greater hydrophilic surfaces. The pure water flux of the PMIA/GO (0.3 wt% GO) composite membrane (125.2 (L/m2/h)) was 2.6 times as high as that of the pristine PMIA NF membrane (48.3 (L/m2/h)) at 0.8 MPa with slightly higher rejections to all tested dyes and better fouling resistance to bovine serum albumin (BSA). This study gave an effective method for preparing composite PMIA NF membranes with high water flux and excellent antifouling property, which showed potential application in water treatment.

1-Cinnamoyl-3,11-dihydroxymeliacarpin is a natural bioactive compound with antiviral and nuclear factor-{kappa}B modulating properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barquero, Andrea A.; Michelini, Flavia M.; Alche, Laura E.

2006-06-09

We have reported the isolation of the tetranortriterpenoid 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM) from partially purified leaf extracts of Melia azedarach L. (MA) that reduced both, vesicular stomatitis virus (VSV) and Herpes simplex virus type 1 (HSV-1) multiplication. CDM blocks VSV entry and the intracellular transport of VSV-G protein, confining it to the Golgi apparatus, by pre- or post-treatment, respectively. Here, we report that HSV-1 glycoproteins were also confined to the Golgi apparatus independently of the nature of the host cell. Considering that MA could be acting as an immunomodulator preventing the development of herpetic stromal keratitis in mice, we also examined anmore » eventual effect of CDM on NF-{kappa}B signaling pathway. CDM is able to impede NF-{kappa}B activation in HSV-1-infected conjunctival cells and leads to the accumulation of p65 NF-{kappa}B subunit in the cytoplasm of uninfected treated Vero cells. In conclusion, CDM is a pleiotropic agent that not only inhibits the multiplication of DNA and RNA viruses by the same mechanism of action but also modulates the NF-{kappa}B signaling pathway.« less

Soyasaponins Can Blunt Inflammation by Inhibiting the Reactive Oxygen Species-Mediated Activation of PI3K/Akt/NF-kB Pathway

PubMed Central

Zha, Longying; Chen, Jiading; Sun, Suxia; Mao, Limei; Chu, Xinwei; Deng, Hong; Cai, Junwei; Li, Xuefeng; Liu, Zhenqi; Cao, Wenhong

2014-01-01

We and others have recently shown that soyasaponins abundant in soybeans can decrease inflammation by suppressing the nuclear factor kappa B (NF-kB)-mediated inflammation. However, the exact molecular mechanisms by which soyasaponins inhibit the NF-kB pathway have not been established. In this study in macrophages, soyasaponins (A1, A2 and I) inhibited the lipopolysaccharide (LPS)-induced release of inflammatory marker prostaglandin E2 (PGE2) to a similar extent as the NF-kB inhibitor (BAY117082). Soyasaponins (A1, A2 and I) also suppressed the LPS-induced expression of cyclooxygenase 2 (COX-2), another inflammatory marker, in a dose-dependent manner by inhibiting NF-kB activation. In defining the associated mechanisms, we found that soyasaponins (A1, A2 and I) blunted the LPS-induced IKKα/β phosphorylation, IkB phosphorylation and degradation, and NF-kB p65 phosphorylation and nuclear translocation. In studying the upstream targets of soyasaponins on the NF-kB pathway, we found that soyasaponins (A1, A2 and I) suppressed the LPS-induced activation of PI3K/Akt similarly as the PI3K inhibitor LY294002, which alone blocked the LPS-induced activation of NF-kB. Additionally, soyasaponins (A1, A2 and I) reduced the LPS-induced production of reactive oxygen species (ROS) to the same extent as the anti-oxidant N-acetyl-L-cysteine, which alone inhibited the LPS-induced phosphorylation of Akt, IKKα/β, IkBα, and p65, transactivity of NF-kB, PGE2 production, and malondialdehyde production. Finally, our results show that soyasaponins (A1, A2 and I) elevated SOD activity and the GSH/GSSG ratio. Together, these results show that soyasaponins (A1, A2 and I) can blunt inflammation by inhibiting the ROS-mediated activation of the PI3K/Akt/NF-kB pathway. PMID:25233217

γ-Oryzanol suppresses COX-2 expression by inhibiting reactive oxygen species-mediated Erk1/2 and Egr-1 signaling in LPS-stimulated RAW264.7 macrophages.

PubMed

Shin, Soon Young; Kim, Heon-Woong; Jang, Hwan-Hee; Hwang, Yu-Jin; Choe, Jeong-Sook; Kim, Jung-Bong; Lim, Yoongho; Lee, Young Han

2017-09-16

Cyclooxygenase (COX)-2 produces prostanoids, which contribute to inflammatory responses. Nuclear factor (NF)-κB is a key transcription factor mediating COX-2 expression. γ-Oryzanol is an active component in rice bran oil, which inhibits lipopolysaccharide (LPS)-mediated COX-2 expression by inhibiting NF-κB. However, the inhibition of COX-2 expression by γ-oryzanol independently of NF-κB is poorly understood. We found that LPS upregulated Egr-1 expression at the transcriptional level. Forced expression of Egr-1 trans-activated the Cox-2 promoter independently of NF-κB. In contrast, silencing of Egr-1 abrogated LPS-mediated COX-2 expression. LPS produced reactive oxygen species (ROS), which, in turn, induced Egr-1 expression via the Erk1/2 MAPK pathway. ROS scavenging activity of γ-oryzanol suppressed Egr-1 expression by inhibiting the Erk1/2 MAPK pathway. Our results suggest that γ-oryzanol inhibits LPS-mediated COX-2 expression by suppressing Erk1/2-mediated Egr-1 expression. This study supports that γ-oryzanol may be useful for ameliorating LPS-mediated inflammatory responses. Copyright © 2017 Elsevier Inc. All rights reserved.

Phloretin Inhibits Phorbol Ester–Induced Tumor Promotion and Expression of Cyclooxygenase-2 in Mouse Skin: Extracellular Signal-Regulated Kinase and Nuclear Factor-κB as Potential Targets

PubMed Central

Shin, Jun-Wan; Kundu, Joydeb Kumar

2012-01-01

Abstract The present study investigated the effect of phloretin [2′,4′,6′-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on 12-O-tetradecanoylphorbol 13-acetate (TPA)–induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and explored the underlying molecular mechanisms. Topical application of phloretin significantly inhibited 7,12-dimethylbenz[a]anthracene-initiated and TPA-promoted mouse skin carcinogenesis. Pretreatment with phloretin on the dorsal skin of mice inhibited TPA-induced COX-2 expression in a dose-dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by phloretin, we examined its effect on TPA-induced activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor responsible for TPA-induced COX-2 expression in mouse skin. Topically applied phloretin decreased the TPA-induced DNA binding of NF-κB. In addition, phloretin inhibited the phosphorylation as well as the catalytic activity of extracellular signal-regulated kinase (ERK), which was previously found to activate NF-κB and induce COX-2 expression in TPA-treated mouse skin. Taken together, the inhibitory effects of phloretin on TPA-induced NF-κB activation and COX-2 expression through the modulation of ERK signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis. PMID:22181070

Phloretin inhibits phorbol ester-induced tumor promotion and expression of cyclooxygenase-2 in mouse skin: extracellular signal-regulated kinase and nuclear factor-κB as potential targets.

PubMed

Shin, Jun-Wan; Kundu, Joydeb Kumar; Surh, Young-Joon

2012-03-01

The present study investigated the effect of phloretin [2',4',6'-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and explored the underlying molecular mechanisms. Topical application of phloretin significantly inhibited 7,12-dimethylbenz[a]anthracene-initiated and TPA-promoted mouse skin carcinogenesis. Pretreatment with phloretin on the dorsal skin of mice inhibited TPA-induced COX-2 expression in a dose-dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by phloretin, we examined its effect on TPA-induced activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor responsible for TPA-induced COX-2 expression in mouse skin. Topically applied phloretin decreased the TPA-induced DNA binding of NF-κB. In addition, phloretin inhibited the phosphorylation as well as the catalytic activity of extracellular signal-regulated kinase (ERK), which was previously found to activate NF-κB and induce COX-2 expression in TPA-treated mouse skin. Taken together, the inhibitory effects of phloretin on TPA-induced NF-κB activation and COX-2 expression through the modulation of ERK signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis.

Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB.

PubMed

Riehemann, K; Behnke, B; Schulze-Osthoff, K

1999-01-08

Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases and is responsible for the enhanced expression of many proinflammatory gene products. Extracts from leaves of stinging nettle (Urtica dioica) are used as antiinflammatory remedies in rheumatoid arthritis. Standardized preparations of these extracts (IDS23) suppress cytokine production, but their mode of action remains unclear. Here we demonstrate that treatment of different cells with IDS23 potently inhibits NF-kappaB activation. An inhibitory effect was observed in response to several stimuli, suggesting that IDS23 suppressed a common NF-kappaB pathway. Inhibition of NF-kappaB activation by IDS23 was not mediated by a direct modification of DNA binding, but rather by preventing degradation of its inhibitory subunit IkappaB-alpha. Our results suggests that part of the antiinflammatory effect of Urtica extract may be ascribed to its inhibitory effect on NF-kappaB activation.

Relationship between carbachol hyperstimulation-induced pancreatic intracellular trypsinogen and NF-kappa B activation in rats in vitro.

PubMed

Jiang, Chunfang; Zheng, Hai; Liu, Sunan; Fang, Kaifeng

2008-02-01

The relationship between intracellular trypsinogen activation and NF-kappa B activation in rat pancreatic acinar cells induced by M3 cholinergic receptor agonist (carbachol) hyperstimulation was studied. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, the active protease inhibitor (pefabloc) and NF-kappa B inhibitor (PDTC) in vitro. Intracellular trypsin activity was measured by using a fluorogenic substrate. The activity of NF-kappa B was monitored by using electrophoretic mobility shift assay. The results showed that after pretreatment with 2 mmol/L pefabloc, the activities of trypsin and NF-kappa B in pancreatic acinar cells treated with high concentrations of carbachol (10(-3) mol/L) in vitro was significantly decreased as compared with control group (P<0.01). The addition of 10(-2) mol/L PDTC resulted in a significant decrease of NF-kappa B activities in pancreatic acinar cells after treated with high concentrations of carbachol (10(-3) mol/L) in vitro, but the intracellular trypsinogen activity was not obviously inhibited (P>0.05). It was concluded that intracellular trypsinogen activation is likely involved in the regulation of high concentrations of carbachol-induced NF-kappa B activation in pancreatic acinar cells in vitro. NF-kappa B activation is likely not necessary for high concentrations of carbachol-induced trypsinogen activation in pancreatic acinar cells in vitro.

Swarming in viscous fluids: three-dimensional patterns in swimmer- and force-induced flows

NASA Astrophysics Data System (ADS)

Chuang, Yao-Li; D'Orsogna, Maria R.; Chou, Tom

Mathematical models of self-propelled interacting particles have reproduced various fascinating ``swarming'' patterns observed in natural and artificial systems. The formulation of such models usually ignores the influence of the surrounding medium in which the particles swarm. Here we develop from first principles a three-dimensional theory of swarming particles in a viscous fluid environment and investigate how the hydrodynamic coupling among the particles may affect their collective behavior. Specifically, we examine the hydrodynamic coupling among self-propelled particles interacting through ``social'' or ``mechanical'' forces. We discover that new patterns arise as a consequence of different interactions and self-propulsion mechanisms. Examples include flocks with prolate or oblate shapes, intermittent mills, recirculating peloton-like structures, and jet-like fluid flows that kinetically destabilize mill-like structures. Our results reveal possible mechanisms for three-dimensional swarms to kinetically control their collective behaviors in fluids. Supported by NSF DMS 1021818 & 1021850, ARO W1911NF-14-1-0472, ARO MURI W1911NF-11-10332.

Synergistic effect of Ebselen and gamma radiation on breast cancer cells.

PubMed

Thabet, Noura M; Moustafa, Enas M

2017-08-01

To explore the synergistic effect of a seleno-organic compound Ebselen (Ebs) and/or γ-radiation to exert antitumor effects on human breast cancer (MCF-7) cell line in vitro. Ebs cytotoxicity at various concentrations (10, 25, 50 and 75 μg), cell proliferation and clonogenic assay of Ebs and/or γ-radiation (at 1, 3 and 6 Gy), expression of p-IκBα and NF-κB, inflammatory cytokines levels (TNF-α, IL-2, INF-γ, IL-10 and TGF-β), apoptotic factors (Caspase-3, Granzyme-B and TRAIL) and angiogenic factor (VEGF) were investigated. The results showed that the effective dosage of this combination was observed at 25 μg/ml of Ebs with γ-radiation at 6 Gy. Data displayed a significant reduction in NF-κB mRNA along with an elevation in granzyme-B mRNA and TRAIL mRNA expression. Furthermore, protein expression of caspase-3 was elevated, whereas p-IκBα and p-NF-κB(p65) protein expression was reduced significantly. Also, a significant decline in TNF-α, IL-2, INF-γ, TGF-β with a significant increase in IL-10 levels were revealed. Meanwhile, a significant decrease in VEGF level and proliferation capacity were observed. We conclude that a combination of Ebs with radiotherapy has a major antitumor efficiency in inducing apoptosis and inhibiting cancer cell progression, due to the synergistic effect in regulating gene and protein expression, and in a modulating response of pro-and anti-inflammatory cytokines.

6-Shogaol Protects against Oxidized LDL-Induced Endothelial Injruries by Inhibiting Oxidized LDL-Evoked LOX-1 Signaling

PubMed Central

Wang, Yun kai; Hong, Ya Jun; Yao, Yong hua; Huang, Xiao Min; Liu, Xue Bo; Zhang, Chun Yu; Zhang, Lei; Xu, Xiaoliang Leon

2013-01-01

Endothelial dysfunction and oxLDL are believed to be early and critical events in atherogenesis. 6-Shogaol is the major bioactive compound present in Zingiber officinale and possesses the anti-atherosclerotic effect. However, the mechanisms remain poorly understood. The goal of this study was to investigate the effects of 6-shogaol on oxLDL-induced Human umbilical vein endothelial cells (HUVECs) injuries and its possible molecular mechanisms. Hence, we studied the effects of 6-shogaol on cell apoptosis, cellular reactive oxygen species (ROS), NF-κB activation, Bcl-2 expression, and caspase -3, -8, -9 activities. In addition, E-selectin, MCP-1, and ICAM-1 were determined by ELISA. Our study show that oxLDL increased LOX-1 expression, ROS levels, NF-κB, caspases-9 and -3 activation and decreased Bcl-2 expression in HUVECs. These alterations were attenuated by 6-shogaol. Cotreatment with 6-shogaol and siRNA of LOX-1 synergistically reduced oxLDL-induced caspases -9, -3 activities and cell apoptosis. Overexpression of LOX-1 attenuated the protection by 6-shogaol and suppressed the effects of 6-shogaol on oxLDL-induced oxidative stress. In addition, oxLDL enhanced the activation of NF-κB and expression of adhesion molecules. Pretreatment with 6-shogaol, however, exerted significant cytoprotective effects in all events. Our data indicate that 6-shogaol might be a potential natural antiapoptotic agent for the treatment of atherosclerosis. PMID:23533490

6-Shogaol Protects against Oxidized LDL-Induced Endothelial Injruries by Inhibiting Oxidized LDL-Evoked LOX-1 Signaling.

PubMed

Wang, Yun Kai; Hong, Ya Jun; Yao, Yong Hua; Huang, Xiao Min; Liu, Xue Bo; Zhang, Chun Yu; Zhang, Lei; Xu, Xiaoliang Leon

2013-01-01

Endothelial dysfunction and oxLDL are believed to be early and critical events in atherogenesis. 6-Shogaol is the major bioactive compound present in Zingiber officinale and possesses the anti-atherosclerotic effect. However, the mechanisms remain poorly understood. The goal of this study was to investigate the effects of 6-shogaol on oxLDL-induced Human umbilical vein endothelial cells (HUVECs) injuries and its possible molecular mechanisms. Hence, we studied the effects of 6-shogaol on cell apoptosis, cellular reactive oxygen species (ROS), NF- κ B activation, Bcl-2 expression, and caspase -3, -8, -9 activities. In addition, E-selectin, MCP-1, and ICAM-1 were determined by ELISA. Our study show that oxLDL increased LOX-1 expression, ROS levels, NF- κ B, caspases-9 and -3 activation and decreased Bcl-2 expression in HUVECs. These alterations were attenuated by 6-shogaol. Cotreatment with 6-shogaol and siRNA of LOX-1 synergistically reduced oxLDL-induced caspases -9, -3 activities and cell apoptosis. Overexpression of LOX-1 attenuated the protection by 6-shogaol and suppressed the effects of 6-shogaol on oxLDL-induced oxidative stress. In addition, oxLDL enhanced the activation of NF- κ B and expression of adhesion molecules. Pretreatment with 6-shogaol, however, exerted significant cytoprotective effects in all events. Our data indicate that 6-shogaol might be a potential natural antiapoptotic agent for the treatment of atherosclerosis.

An Alpha and Theta Intensive and Short Neurofeedback Protocol for Healthy Aging Working-Memory Training

PubMed Central

Reis, Joana; Portugal, Ana Maria; Fernandes, Luís; Afonso, Nuno; Pereira, Mariana; Sousa, Nuno; Dias, Nuno S.

2016-01-01

The present study tested the effects of an intensive and short alpha and theta neurofeedback (NF) protocol in working memory (WM) performance in a healthy elder population and explored the effects of a multimodal approach, by supplementing NF with cognitive tasks. Participants were allocated to four groups: NF (N = 9); neurofeedback supplemented with cognitive training (NFCT) (N = 8); cognitive training (CT) (N = 7) and sham neurofeedback (Sham-NF) (N = 6). The intervention consisted in 30-min sessions for 8 days. The NF group presented post intervention increases of alpha and theta relative power as well as performance in the matrix rotation task. In addition, a successful up training of frontal theta showed positive correlation with an improvement of post-training alpha and a better performance in the matrix rotation task. The results presented herein suggest that an intensive and short NF protocol enables elders to learn alpha and theta self-modulation and already presents moderate improvements in cognition and basal EEG. Also, CT group showed moderate performance gains on the cognitive tasks used during the training sessions but no clear improvements on neurophysiology and behavioral measurements were observed. This study represents a first attempt to study the effects of an intensive and short NF protocol in WM performance of elders. The evidence presented here suggests that an intensive and short NF intervention could be a valid alternative for introduction of older populations to NF methodologies. PMID:27458369

[Expression of PARP/NF-κB and intervention effect of 5-AIQ/PDTC in SAP rats with adrenal damage].

PubMed

Yang, Bo; Guo, Wen-Yi; Yu, Jia; Zhao, Kai-liang; Shi, Qiao; Zuo, Teng; Wang, Wei-xing

2013-10-15

To explore the expression of poly (ADP-ribose) polymerase/nuclear factor-κB (PARP/NF-κB) and intervention effect of 5-aminoisoquinolinone/pyrrolidine dithiocarbamate (5-AIQ/PDTC) in severe acute pancreatitis (SAP) rats with adrenal damage. The primarily cultured adrenocortical cells were quantitatively divided into control group (SO), pancreatitis group (SAP), PDTC drug control group (SO+PDTC), PDTC intervention group (SAP+PDTC), 5-AIQ drug control group (SO+ 5-AIQ) and 5-AIQ intervention group (SAP+5-AIQ). The SAP and 2 intervention groups were stimulated with the sera of SAP rats. Then corresponding drugs were added and culture continued for 12 hours. The corticosterone levels and PARP/NF-κB expression were observed for each group. Adrenal cells in vitro cultured were round or oval, had secretory granules and could be stained by 3β-hydroxysteroid dehydrogenase antibody. The adherence rate was 60% after 48-hour culturing. The corticosterone level of SAP group was significantly lower than that of SO group [ (216.4 ± 15.7) vs (294.8 ± 16.3) µg/L, P < 0.05]. The 2 intervention groups were (258.6 ± 19.0) and (264.3 ± 18.2) µg/L respectively. These two values were higher than those of SAP group (P < 0.05), but lower than those of SO group (P < 0.05). With regards to the expression of PARP-1, the SAP and PDTC intervention groups were higher than SO group while 5-AIQ intervention group was significantly lower than SAP and PDTC intervention groups, but higher than SO and drug control groups. The expression of NF-κB in SAP group was higher than that in SO group. Two intervention groups were lower than SAP group, but higher than SO and drug control groups. The pathway of PARP/NF-κB participates in adrenal damage of SAP rats. To a certain extent, the uses of 5-AIQ and PDTC may alleviate adrenal damage.

Motor dysfunction in NF1: Mediated by attention deficit or inherent to the disorder?

PubMed

Haas-Lude, Karin; Heimgärtner, Magdalena; Winter, Sarah; Mautner, Victor-Felix; Krägeloh-Mann, Ingeborg; Lidzba, Karen

2018-01-01

Attention deficit and compromised motor skills are both prevalent in Neurofibromatosis type 1 (NF1), but the relationship is unclear. We investigated motor function in children with NF1 and in children with Attention Deficit/Hyperactivity Disorder (ADHD), and explored if, in patients with NF1, attention deficit influences motor performance. Motor performance was measured using the Movement Assessment Battery for Children (M-ABC) in 71 children (26 with NF1 plus ADHD, 14 with NF1 without ADHD, and 31 with ADHD without NF1) aged 6-12 years. There was a significant effect of group on motor performance. Both NF1 groups scored below children with ADHD without NF1. Attention performance mediated motor performance in children with ADHD without NF1, but not in children with NF1. Motor function is not mediated by attention performance in children with NF1. While in ADHD, attention deficit influences motor performance, motor problems in NF1 seem to be independent from attention deficit. This argues for different pathomechanisms in these two groups of developmental disorders. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Shigella IpaH0722 E3 Ubiquitin Ligase Effector Targets TRAF2 to Inhibit PKC–NF-κB Activity in Invaded Epithelial Cells

PubMed Central

Ashida, Hiroshi; Nakano, Hiroyasu; Sasakawa, Chihiro

2013-01-01

NF-κB plays a central role in modulating innate immune responses to bacterial infections. Therefore, many bacterial pathogens deploy multiple mechanisms to counteract NF-κB activation. The invasion of and subsequent replication of Shigella within epithelial cells is recognized by various pathogen recognition receptors as pathogen-associated molecular patterns. These receptors trigger innate defense mechanisms via the activation of the NF-κB signaling pathway. Here, we show the inhibition of the NF-κB activation by the delivery of the IpaH E3 ubiquitin ligase family member IpaH0722 using Shigella's type III secretion system. IpaH0722 dampens the acute inflammatory response by preferentially inhibiting the PKC-mediated activation of NF-κB by ubiquitinating TRAF2, a molecule downstream of PKC, and by promoting its proteasome-dependent degradation. PMID:23754945

Additivity rules using similarity models for chemical reactivity: calculation and interpretation of electrofugality and nucleofugality.

PubMed

Bentley, T William

2006-08-25

A recently proposed, multi-parameter correlation: log k (25 degrees C)=s(f) (Ef + Nf), where Ef is electrofugality and Nf is nucleofugality, for the substituent and solvent effects on the rate constants for solvolyses of benzhydryl and substituted benzhydryl substrates, is re-evaluated. A new formula (Ef=log k (RCl/EtOH/25 degrees C) -1.87), where RCl/EtOH refers to ethanolysis of chlorides, reproduces published values of Ef satisfactorily, avoids multi-parameter optimisations and provides additional values of Ef. From the formula for Ef, it is shown that the term (sfxEf) is compatible with the Hammett-Brown (rho+sigma+) equation for substituent effects. However, the previously published values of N(f) do not accurately account for solvent and leaving group effects (e.g. nucleofuge Cl or X), even for benzhydryl solvolyses; alternatively, if the more exact, two-parameter term, (sfxNf) is used, calculated effects are less accurate. A new formula (Nf=6.14 + log k(BX/any solvent/25 degrees C)), where BX refers to solvolysis of the parent benzhydryl as electrofuge, defines improved Nf values for benzhydryl substrates. The new formulae for Ef and Nf are consistent with an assumption that sf=1.00(,) and so improved correlations for benzhydryl substrates can be obtained from the additive formula: log k(RX/any solvent/25 degrees C)=(Ef + Nf). Possible extensions of this approach are also discussed.

Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-κB pathways.

PubMed

Dai, Jianping; Gu, Liming; Su, Yun; Wang, Qianwen; Zhao, Ying; Chen, Xiaoxua; Deng, Huixiong; Li, Weizhong; Wang, Gefei; Li, Kangsheng

2018-01-01

Oxidative stress, Nrf2-HO-1 and TLR-MAPK/NF-κB signaling pathways have been proved to be involved in influenza A virus (IAV) replication and influenzal pneumonia. In the previous studies, we have performed several high-throughput drug screenings based on the TLR pathways. In the present study, through plaque inhibition test, luciferase reporter assay, TCID 50 , qRT-PCR, western blotting, ELISA and siRNA assays, we investigated the effect and mechanism of action of curcumin against IAV infection in vitro and in vivo. The results showed that curcumin could directly inactivate IAV, blocked IAV adsorption and inhibited IAV proliferation. As for the underlying mechanisms, we found that curcumin could significantly inhibit IAV-induced oxidative stress, increased Nrf2, HO-1, NQO1, GSTA3 and IFN-β production, and suppressed IAV-induced activation of TLR2/4/7, Akt, p38/JNK MAPK and NF-κB pathways. Suppression of Nrf2 via siRNA significantly abolished the stimulatory effect of curcumin on HO-1, NQO1, GSTA3 and IFN-β production and meanwhile blocked the inhibitory effect of curcumin on IAV M2 production. Oxidant H 2 O 2 and TLR2/4, p38/JNK and NF-κB agonists could significantly antagonize the anti-IAV activity of curcumin in vitro. Additionally, curcumin significantly increased the survival rate of mice, reduced lung index, inflammatory cytokines and lung IAV titer, and finally improved pulmonary histopathological changes after IAV infection. In conclusion, curcumin can directly inactivate IAV, inhibits IAV adsorption and replication; and its inhibition on IAV replication may be via activating Nrf2 signal and inhibiting IAV-induced activation of TLR2/4, p38/JNK MAPK and NF-κB pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

Exendin-4 ameliorates oxidized-LDL-induced inhibition of macrophage migration in vitro via the NF-κB pathway

PubMed Central

Ma, Ge-fei; Chen, Song; Yin, Lei; Gao, Xiang-dong; Yao, Wen-bing

2014-01-01

Aim: To investigate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 on oxidized low-density lipoprotein (ox-LDL)-induced inhibition of macrophage migration and the mechanisms underlying the effects of exendin-4. Methods: Primary peritoneal macrophages were extracted from the peritoneal cavity of mice treated with 3% thioglycollate (2 mL, ip). Migration of the macrophages was examined using a cell migration assay. Macrophage migration-related factors including leptin-like ox-LDL receptor (LOX-1), cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-α, interleukin-1 (IL-1)β, matrix metalloproteinase-2 (MMP-2), intercellular adhesion molecule (ICAM)-1 and macrophage migration inhibitory factor (MIF) were measured using semi-quantitative RT-PCR. Expression of MIF and ICAM-1 proteins was examined with ELISA. Gelatin zymography was used to evaluate the activity of MMP-9. Activation of the NF-κB pathway was determined by confocal laser scanning microscopy. Results: Treatment of the macrophages with ox-LDL (50 μg/mL) markedly suppressed the macrophage migration. Furthermore, ox-LDL treatment substantially increased the expression of the macrophage migration-related factors, the activity of MMP-9 and the translocation of the NF-κB p65 subunit. These effects of ox-LDL were significantly ameliorated by pretreatment with the specific NF-κB inhibitor ammonium pyrrolidine dithiocarbamate (100 μmol/L). These effects of ox-LDL were also significantly ameliorated by pretreatment with exendin-4 (25 and 50 nmol/L). Conclusion: Exendin-4 ameliorates the inhibition of ox-LDL on macrophage migration in vitro, via suppressing ox-LDL-induced expression of ICAM-1 and MIF, which is probably mediated by the NF-κB pathway. PMID:24335838

Exendin-4 ameliorates oxidized-LDL-induced inhibition of macrophage migration in vitro via the NF-κB pathway.

PubMed

Ma, Ge-fei; Chen, Song; Yin, Lei; Gao, Xiang-dong; Yao, Wen-bing

2014-02-01

To investigate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 on oxidized low-density lipoprotein (ox-LDL)-induced inhibition of macrophage migration and the mechanisms underlying the effects of exendin-4. Primary peritoneal macrophages were extracted from the peritoneal cavity of mice treated with 3% thioglycollate (2 mL, ip). Migration of the macrophages was examined using a cell migration assay. Macrophage migration-related factors including leptin-like ox-LDL receptor (LOX-1), cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-α, interleukin-1 (IL-1)β, matrix metalloproteinase-2 (MMP-2), intercellular adhesion molecule (ICAM)-1 and macrophage migration inhibitory factor (MIF) were measured using semi-quantitative RT-PCR. Expression of MIF and ICAM-1 proteins was examined with ELISA. Gelatin zymography was used to evaluate the activity of MMP-9. Activation of the NF-κB pathway was determined by confocal laser scanning microscopy. Treatment of the macrophages with ox-LDL (50 μg/mL) markedly suppressed the macrophage migration. Furthermore, ox-LDL treatment substantially increased the expression of the macrophage migration-related factors, the activity of MMP-9 and the translocation of the NF-κB p65 subunit. These effects of ox-LDL were significantly ameliorated by pretreatment with the specific NF-κB inhibitor ammonium pyrrolidine dithiocarbamate (100 μmol/L). These effects of ox-LDL were also significantly ameliorated by pretreatment with exendin-4 (25 and 50 nmol/L). Exendin-4 ameliorates the inhibition of ox-LDL on macrophage migration in vitro, via suppressing ox-LDL-induced expression of ICAM-1 and MIF, which is probably mediated by the NF-κB pathway.

Grape seed extract has superior beneficial effects than vitamin E on oxidative stress and apoptosis in the hippocampus of streptozotocin induced diabetic rats.

PubMed

Yonguc, Goksin Nilufer; Dodurga, Yavuz; Adiguzel, Esat; Gundogdu, Gulsah; Kucukatay, Vural; Ozbal, Seda; Yilmaz, Ismail; Cankurt, Ulker; Yilmaz, Yusuf; Akdogan, Ilgaz

2015-01-25

We aimed to investigate the effects of grape seed extract (GSE) and vitamin E (Vit E) on oxidative stress and apoptosis in the hippocampus of streptozotocin-induced diabetic rats. In Control, Diabetic, and Diabetic treated with GSE (Diabetic+GSE) and vitamin E (Diabetic+Vit E) groups, oxidative stress index (OSI), TUNEL staining and Bcl-2, Bcl-XL, Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB gene expressions were evaluated. OSI was significantly increased in the plasma and hippocampus of the Diabetic compared to Control group and decreased in Diabetic+GSE and Diabetic+Vit E groups compared to Diabetic. TUNEL positive neurons significantly increased in the hippocampus of the Diabetic group compared to Control and decreased in Diabetic+GSE (more prominently) and Diabetic+Vit E groups compared to Diabetic. In the hippocampus of the Diabetic group, Bcl-2 and Bcl-XL gene expressions were significantly decreased; Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB gene expressions were significantly increased compared to Control. In Diabetic+GSE and Diabetic+Vit E groups, Bcl-2 gene expressions were significantly increased; Bcl-XL gene expressions did not differ compared to the Diabetic group. The expression of Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB genes in the Diabetic+GSE group and the expression of caspase-3 and -9, TNF-α, and NF-κB genes in the Diabetic+Vit E group were significantly decreased compared to Diabetic. In conclusion, GSE (more prominently) and vitamin E decreased oxidative stress and neuronal apoptosis occurring in the hippocampus of diabetic rats. Copyright © 2014 Elsevier B.V. All rights reserved.

Alcohol use disorder increases the risk of necrotizing fasciitis

PubMed Central

Yii, Yong-Cheng; Hsieh, Vivian Chia-Rong; Lin, Cheng-Li; Wang, Yu-Chiao; Chen, Wei-Kung

2017-01-01

Abstract This nationwide retrospective cohort study determined the association between alcohol use disorder (AUD) and the risk of necrotizing fasciitis (NF). This study used health insurance claims data of 52,212 in-patients with AUD and 208,848 controls randomly frequency-matched by age and sex at a 1:4 ratio. The AUD cohort included patients newly diagnosed with AUD between January 1, 2000 and December 31, 2008. The NF event occurrence was observed until December 31, 2011. We used the Kaplan–Meier method to present the cumulative incidence curve and Cox proportional hazard models to depict the risk of NF in patients with AUD. The incidence of NF was 19.4 per 10,000 person-years in the AUD cohort, which was nearly 7.73-fold higher than that in the comparison cohort (2.54 per 10,000 person-years). After adjustment for age, sex, and comorbidities, the patients with AUD exhibited a 3.55-fold higher risk of NF than did the controls (hazard ratio [HR] = 3.55, 95% confidence interval [CI] = 3.00–4.20). Nevertheless, in the AUD groups without any comorbidity, patients with AUD exhibited a significant 15.2-fold higher risk of NF than did the comparison cohort (HR = 15.2, 95% CI = 10.9–21.3). Moreover, the adjusted HRs of NF risk with respect to the severity of AUD were 2.15 (95% CI = 1.76–2.62), 4.54 (95% CI = 3.67–5.62), and 10.7 (95% CI = 8.66–13.2) for mild, moderate, and severe AUD, respectively. This study indicated that AUD should be considered an independent and significant risk factor for NF. PMID:28796035

Human T Cell Leukemia Virus Type I Tax-Induced IκB-ζ Modulates Tax-Dependent and Tax-Independent Gene Expression in T Cells1

PubMed Central

Kimura, Ryuichiro; Senba, Masachika; Cutler, Samuel J; Ralph, Stephen J; Xiao, Gutian; Mori, Naoki

2013-01-01

Human T cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL) and various inflammatory disorders including HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I oncoprotein Tax is known to cause permanent activation of many cellular transcription factors including nuclear factor-κB (NF-κB), cyclic adenosine 3′,5′-monophosphate response element-binding protein, and activator protein 1 (AP-1). Here, we show that NF-κB-binding cofactor inhibitor of NF-κB-ζ (IκB-ζ) is constitutively expressed in HTLV-I-infected T cell lines and ATL cells, and Tax transactivates the IκB-ζ gene, mainly through NF-κB. Microarray analysis of IκB-ζ-expressing uninfected T cells demonstrated that IκB-ζ induced the expression of NF-κB. and interferon-regulatory genes such as B cell CLL/lymphoma 3 (Bcl3), guanylate-binding protein 1, and signal transducer and activator of transcription 1. The transcriptional activation domain, nuclear localization signal, and NF-κB-binding domain of IκB-ζ were required for Bcl3 induction, and IκB-ζ synergistically enhanced Tax-induced Bcl3 transactivation in an NF-κB-dependent manner. Interestingly, IκB-ζ inhibited Tax-induced NF-κB, AP-1 activation, and HTLV-I transcription. Furthermore, IκB-ζ interacted with Tax in vitro and this interaction was also observed in an HTLV-I-transformed T cell line. These results suggest that IκB-ζ modulates Tax-dependent and Tax-independent gene transcription in T cells. The function of IκB-ζ may be of significance in ATL genesis and pathogenesis of HTLV-I-associated diseases. PMID:24027435

NF-κB deregulation in Hodgkin lymphoma.

PubMed

Weniger, Marc A; Küppers, Ralf

2016-08-01

Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (HL) show constitutive activity of both the canonical and non-canonical NF-κB signaling pathways. The central pathogenetic role of this activity is indicated from studies with HL cell lines, which undergo apoptosis upon NF-κB inhibition. Multiple factors contribute to the strong NF-κB activity of HRS cells. This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3, NFKBIA), and copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14). In Epstein-Barr virus-positive cases of classical HL, the virus-encoded latent membrane protein 1 causes NF-κB activation by mimicking an active CD40 receptor. NF-κB activity is also seen in the tumor cells of the rare nodular lymphocyte predominant form of HL, but the causes for this activity are largely unclear. Copyright © 2016 Elsevier Ltd. All rights reserved.

6-gingerol ameliorated doxorubicin-induced cardiotoxicity: role of nuclear factor kappa B and protein glycation.

PubMed

El-Bakly, Wesam M; Louka, Manal L; El-Halawany, Ali M; Schaalan, Mona F

2012-12-01

Doxorubicin is a widely used antitumour drug. Cardiotoxicity is considered a major limitation for its clinical use. The present study was designed to assess the possible antioxidant and antiapoptotic effects of 6-gingerol in attenuating doxorubicin-induced cardiac damage. Male albino rats were treated with either intraperitoneal doxorubicin (18 mg/kg divided into six equal doses for 2 weeks) and/or oral 6-gingerol (10 mg/kg starting 5 days before and continued till the end of the experiment). 6-gingerol significantly ameliorated the doxorubicin-induced elevation in the cardiac enzymes. The stimulation of oxidative stress by doxorubicin was evidenced by the significant decrease in the serum soluble receptor for advanced glycation endproduct allowing unopposed serum advanced glycation endproduct availability. Moreover, doxorubicin activated nuclear factor kappa B (NF-κB) which was indicated by an increase in its immunohistochemical staining in the nucleus. In addition, doxorubicin-induced cardiotoxicity was accompanied by elevation of cardiac caspase-3. Notably, pretreatment with 6-gingerol significantly ameliorated the changes in sRAGE, NF-κB and cardiac caspase-3. Cardiac enzymes showed significant positive correlation with NF-κB and caspase-3 but negative with serum sRAGE, suggesting their role in doxorubicin-induced cardiac injury. These findings were confirmed by cardiac tissue histopathology. 6-gingerol, a known single compound from ginger with anticancer activity, was shown to have a promising role in cardioprotection against doxorubicin-induced cardiotoxicity. This study suggested a novel mechanism for 6-gingerol cardioprotection, which might be mediated through its antioxidative effect and modulation of NF-κB as well as apoptosis.

Removal of heavy metals from aluminum anodic oxidation wastewaters by membrane filtration.

PubMed

Ates, Nuray; Uzal, Nigmet

2018-05-27

Aluminum manufacturing has been reported as one of the largest industries and wastewater produced from the aluminum industry may cause significant environmental problems due to variable pH, high heavy metal concentration, conductivity, and organic load. The management of this wastewater with a high pollution load is of great importance for practitioners in the aluminum sector. There are hardly any studies available on membrane treatment of wastewater originated from anodic oxidation. The aim of this study is to evaluate the best treatment and reuse alternative for aluminum industry wastewater using membrane filtration. Additionally, the performance of chemical precipitation, which is the existing treatment used in the aluminum facility, was also compared with membrane filtration. Wastewater originated from anodic oxidation coating process of an aluminum profile manufacturing facility in Kayseri (Turkey) was used in the experiments. The characterization of raw wastewater was in very low pH (e.g., 3) with high aluminum concentration and conductivity values. Membrane experiments were carried out with ultrafiltration (PTUF), nanofiltration (NF270), and reverse osmosis (SW30) membranes with MWCO 5000, 200-400, and 100 Da, respectively. For the chemical precipitation experiments, FeCl 3 and FeSO 4 chemicals presented lower removal performances for aluminum and chromium, which were below 35% at ambient wastewater pH ~ 3. The membrane filtration experimental results show that, both NF and RO membranes tested could effectively remove aluminum, total chromium and nickel (>90%) from the aluminum production wastewater. The RO (SW30) membrane showed a slightly higher performance at 20 bar operating pressure in terms of conductivity removal values (90%) than the NF 270 membrane (87%). Although similar removal performances were observed for heavy metals and conductivity by NF270 and SW30, significantly higher fluxes were obtained in NF270 membrane filtration at any pressure that there were more than three times the flux values in SW30 membrane filtration. Due to the lower heavy metal (<65%) and conductivity (<30%) removal performances of UF membrane, it could be evaluated as pretreatment followed by NF filtration to protect and extend NF membrane life. The water treated by both NF and RO could be recycled back into the process to be reused with economic and environmental benefits.

Integration of membrane separation and Fenton processes for sanitary landfill leachate treatment.

PubMed

Santos, Amanda Vitória; Andrade, Laura Hamdan de; Amaral, Míriam Cristina Santos; Lange, Liséte Celina

2018-04-06

The appropriate treatment of sanitary landfill leachate is one of the greatest challenges nowadays due to the large volumes of solid waste generated. Thus, the aim of this study is to evaluate the performance of different routes involving the integration of advanced oxidation processes based on Fenton's reagents (AOP-Fenton) and microfiltration (MF) and nanofiltration (NF) membrane processes for the treatment of landfill leachate. MF module configuration (submerged or sidestream) and MF and NF recovery rate were evaluated. The combination of AOP-Fenton, MF and NF proved to be an effective treatment for landfill leachate. High removal efficiencies of chemical oxidation demand (94-96%) and colour (96-99%) were obtained. The configuration named route 3, composed of MF of raw landfill leachate (MF1), POA-Fenton-MF2 of the MF1 concentrate and NF of both MF1 and MF2 permeates, showed a higher global water recovery and was responsible for lower waste generation. It was considered the best one in terms of environmental, technical and economical aspects.

Effect of low extracellular pH on NF-κB activation in macrophages.

PubMed

Gerry, A B; Leake, D S

2014-04-01

Many diseases, including atherosclerosis, involve chronic inflammation. The master transcription factor for inflammation is NF-κB. Inflammatory sites have a low extracellular pH. Our objective was to demonstrate the effect of pH on NF-κB activation and cytokine secretion. Mouse J774 macrophages or human THP-1 or monocyte-derived macrophages were incubated at pH 7.0-7.4 and inflammatory cytokine secretion and NF-κB activity were measured. A pH of 7.0 greatly decreased pro-inflammatory cytokine secretion (TNF or IL-6) by J774 macrophages, but not THP-1 or human monocyte-derived macrophages. Upon stimulation of mouse macrophages, the levels of IκBα, which inhibits NF-κB, fell but low pH prevented its later increase, which normally restores the baseline activity of NF-κB, even though the levels of mRNA for IκBα were increased. pH 7.0 greatly increased and prolonged NF-κB binding to its consensus promoter sequence, especially the anti-inflammatory p50:p50 homodimers. Human p50 was overexpressed using adenovirus in THP-1 macrophages and monocyte-derived macrophages to see if it would confer pH sensitivity to NF-κB activity in human cells. Overexpression of p50 increased p50:p50 DNA-binding and in THP-1 macrophages inhibited considerably TNF and IL-6 secretion, but there was still no effect of pH on p50:p50 DNA binding or cytokine secretion. A modest decrease in pH can sometimes have marked effects on NF-κB activation and cytokine secretion and might be one reason to explain why mice normally develop less atherosclerosis than do humans. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

PTP1B Inhibitory and Anti-Inflammatory Effects of Secondary Metabolites Isolated from the Marine-Derived Fungus Penicillium sp. JF-55

PubMed Central

Lee, Dong-Sung; Jang, Jae-Hyuk; Ko, Wonmin; Kim, Kyoung-Su; Sohn, Jae Hak; Kang, Myeong-Suk; Ahn, Jong Seog; Kim, Youn-Chul; Oh, Hyuncheol

2013-01-01

Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the negative regulation of insulin signaling, and is thus considered as an attractive therapeutic target for the treatment of diabetes. Bioassay-guided investigation of the methylethylketone extract of marine-derived fungus Penicillium sp. JF-55 cultures afforded a new PTP1B inhibitory styrylpyrone-type metabolite named penstyrylpyrone (1), and two known metabolites, anhydrofulvic acid (2) and citromycetin (3). Compounds 1 and 2 inhibited PTP1B activity in a dose-dependent manner, and kinetic analyses of PTP1B inhibition suggested that these compounds inhibited PTP1B activity in a competitive manner. In an effort to gain more biological potential of the isolated compounds, the anti-inflammatory effects of compounds 1–3 were also evaluated. Among the tested compounds, only compound 1 inhibited the production of NO and PGE2, due to the inhibition of the expression of iNOS and COX-2. Penstyrylpyrone (1) also reduced TNF-α and IL-1β production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of IκB-α, NF-κB nuclear translocation, and NF-κB DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of penstyrylpyrone (1) on the pro-inflammatory mediators and NF-κB DNA binding activity were associated with the HO-1 expression. Therefore, these results suggest that penstyrylpyrone (1) suppresses PTP1B activity, as well as the production of pro-inflammatory mediators via NF-κB pathway, through expression of anti-inflammatory HO-1. PMID:23612372

Effect of 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate sodium on expression of GSTP1 and NQO1 genes and protein transcription factors in BALB/c mouse liver.

PubMed

Shintyapina, A B; Safronova, O G; Vavilin, V A; Kandalintseva, N V; Prosenko, A E; Lyakhovich, V V

2014-08-01

The study examined dynamics of the effect of novel phenol antioxidant preparation 3-(3'-tertbutyl- 4'-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on expression of antioxidant protection enzymes genes GSTP1 and NQO1 and on the content of protein transcription factors NF-κB and ATF-2 in mouse liver. Expression of GSTP1 gene decreased significantly on days 4 and 7 after per os administration of TS-13 (100 mg/kg), but increased on post-administration day 14. On days 7 and 14 post-administration, expression of NQO1 gene was significantly increased. On day 7, the hepatic content of the phosphorylated form of ATF-2 and two subunits of nuclear factor NF-κB (p50, p65) decreased significantly.

Effects of blue honeysuckle (Lonicera caerulea L.) extract on lipopolysaccharide-induced inflammation in vitro and in vivo.

PubMed

Jin, Xue-Hai; Ohgami, Kazuhiro; Shiratori, Kenji; Suzuki, Yukari; Koyama, Yoshikazu; Yoshida, Kazuhiko; Ilieva, Iliyana; Tanaka, Tsuneo; Onoe, Kazunori; Ohno, Shigeaki

2006-05-01

The aim of the present study was to investigate the effects of blue honeysuckle extract (BHE), which contains high level of phenolic compounds, on endotoxin-induced uveitis (EIU). Male Lewis rats were randomly divided into 5 groups with 14 rats in each (eight rats for collection of aqueous humor, six rats for histologic examination). EIU was induced by a footpad injection of lipopolysaccharide (LPS). 1, 10, or 100 mg of BHE was injected intravenously immediately after LPS injection. The aqueous humor was collected at 24 h after LPS injection, the number of infiltrating cells, protein concentration, nitric oxide (NO), tumor necrosis factor (TNF)-alpha, and prostaglandin (PG)-E2 levels in the aqueous humor were determined. Some eyes were enucleated for histologic examination and immunohistochemical analysis. Immunohistochemical staining with a monoclonal antibody against activated nuclear factor (NF)-kappaB was performed to evaluate the effect of BHE on NF-kappaB activation. To further clarify the anti-inflammatory effect, RAW264.7 cells (a mouse macrophage cell line) were stimulated with LPS in the presence or absence of BHE and its major phenolics, cyanidin 3-glucoside (C3G), cyanidin 3-rutinoside (C3R), chlorogenic acid (CA). Expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were analyzed by Western blot method. BHE treatment significantly reduced the inflammatory cell infiltration, the protein concentration, the levels of NO, TNF-alpha and PGE2 in the aqueous humor and improved histologic status of the ocular tissue. The number of activated NF-kappaB-positive cells was lower in the iris-ciliary body treated with BHE at 3 h after LPS injection. BHE significantly suppressed the production of NO, PGE2 and TNF-alpha in the culture medium as well as the expression of iNOS and COX-2 by LPS-stimulated RAW264.7 cells in a dose-dependent fashion. C3G, C3R and CA showed no or weak inhibitory effects on the level of inflammatory mediators and the expression of iNOS and COX-2. These results suggest that BHE attenuates the degree of inflammation in eyes with EIU by inhibiting the NF-kappaB dependent signaling pathway and the subsequent production of proinflammatory mediators.

Consensus Recommendations for Current Treatments and Accelerating Clinical Trials for Patients with Neurofibromatosis Type 2

PubMed Central

Blakeley, Jaishri O; Evans, D. Gareth; Adler, John; Brackmann, Derald; Chen, Ruihong; Ferner, Rosalie E.; Hanemann, C. Oliver; Harris, Gordon; Huson, Susan M.; Jacob, Abraham; Kalamarides, Michel; Karajannis, Matthias A.; Korf, Bruce R.; Mautner, Victor-Felix; McClatchey, Andrea I.; Miao, Harry; Plotkin, Scott R.; Slattery, William; Stemmer-Rachamimov, Anat O.; Welling, D. Bradley; Wen, Patrick Y.; Widemann, Brigitte; Hunter-Schaedle, Kim; Giovannini, Marco

2011-01-01

Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome characterized by bilateral vestibular schwannomas (VS) which often result in deafness despite aggressive management. Meningiomas, ependymomas and other cranial nerve and peripheral schwannomas are also commonly found in NF2 and collectively lead to major neurologic morbidity and mortality. Traditionally, the overall survival rate in patients with NF2 is estimated to be 38% at 20 years from diagnosis. Hence, there is a desperate need for new, effective therapies. Recent progress in understanding the molecular basis of NF2 related tumors has aided in the identification of potential therapeutic targets and emerging clinical therapies. In June 2010, representatives of the international NF2 research and clinical community convened under the leadership of Drs. D. Gareth Evans (University of Manchester) and Marco Giovannini (House Research Institute) to review the state of NF2 treatment and clinical trials. This manuscript summarizes the expert opinions about current treatments for NF2 associated tumors and recommendations for advancing therapies emerging from that meeting. The development of effective therapies for NF2 associated tumors has the potential for significant clinical advancement not only for patients with NF2 but for thousands of neuro-oncology patients afflicted with these tumors. PMID:22140088

NF-kappaB modulators from Valeriana officinalis.

PubMed

Jacobo-Herrera, Nadia J; Vartiainen, Nina; Bremner, Paul; Gibbons, Simon; Koistinaho, Jari; Heinrich, Michael

2006-10-01

Valeriana officinalis (Valerianaceae) has been of great interest for its therapeutic uses for treating mild nervous tension and temporary sleeping problems. In traditional European medicine it has been also reported as an antiinflammatory remedy. This study reports that the EtOAc extract of the underground parts of V. officinalis showed inhibitory activity against NF-kappaB at 100 microg/mL in the IL-6/Luc assay on HeLa cells and provided protection against excitotoxicity in primary brain cell cultures at micromolar concentrations. Bioassay-guided fractionation of the EtOAc extract led to the isolation of three known sesquiterpenes: acetylvalerenolic acid (1), valerenal (2) and valerenic acid (3), 1 and 3 were active as inhibitors of NF-kappaB at a concentration of 100 microg/mL. Acetylvalerenolic acid (1) reduced NF-kappaB activity to 4%, whereas valerenic acid (3) reduced NF-kappaB activity to 25%. Copyright 2006 John Wiley & Sons, Ltd.

Theta/beta neurofeedback in children with ADHD: Feasibility of a short-term setting and plasticity effects.

PubMed

Van Doren, Jessica; Heinrich, Hartmut; Bezold, Mareile; Reuter, Nina; Kratz, Oliver; Horndasch, Stefanie; Berking, Matthias; Ros, Tomas; Gevensleben, Holger; Moll, Gunther H; Studer, Petra

2017-02-01

Neurofeedback (NF) is increasingly used as a therapy for attention-deficit/hyperactivity disorder (ADHD), however behavioral improvements require 20 plus training sessions. More economic evaluation strategies are needed to test methodological optimizations and mechanisms of action. In healthy adults, neuroplastic effects have been demonstrated directly after a single session of NF training. The aim of our study was to test the feasibility of short-term theta/beta NF in children with ADHD and to learn more about the mechanisms underlying this protocol. Children with ADHD conducted two theta/beta NF sessions. In the first half of the sessions, three NF trials (puzzles as feedback animations) were run with pre- and post-reading and picture search tasks. A significant decrease of the theta/beta ratio (TBR), driven by a decrease of theta activity, was found in the NF trials of the second session demonstrating rapid and successful neuroregulation by children with ADHD. For pre-post comparisons, children were split into good vs. poor regulator groups based on the slope of their TBR over the NF trials. For the reading task, significant EEG changes were seen for the theta band from pre- to post-NF depending on individual neuroregulation ability. This neuroplastic effect was not restricted to the feedback electrode Cz, but appeared as a generalized pattern, maximal over midline and right-hemisphere electrodes. Our findings indicate that short-term NF may be a valuable and economical tool to study the neuroplastic mechanisms of targeted NF protocols in clinical disorders, such as theta/beta training in children with ADHD. Copyright © 2016 Elsevier B.V. All rights reserved.

Src-family-tyrosine kinase Lyn is critical for TLR2-mediated NF-κB activation through the PI 3-kinase signaling pathway.

PubMed

Toubiana, Julie; Rossi, Anne-Lise; Belaidouni, Nadia; Grimaldi, David; Pene, Frederic; Chafey, Philippe; Comba, Béatrice; Camoin, Luc; Bismuth, Georges; Claessens, Yann-Erick; Mira, Jean-Paul; Chiche, Jean-Daniel

2015-10-01

TLR2 has a prominent role in host defense against a wide variety of pathogens. Stimulation of TLR2 triggers MyD88-dependent signaling to induce NF-κB translocation, and activates a Rac1-PI 3-kinase dependent pathway that leads to transactivation of NF-κB through phosphorylation of the P65 NF-κB subunit. This transactivation pathway involves tyrosine phosphorylations. The role of the tyrosine kinases in TLR signaling is controversial, with discrepancies between studies using only chemical inhibitors and knockout mice. Here, we show the involvement of the tyrosine-kinase Lyn in TLR2-dependent activation of NF-κB in human cellular models, by using complementary inhibition strategies. Stimulation of TLR2 induces the formation of an activation cluster involving TLR2, CD14, PI 3-kinase and Lyn, and leads to the activation of AKT. Lyn-dependent phosphorylation of the p110 catalytic subunit of PI 3-kinase is essential to the control of PI 3-kinase biological activity upstream of AKT and thereby to the transactivation of NF-κB. Thus, Lyn kinase activity is crucial in TLR2-mediated activation of the innate immune response in human mononuclear cells. © The Author(s) 2015.

CTF Meeting 2012: Translation of the Basic Understanding of the Biology and Genetics of NF1, NF2, and Schwannomatosis Toward the Development of Effective Therapies

PubMed Central

Widemann, Brigitte C.; Acosta, Maria T.; Ammoun, Sylvia; Belzberg, Allan J.; Bernards, Andre; Blakeley, Jaishri; Bretscher, Antony; Cichowski, Karen; Clapp, D. Wade; Dombi, Eva; Evans, Gareth D.; Ferner, Rosalie; Fernandez-Valle, Cristina; Fisher, Michael J.; Giovannini, Marco; Gutmann, David H.; Hanemann, C. Oliver; Hennigan, Robert; Huson, Susan; Ingram, David; Kissil, Joe; Korf, Bruce R.; Legius, Eric; Packer, Roger J.; McClatchey, Andrea I; McCormick, Frank; North, Kathryn; Pehrsson, Minja; Plotkin, Scott R.; Ramesh, Vijaya; Ratner, Nancy; Schirmer, Susann; Sherman, Larry; Schorry, Elizabeth; Stevenson, David; Stewart, Douglas R.; Ullrich, Nicole; Bakker, Annette C.; Morrison, Helen

2014-01-01

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a “state-of-the-field” for NF research in 2012. PMID:24443315

CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies.

PubMed

Widemann, Brigitte C; Acosta, Maria T; Ammoun, Sylvia; Belzberg, Allan J; Bernards, Andre; Blakeley, Jaishri; Bretscher, Antony; Cichowski, Karen; Clapp, D Wade; Dombi, Eva; Evans, Gareth D; Ferner, Rosalie; Fernandez-Valle, Cristina; Fisher, Michael J; Giovannini, Marco; Gutmann, David H; Hanemann, C Oliver; Hennigan, Robert; Huson, Susan; Ingram, David; Kissil, Joe; Korf, Bruce R; Legius, Eric; Packer, Roger J; McClatchey, Andrea I; McCormick, Frank; North, Kathryn; Pehrsson, Minja; Plotkin, Scott R; Ramesh, Vijaya; Ratner, Nancy; Schirmer, Susann; Sherman, Larry; Schorry, Elizabeth; Stevenson, David; Stewart, Douglas R; Ullrich, Nicole; Bakker, Annette C; Morrison, Helen

2014-03-01

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012. © 2014 Wiley Periodicals, Inc.

Nitric oxide sensitizes prostate carcinoma cell lines to TRAIL-mediated apoptosis via inactivation of NF-kappa B and inhibition of Bcl-xl expression.

PubMed

Huerta-Yepez, Sara; Vega, Mario; Jazirehi, Ali; Garban, Hermes; Hongo, Fumiya; Cheng, Genhong; Bonavida, Benjamin

2004-06-24

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be selective in the induction of apoptosis in cancer cells with minimal toxicity to normal tissues and this prompted its potential therapeutic application in cancer. However, not all cancers are sensitive to TRAIL-mediated apoptosis and, therefore, TRAIL-resistant cancer cells must be sensitized first to become sensitive to TRAIL. Treatment of prostate cancer (CaP) cell lines (DU145, PC-3, CL-1, and LNCaP) with nitric oxide donors (e.g. (Z)-1-[2-(2-aminoethyl)-N-(2-ammonio-ethyl)amino]diazen-1-ium-1, 2-diolate (DETANONOate)) sensitized CaP cells to TRAIL-induced apoptosis and synergy was achieved. The mechanism by which DETANONOate mediated the sensitization was examined. DETANONOate inhibited the constitutive NF-kappa B activity as assessed by EMSA. Also, p50 was S-nitrosylated by DETANONOate resulting in inhibition of NF-kappa B. Inhibition of NF-kappa B activity by the chemical inhibitor Bay 11-7085, like DETANONOate, sensitized CaP to TRAIL apoptosis. In addition, DETANONOate downregulated the expression of Bcl-2 related gene (Bcl-(xL)) which is under the transcriptional regulation of NF-kappa B. The regulation of NF-kappa B and Bcl-(xL) by DETANONOate was corroborated by the use of Bcl-(xL) and Bcl-x kappa B reporter systems. DETANONOate inhibited luciferase activity in the wild type and had no effect on the mutant cells. Inhibition of NF-kappa B resulted in downregulation of Bcl-(xL) expression and sensitized CaP to TRAIL-induced apoptosis. The role of Bcl-(xL) in the regulation of TRAIL apoptosis was corroborated by inhibiting Bcl-(xL) function by the chemical inhibitor 2-methoxyantimycin A(3) and this resulted in sensitization of the cells to TRAIL apoptosis. Signaling by DETANONOate and TRAIL for apoptosis was examined. DETANONOate altered the mitochondria by inducing membrane depolarization and releasing modest amounts of cytochrome c and Smac/DIABLO in the absence of downstream activation of caspases 9 and 3. However, the combination of DETANONOate and TRAIL resulted in activation of the mitochondrial pathway and activation of caspases 9 and 3, and induction of apoptosis. These findings demonstrate that DETANONOate-mediated sensitization of CaP to TRAIL-induced apoptosis is via inhibition of constitutive NF-kappa B activity and Bcl-(xL) expression.

Facile one-pot fabrication of nano-Fe3O4/carboxyl-functionalized baker's yeast composites and their application in methylene blue dye adsorption

NASA Astrophysics Data System (ADS)

Du, Zongjun; Zhang, Yue; Li, Zhengjie; Chen, Hui; Wang, Ying; Wang, Guangtu; Zou, Ping; Chen, Huaping; Zhang, Yunsong

2017-01-01

Nano-Fe3O4/carboxyl-functionalized baker's yeast composites (NF/CF-BYs) were prepared for the first time based on the ultrasonic cavitation assisted oxygen implosion method using single Fe2+ as iron source. The series of characterization analysis results showed that the obtained NF/CF-BYs had not only the superparamagnetic properties of nano-Fe3O4, but their surface also had plenty of functional groups (especially carboxyl groups) introduced by strong oxidization. The adsorption properties of NF/CF-BYs for methylene blue (MB) were also evaluated. The results displayed that the uptakes of NF/CF-BYs for MB were higher than that of pristine baker's yeast (P-BYs), and the adsorption process was followed by the pseudo-second-order kinetic model and Langmuir isotherm. The maximum adsorption capacity of NF/CF-BYs for MB was estimated to be 141.75 mg g-1 at pH 6. The regeneration efficiency of the obtained NF/CF-BYs was attained to be more than 90%.