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Sample records for inflammatory pathways protects

  1. The protective effect of the cholinergic anti-inflammatory pathway against septic shock in rats.

    PubMed

    Song, Xue-Min; Li, Jian-Guo; Wang, Yan-Lin; Hu, Zheng-Fang; Zhou, Qing; Du, Zhao-Hui; Jia, Bao-Hui

    2008-10-01

    hepatic NF-kappaB activation. Our results showed that the cholinergic anti-inflammatory pathway might produce a potential protective effect on polymicrobial sepsis in rats.

  2. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression.

    PubMed

    Chen, Xi-Lin; Dodd, Geraldine; Thomas, Suzanne; Zhang, Xiaolan; Wasserman, Martin A; Rovin, Brad H; Kunsch, Charles

    2006-05-01

    The antioxidant response element (ARE) is a transcriptional control element that mediates expression of a set of antioxidant proteins. NF-E2-related factor 2 (Nrf2) is a transcription factor that activates ARE-containing genes. In endothelial cells, the ARE-mediated genes are upregulated by atheroprotective laminar flow through a Nrf2-dependent mechanism. We tested the hypothesis that activation of ARE-regulated genes via adenovirus-mediated expression of Nrf2 may suppress redox-sensitive inflammatory gene expression. Expression of Nrf2 in human aortic endothelial cells (HAECs) resulted in a marked increase in ARE-driven transcriptional activity and protected HAECs from H2O2-mediated cytotoxicity. Nrf2 suppressed TNF-alpha-induced monocyte chemoattractant protein (MCP)-1 and VCAM-1 mRNA and protein expression in a dose-dependent manner and inhibited TNF-alpha-induced monocytic U937 cell adhesion to HAECs. Nrf2 also inhibited IL-1beta-induced MCP-1 gene expression in human mesangial cells. Expression of Nrf2 inhibited TNF-alpha-induced activation of p38 MAP kinase. Furthermore, expression of a constitutively active form of MKK6 (an upstream kinase for p38 MAP kinase) partially reversed Nrf2-mediated inhibition of VCAM-1 expression, suggesting that p38 MAP kinase, at least in part, mediates Nrf2's anti-inflammatory action. In contrast, Nrf2 did not inhibit TNF-alpha-induced NF-kappaB activation. These data identify the Nrf2/ARE pathway as an endogenous atheroprotective system for antioxidant protection and suppression of redox-sensitive inflammatory genes, suggesting that targeting the Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of inflammatory diseases such as atherosclerosis.

  3. Protective effect of Schizandrin B against damage of UVB irradiated skin cells depend on inhibition of inflammatory pathways.

    PubMed

    Gao, Chenguang; Chen, Hong; Niu, Cong; Hu, Jie; Cao, Bo

    2017-01-02

    Schizandrin B is extracted from Schisandra chinensis (Turcz.) Baill. This study evaluated the photoprotective effect of Schizandrin B on oxidative stress injury of the skin caused by UVB-irradiation and the molecular mechanism of the photoprotective effect of Schizandrin B, and we firstly found that Schizandrin B could block Cox-2, IL-6 and IL-18 signal pathway to protect damage of skin cells given by UVB-irradiation. In the research, we found that Schizandrin B can attenuate the UVB-induced toxicity on keratinocytes and dermal fibroblasts in human body, and can outstandingly eliminated intracellular ROS produced by UVB-irradiation. These results demonstrate that Schizandrin B can regulate the function of decreasing intracellular SOD's activity and increasing the expression level of MDA in HaCaT cells result from the guidance of UVB, and it markedly reduced the production of inflammatory factors such as Cox-2, IL-6 or IL-18, decreased the expression level of MMP-1, and interdicted degradation process of collagens in UVB-radiated cells. Therefore, skin keratinocytes can be effectively protected from UVB-radiated damage by Schizandrin B, and UVB-irradiation caused inflammatory responses can be inhibited by attenuating process of ROS generating.

  4. Adenosine A1 Receptor Protects Against Cisplatin Ototoxicity by Suppressing the NOX3/STAT1 Inflammatory Pathway in the Cochlea

    PubMed Central

    Kaur, Tejbeer; Borse, Vikrant; Sheth, Sandeep; Sheehan, Kelly; Ghosh, Sumana; Tupal, Srinivasan; Jajoo, Sarvesh; Mukherjea, Debashree; Rybak, Leonard P.

    2016-01-01

    Cisplatin is a commonly used antineoplastic agent that produces ototoxicity that is mediated in part by increasing levels of reactive oxygen species (ROS) via the NOX3 NADPH oxidase pathway in the cochlea. Recent studies implicate ROS generation in mediating inflammatory and apoptotic processes and hearing loss by activating signal transducer and activator of transcription (STAT1). In this study, we show that the adenosine A1 receptor (A1AR) protects against cisplatin ototoxicity by suppressing an inflammatory response initiated by ROS generation via NOX3 NADPH oxidase, leading to inhibition of STAT1. Trans-tympanic administration of the A1AR agonist R-phenylisopropyladenosine (R-PIA) inhibited cisplatin-induced ototoxicity, as measured by auditory brainstem responses and scanning electron microscopy in male Wistar rats. This was associated with reduced NOX3 expression, STAT1 activation, tumor necrosis factor-α (TNF-α) levels, and apoptosis in the cochlea. In vitro studies in UB/OC-1 cells, an organ of Corti immortalized cell line, showed that R-PIA reduced cisplatin-induced phosphorylation of STAT1 Ser727 (but not Tyr701) and STAT1 luciferase activity by suppressing the ERK1/2, p38, and JNK mitogen-activated protein kinase (MAPK) pathways. R-PIA also decreased the expression of STAT1 target genes, such as TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced cisplatin-mediated apoptosis. These data suggest that the A1AR provides otoprotection by suppressing NOX3 and inflammation in the cochlea and could serve as an ideal target for otoprotective drug therapy. SIGNIFICANCE STATEMENT Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. Its use results in significant and permanent hearing loss, for which no US Food and Drug Administration-approved treatment is currently available. In this study, we targeted the cochlear adenosine A1 receptor (A1AR) by trans-tympanic injections of the agonist R

  5. Sulforaphane Protects Pancreatic Acinar Cell Injury by Modulating Nrf2-Mediated Oxidative Stress and NLRP3 Inflammatory Pathway

    PubMed Central

    Dong, Zhaojun; Shang, Haixiao; Chen, Yong Q.; Pan, Li-Long

    2016-01-01

    Acute pancreatitis (AP) is characterized by early activation of intra-acinar proteases followed by acinar cell death and inflammation. Cellular oxidative stress is a key mechanism underlying these pathological events. Sulforaphane (SFN) is a natural organosulfur antioxidant with undescribed effects on AP. Here we investigated modulatory effects of SFN on cellular oxidation and inflammation in AP. AP was induced by cerulean hyperstimulation in BALB/c mice. Treatment group received a single dose of 5 mg/kg SFN for 3 consecutive days before AP. We found that SFN administration attenuated pancreatic injury as evidenced by serum amylase, pancreatic edema, and myeloperoxidase, as well as by histological examination. SFN administration reverted AP-associated dysregulation of oxidative stress markers including pancreatic malondialdehyde and redox enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). In acinar cells, SFN treatment upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes including quinoneoxidoreductase-1, heme oxidase-1, SOD1, and GPx1. In addition, SFN selectively suppressed cerulein-induced activation of the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome, in parallel with reduced nuclear factor- (NF-) κB activation and modulated NF-κB-responsive cytokine expression. Together, our data suggested that SFN modulates Nrf2-mediated oxidative stress and NLRP3/NF-κB inflammatory pathways in acinar cells, thereby protecting against AP. PMID:27847555

  6. Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway.

    PubMed

    Jiao, M; Ren, F; Zhou, L; Zhang, X; Zhang, L; Wen, T; Wei, L; Wang, X; Shi, H; Bai, L; Zhang, X; Zheng, S; Zhang, J; Chen, Y; Han, Y; Zhao, C; Duan, Z

    2014-08-28

    Peroxisome proliferator-activated receptor α (PPARα) has been reported to induce a potent anti-inflammatory response. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that PPARα activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPARα expression during ALF and the impact of PPARα activation by Wy-14 643 on the hepatic immune response were studied in a D-galactosamine/lipopolysaccharide-induced mouse model. Autophagy was inhibited by 3-methyladenine or small interfering RNA (siRNA) against Atg7. In both the mouse model and human ALF subjects, PPARα was significantly downregulated in the injured liver. PPARα activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPARα activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPARα activation suppressed proinflammatory responses and inhibited phosphorylated NF-κBp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPARα activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPARα activation directly induced autophagy in primary macrophages in vitro, which protected cells from a lipopolysaccharide-induced proinflammatory response. Here, for the first time, we have demonstrated that PPARα-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.

  7. Decitabine and 5-azacitidine both alleviate LPS induced ARDS through anti-inflammatory/antioxidant activity and protection of glycocalyx and inhibition of MAPK pathways in mice.

    PubMed

    Huang, Xiao; Kong, Guiqing; Li, Yan; Zhu, Weiwei; Xu, Haixiao; Zhang, Xiaohua; Li, Jiankui; Wang, Lipeng; Zhang, Zhongwen; Wu, Yaru; Liu, Xiangyong; Wang, Xiaozhi

    2016-12-01

    Decitabine (5-aza-2'-deoxycytidine, DAC) and 5-azacitidine (Aza), an inhibitor of DNA methyltransferases, possess a wide range of anti-metabolic and anti-cancer activities. This study examined the effects of DAC and Aza on inflammatory and oxidative injuries, as well as on glycocalyx and MAPK signaling pathways, in a LPS-stimulated ARDS mouse model. Results of ELISA revealed that DAC and Aza significantly inhibited the production of TNF-α and IL-1β and prevented LPS-induced elevation of myeloperoxidase and malondialdehyde levels in serum. The W/D ratio of lung and histopathologic examination with hematoxylin and eosin staining showed that DAC and Aza pretreatment substantially improved lung tissue injury. DAC and Aza reduced the level of glycocalyx degradation products (e.g., heparan sulfate and haluronic acid) and protected glycocalyx integrity. Western blot assay demonstrated that DAC and Aza both significantly suppressed LPS-induced activation of the MAPK signaling pathways by blocking the phosphorylation of JNK, ERK and P38 in lung tissues. Bisulfite sequencing PCR and real time-PCR showed that DAC reversed the RASSF1A promoter hypermethylation and furthermore elevated the expression of RASSF1A, which is a tumor suppressor that regulates MAPK signaling pathway. These results suggested that DAC inhibited the MAPK signaling pathway in LPS-induced ARDS mice might via demethylation in RASSF1A promoter region and by restoring its expression. This study highlighted the close relationship between DNA methylation and the development and progression of ARDS.

  8. Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats.

    PubMed

    Zhang, Tingting; Su, Jingyuan; Guo, Bingyu; Wang, Kaiwen; Li, Xiaoming; Liang, Guobiao

    2015-09-01

    Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Inflammation has been considered as the major contributor to brain damage after SAH. SAH induces a systemic increase in pro-inflammatory cytokines and chemokines. Disruption of blood-brain barrier (BBB) facilitates the influx of inflammatory cells. It has been reported that the activation of toll-like receptor 4 (TLR4)/NF-κB signaling pathway plays a vital role in the central nervous system diseases. Apigenin, a common plant flavonoid, possesses anti-inflammation effect. In this study, we focused on the effects of apigenin on EBI following SAH and its anti-inflammation mechanism. Our results showed that apigenin (20mg/kg) administration significantly attenuated EBI (including brain edema, BBB disruption, neurological deficient, severity of SAH, and cell apoptosis) after SAH in rats by suppressing the expression of TLR4, NF-κB and their downstream pro-inflammatory cytokines in the cortex and by up-regulating the expression of tight junction proteins of BBB. Double immunofluorescence staining demonstrated that TLR4 was activated following SAH in neurons, microglia cells, and endothelial cells but not in astrocytes. Apigenin could suppress the activation of TLR4 induced by SAH and inhibit apoptosis of cells in the cortex. These results suggested that apigenin could attenuate EBI after SAH in rats by suppressing TLR4-mediated inflammation and protecting against BBB disruption.

  9. Methane-rich saline protects against concanavalin A-induced autoimmune hepatitis in mice through anti-inflammatory and anti-oxidative pathways.

    PubMed

    He, Rong; Wang, Liping; Zhu, Jiali; Fei, Miaomiao; Bao, Suhong; Meng, Yan; Wang, Yuanyuan; Li, Jinbao; Deng, Xiaoming

    2016-01-29

    Methane is a common gas which has been reported to play a protective role in organ injury and presents an anti-inflammatory property. However, its effects on Concanavalin A (Con A)-induced autoimmune hepatitis (AIH) remain unknown. Thus, the aim of this study was to investigate the effects of methane on Con A-induced autoimmune hepatitis in mice and its underlying mechanism. Autoimmune hepatitis was induced by Con A (15 mg/kg) in healthy C57BL/6 mice and methane-rich saline (MS) (20 ml/kg) was intraperitoneally injected 30 min after the challenge with Con A. We found that methane treatment significantly reduced the elevated serum aminotransferase levels and ameliorated liver pathological damage. Furthermore, methane treatment obviously suppressed the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and increased anti-inflammatory cytokine interleukin-10 (IL-10). Moreover, we found that the levels of malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were highly increased while the activities of superoxide dismutase (SOD) and catalase (CAT) were decreased in liver with the injection of Con A, which was reversed by methane. Also, the data demonstrated that the phosphorylated IκB, NF-κB and P38 MAPK in liver were significantly down-regulated by methane. These results suggested that methane protected liver against Con A-induced injury through anti-inflammatory and anti-oxidative pathways.

  10. Microbial Anti-Inflammatory Molecule (MAM) from Faecalibacterium prausnitzii Shows a Protective Effect on DNBS and DSS-Induced Colitis Model in Mice through Inhibition of NF-κB Pathway

    PubMed Central

    Breyner, Natalia M.; Michon, Cristophe; de Sousa, Cassiana S.; Vilas Boas, Priscilla B.; Chain, Florian; Azevedo, Vasco A.; Langella, Philippe; Chatel, Jean M.

    2017-01-01

    Faecalibacterium prausnitzii and its supernatant showed protective effects in different chemically-induced colitis models in mice. Recently, we described 7 peptides found in the F. prausnitzii supernatant, all belonging to a protein called Microbial Anti-inflammatory Molecule (MAM). These peptides were able to inhibit NF-κB pathway in vitro and showed anti-inflammatory properties in vivo in a DiNitroBenzene Sulfate (DNBS)-induced colitis model. In this current proof we tested MAM effect on NF-κB pathway in vivo, using a transgenic model of mice producing luciferase under the control of NF-κB promoter. Moreover, we tested this protein on Dextran Sodium Sulfate (DSS)-induced colitis in mice. To study the effect of MAM we orally administered to the mice a Lactococcus lactis strain carrying a plasmid containing the cDNA of MAM under the control of a eukaryotic promoter. L. lactis delivered plasmids in epithelial cells of the intestinal membrane allowing thus the production of MAM directly by host. We showed that MAM administration inhibits NF-κB pathway in vivo. We confirmed the anti-inflammatory properties of MAM in DNBS-induced colitis but also in DSS model. In DSS model MAM was able to inhibit Th1 and Th17 immune response while in DNBS model MAM reduced Th1, Th2, and Th17 immune response and increased TGFβ production. PMID:28203226

  11. Microbial Anti-Inflammatory Molecule (MAM) from Faecalibacterium prausnitzii Shows a Protective Effect on DNBS and DSS-Induced Colitis Model in Mice through Inhibition of NF-κB Pathway.

    PubMed

    Breyner, Natalia M; Michon, Cristophe; de Sousa, Cassiana S; Vilas Boas, Priscilla B; Chain, Florian; Azevedo, Vasco A; Langella, Philippe; Chatel, Jean M

    2017-01-01

    Faecalibacterium prausnitzii and its supernatant showed protective effects in different chemically-induced colitis models in mice. Recently, we described 7 peptides found in the F. prausnitzii supernatant, all belonging to a protein called Microbial Anti-inflammatory Molecule (MAM). These peptides were able to inhibit NF-κB pathway in vitro and showed anti-inflammatory properties in vivo in a DiNitroBenzene Sulfate (DNBS)-induced colitis model. In this current proof we tested MAM effect on NF-κB pathway in vivo, using a transgenic model of mice producing luciferase under the control of NF-κB promoter. Moreover, we tested this protein on Dextran Sodium Sulfate (DSS)-induced colitis in mice. To study the effect of MAM we orally administered to the mice a Lactococcus lactis strain carrying a plasmid containing the cDNA of MAM under the control of a eukaryotic promoter. L. lactis delivered plasmids in epithelial cells of the intestinal membrane allowing thus the production of MAM directly by host. We showed that MAM administration inhibits NF-κB pathway in vivo. We confirmed the anti-inflammatory properties of MAM in DNBS-induced colitis but also in DSS model. In DSS model MAM was able to inhibit Th1 and Th17 immune response while in DNBS model MAM reduced Th1, Th2, and Th17 immune response and increased TGFβ production.

  12. Acerola (Malpighia emarginata DC.) juice intake protects against alterations to proteins involved in inflammatory and lipolysis pathways in the adipose tissue of obese mice fed a cafeteria diet

    PubMed Central

    2014-01-01

    Background Obesity has been studied as a metabolic and an inflammatory disease and is characterized by increases in the production of pro-inflammatory adipokines in the adipose tissue. To elucidate the effects of natural dietary components on the inflammatory and metabolic consequences of obesity, we examined the effects of unripe, ripe and industrial acerola juice (Malpighia emarginata DC.) on the relevant inflammatory and lipolysis proteins in the adipose tissue of mice with cafeteria diet-induced obesity. Materials/methods Two groups of male Swiss mice were fed on a standard diet (STA) or a cafeteria diet (CAF) for 13 weeks. Afterwards, the CAF-fed animals were divided into five subgroups, each of which received a different supplement for one further month (water, unripe acerola juice, ripe acerola juice, industrial acerola juice, or vitamin C) by gavage. Enzyme-linked immunosorbent assays, Western blotting, a colorimetric method and histology were utilized to assess the observed data. Results The CAF water (control obese) group showed a significant increase in their adiposity indices and triacylglycerol levels, in addition to a reduced IL-10/TNF-α ratio in the adipose tissue, compared with the control lean group. In contrast, acerola juice and Vitamin C intake ameliorated the weight gain, reducing the TAG levels and increasing the IL-10/TNF-α ratio in adipose tissue. In addition, acerola juice intake led to reductions both in the level of phosphorylated JNK and to increases in the phosphorylation of IκBα and HSLser660 in adipose tissue. Conclusions Taken together, these results suggest that acerola juice reduces low-grade inflammation and ameliorates obesity-associated defects in the lipolytic processes. PMID:24495336

  13. High content cell-based assay for the inflammatory pathway

    NASA Astrophysics Data System (ADS)

    Mukherjee, Abhishek; Song, Joon Myong

    2015-07-01

    Cellular inflammation is a non-specific immune response to tissue injury that takes place via cytokine network orchestration to maintain normal tissue homeostasis. However chronic inflammation that lasts for a longer period, plays the key role in human diseases like neurodegenerative disorders and cancer development. Understanding the cellular and molecular mechanisms underlying the inflammatory pathways may be effective in targeting and modulating their outcome. Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine that effectively combines the pro-inflammatory features with the pro-apoptotic potential. Increased levels of TNF-α observed during acute and chronic inflammatory conditions are believed to induce adverse phenotypes like glucose intolerance and abnormal lipid profile. Natural products e. g., amygdalin, cinnamic acid, jasmonic acid and aspirin have proven efficacy in minimizing the TNF-α induced inflammation in vitro and in vivo. Cell lysis-free quantum dot (QDot) imaging is an emerging technique to identify the cellular mediators of a signaling cascade with a single assay in one run. In comparison to organic fluorophores, the inorganic QDots are bright, resistant to photobleaching and possess tunable optical properties that make them suitable for long term and multicolor imaging of various components in a cellular crosstalk. Hence we tested some components of the mitogen activated protein kinase (MAPK) pathway during TNF-α induced inflammation and the effects of aspirin in HepG2 cells by QDot multicolor imaging technique. Results demonstrated that aspirin showed significant protective effects against TNF-α induced cellular inflammation. The developed cell based assay paves the platform for the analysis of cellular components in a smooth and reliable way.

  14. Deoxysappanone B, a homoisoflavone from the Chinese medicinal plant Caesalpinia sappan L., protects neurons from microglia-mediated inflammatory injuries via inhibition of IκB kinase (IKK)-NF-κB and p38/ERK MAPK pathways.

    PubMed

    Zeng, Ke-Wu; Yu, Qian; Song, Fang-Jiao; Liao, Li-Xi; Zhao, Ming-Bo; Dong, Xin; Jiang, Yong; Tu, Peng-Fei

    2015-02-05

    Caesalpinia sappan L. (Lignum Sappan) is a Chinese medicinal plant for treating ischemic cerebral apoplexy. Deoxysappanone B (DSB), a homoisoflavone compound isolated from C. sappan L. (Lignum Sappan), was studied for anti-neuroinflammatory and neuroprotective properties using lipopolysaccharide (LPS)-induced BV-2 microglia neuroinflammation model and LPS-induced microglia-neuron co-culture system. Our findings showed that DSB effectively inhibited BV-2 microglia-mediated neuroinflammatory mediators׳ release including NO, PGE₂, TNF-α, IL-6 and reactive oxygen species. Moreover, DSB markedly protected neurons against inflammatory microglia-mediated neurotoxicity in a microglia-neuron co-culture system. Mechanism study revealed that DSB blocked two major neuroinflammation-related signaling pathways including IKK-IκB-nuclear factor kappaB (NF-κB) and p38/ERK mitogen-activated protein kinase (MAPK) cascades, further leading to the inhibition of neuroinflammatory mediators׳ production. The present study provides evidence that the anti-neuroinflammatory and neuroprotective effect of DSB are due to the suppression of neuroinflammatory mediators׳ production as well as inflammation-induced neurotoxicity through regulation of multi-targets. Therefore, DSB may serve as a neuroprotective agent for the treatment of neuroinflammatory disorders and inflammation-related neuronal injury.

  15. Exploitation of the nicotinic anti-inflammatory pathway for the treatment of epithelial inflammatory diseases.

    PubMed

    Scott, David A; Martin, Michael

    2006-12-14

    Discoveries in the first few years of the 21st century have led to an understanding of important interactions between the nervous system and the inflammatory response at the molecular level, most notably the acetylcholine (ACh)-triggered, alpha7-nicotinic acetylcholine receptor (alpha7nAChR)-dependent nicotinic anti-inflammatory pathway. Studies using the alpha7nAChR agonist, nicotine, for the treatment of mucosal inflammation have been undertaken but the efficacy of nicotine as a treatment for inflammatory bowel diseases remains debatable. Further understanding of the nicotinic anti-inflammatory pathway and other endogenous anti-inflammatory mechanisms is required in order to develop refined and specific therapeutic strategies for the treatment of a number of inflammatory diseases and conditions, including periodontitis, psoriasis, sarcoidosis, and ulcerative colitis.

  16. A short course of infusion of a hydrogen sulfide-donor attenuates endotoxemia induced organ injury via stimulation of anti-inflammatory pathways, with no additional protection from prolonged infusion.

    PubMed

    Aslami, Hamid; Beurskens, Charlotte J P; de Beer, Friso M; Kuipers, Maria T; Roelofs, Joris J T H; Hegeman, Maria A; Van der Sluijs, Koen F; Schultz, Marcus J; Juffermans, Nicole P

    2013-02-01

    Organ failure is associated with increased mortality and morbidity in patients with systemic inflammatory response syndrome. Previously, we showed that a short course of infusion of a hydrogen sulfide (H(2)S) donor reduced metabolism with concurrent reduction of lung injury. Here, we hypothesize that prolonged H(2)S infusion is more protective than a short course in endotoxemia with organ failure. Also, as H(2)S has both pro- and anti-inflammatory effects, we explored the effect of H(2)S on interleukin production. Endotoxemia was induced by an intravenous bolus injection of LPS (7.5mg/kg) in mechanically ventilated rats. H(2)S donor NaHS (2mg/kg) or vehicle (saline) was infused and organ injury was determined after either 4 or 8h. A short course of H(2)S infusion was associated with reduction of lung and kidney injury. Prolonged infusion did not enhance protection. Systemically, infusion of H(2)S increased both the pro-inflammatory response during endotoxemia, as demonstrated by increased TNF-α levels, as well as the anti-inflammatory response, as demonstrated by increased IL-10 levels. In LPS-stimulated whole blood of healthy volunteers, co-incubation with H(2)S had solely anti-inflammatory effects, resulting in decreased TNF-α levels and increased IL-10 levels. Co-incubation with a neutralizing IL-10 antibody partly abrogated the decrease in TNF-α levels. In conclusion, a short course of H(2)S infusion reduced organ injury during endotoxemia, at least in part via upregulation of IL-10.

  17. Dexmedetomidine attenuates inflammatory reaction in the lung tissues of septic mice by activating cholinergic anti-inflammatory pathway.

    PubMed

    Liu, Zhaoguo; Wang, Yueping; Wang, Yaoqi; Ning, Qiaoqing; Zhang, Yong; Gong, Chunzhi; Zhao, Wenxiang; Jing, Guangjian; Wang, Qianqian

    2016-06-01

    Dexmedetomidine (Dex) is a highly selective α2-adrenergic receptor agonist that is widely used for sedation in intensive care units and in clinical anesthesia. Dex has also been shown to possess anti-inflammatory benefits. However, the underlying mechanism by which Dex relieves the inflammatory reaction in the lung tissues of septic mice has not been fully elucidated. In this study, we aimed to evaluate the protective effects and possible mechanism of Dex on the sepsis-induced lung inflammatory response in mice. Sepsis was induced in mice models through the intraperitoneal injection of lipopolysaccharide (LPS). The preemptive administration of Dex substantially abated sepsis-induced pulmonary edema, pulmonary histopathological changes, and NF-κB p65 activity. The production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) at both the mRNA and protein levels was also reduced. Moreover, these effects were significantly blocked by the α7 nicotinic acetylcholine receptor (α7nAChR) antagonist α-bungarotoxin (α-Bgt). α-Bgt aggravated pulmonary edema and pulmonary histopathological changes, as well as increased NF-κB p65 activity and TNF-α and IL-6 expression at both the mRNA and protein levels. The overall results demonstrate that Dex inhibits the LPS-induced inflammatory reaction in the lung tissues of septic mice partly through the α7nAChR-dependent cholinergic anti-inflammatory pathway.

  18. The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases

    PubMed Central

    Cuda, Carla M.; Pope, Richard M.; Perlman, Harris

    2017-01-01

    Rheumatoid arthritis affects nearly 1% of the world's population and is a debilitating autoimmune condition that can result in joint destruction. During the past decade, inflammatory functions have been described for signalling molecules classically involved in apoptotic and non-apoptotic death pathways, including but not limited to toll-like receptor signalling, inflammasome activation, cytokine production, macrophage polarization and antigen citrullination. In light of these remarkable advances in the understanding of inflammatory mechanisms of the death machinery, this review provides a snapshot of the available evidence implicating death pathways, especially within the phagocyte populations of the innate immune system, in the perpetuation of rheumatoid arthritis. Elevated levels of signalling mediators of both the extrinsic and intrinsic apoptotic as well as the autophagy death pathways are observed in the joints of patients with rheumatoid arthritis. Furthermore, in rheumatoid arthritis patients, risk polymorphisms are present in signalling molecules of the extrinsic apoptotic and autophagy death pathways. Although research into the mechanisms underlying these death pathways has made considerable progress, this review highlights areas where further investigation is particularly needed. This exploration is critical, as new discoveries in this field could lead to the development of novel therapeutic targets for rheumatoid arthritis and other rheumatic diseases. PMID:27549026

  19. Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis

    PubMed Central

    Li, Ruidong; Wang, Yaxin; Ma, Zhijun; Ma, Muyuan; Wang, Di; Xie, Gengchen; Yin, Yuping

    2016-01-01

    Sepsis, frequently caused by infection of bacteria, is considered as an uncontrollable systematic inflammation response syndrome (SIRS). Maresin 1 (Mar1) is a new proresolving mediator with potent anti-inflammatory effect in several animal models. However, its effect in sepsis is still not investigated. To address this question, we developed sepsis model in BALB/c mice by cecal ligation and puncture (CLP) with or without Mar1 treatment. Our data showed that Mar1 markedly improved survival rate and decreased the levels of proinflammatory cytokines in CLP mice such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Furthermore, Mar1 reduced serum level of lipopolysaccharide (LPS) and enhanced the bacteria clearance in mice sepsis model. Moreover, Mar1 attenuated lung injury and decreased level of alanine transaminase (ALT), aspartate transaminase (AST), creatinine (Cre), and blood urea nitrogen (BUN) in serum in mice after CLP surgery. Treatment with Mar1 inhibited activation of nuclear factor kappa B (NF-κb) pathway. In conclusion, Mar1 exhibited protective effect in sepsis by reducing LPS, bacteria burden in serum, inhibiting inflammation response, and improving vital organ function. The possible mechanism is partly involved in inhibition of NF-κb activation. PMID:28042205

  20. Neural immune pathways and their connection to inflammatory diseases

    PubMed Central

    Eskandari, Farideh; Webster, Jeanette I; Sternberg, Esther M

    2003-01-01

    Inflammation and inflammatory responses are modulated by a bidirectional communication between the neuroendocrine and immune system. Many lines of research have established the numerous routes by which the immune system and the central nervous system (CNS) communicate. The CNS signals the immune system through hormonal pathways, including the hypothalamic–pituitary–adrenal axis and the hormones of the neuroendocrine stress response, and through neuronal pathways, including the autonomic nervous system. The hypothalamic–pituitary–gonadal axis and sex hormones also have an important immunoregulatory role. The immune system signals the CNS through immune mediators and cytokines that can cross the blood–brain barrier, or signal indirectly through the vagus nerve or second messengers. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. This review discusses neuroimmune interactions and evidence for the role of such neural immune regulation of inflammation, rather than a discussion of the individual inflammatory mediators, in rheumatoid arthritis. PMID:14680500

  1. Obesity-Driven Gut Microbiota Inflammatory Pathways to Metabolic Syndrome

    PubMed Central

    Cavalcante-Silva, Luiz H. A.; Galvão, José G. F. M.; da Silva, Juliane Santos de França; de Sales-Neto, José M.; Rodrigues-Mascarenhas, Sandra

    2015-01-01

    The intimate interplay between immune system, metabolism, and gut microbiota plays an important role in controlling metabolic homeostasis and possible obesity development. Obesity involves impairment of immune response affecting both innate and adaptive immunity. The main factors involved in the relationship of obesity with inflammation have not been completely elucidated. On the other hand, gut microbiota, via innate immune receptors, has emerged as one of the key factors regulating events triggering acute inflammation associated with obesity and metabolic syndrome. Inflammatory disorders lead to several signaling transduction pathways activation, inflammatory cytokine, chemokine production and cell migration, which in turn cause metabolic dysfunction. Inflamed adipose tissue, with increased macrophages infiltration, is associated with impaired preadipocyte development and differentiation to mature adipose cells, leading to ectopic lipid accumulation and insulin resistance. This review focuses on the relationship between obesity and inflammation, which is essential to understand the pathological mechanisms governing metabolic syndrome. PMID:26635627

  2. miR-146a Attenuates Inflammatory Pathways Mediated by TLR4/NF-κB and TNFα to Protect Primary Human Retinal Microvascular Endothelial Cells Grown in High Glucose

    PubMed Central

    Ye, Eun-Ah; Steinle, Jena J.

    2016-01-01

    Pathological mechanisms underlying diabetic retinopathy are still not completely understood. Increased understanding of potential cellular pathways responsive to hyperglycemia is essential to develop novel therapeutic strategies for diabetic retinopathy. A growing body of evidence shows that microRNA (miRNA) play important roles in pathological mechanisms involved in diabetic retinopathy, as well as possessing potential as novel therapeutic targets. The hypothesis of this study was that miR-146a plays a key role in attenuating hyperglycemia-induced inflammatory pathways through reduced TLR4/NF-κB and TNFα signaling in primary human retinal microvascular endothelial cells (REC). We cultured human REC in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. Transfection was performed on REC with miRNA mimic (hsa-miR-146a-5p). Our results demonstrate that miR-146a expression was decreased in human REC cultured in high glucose. Overexpression of miR-146a using mimics reduced the levels of TLR4/NF-κB and TNFα in REC cultured in high glucose. Both MyD88-dependent and -independent signaling were decreased by miR-146a overexpression in REC in high glucose conditions. The results suggest that miR-146a is a potential therapeutic target for reducing inflammation in REC through inhibition of TLR4/NF-κB and TNFα. Our study will contribute to understanding of diabetic retinal pathology, as well as providing important clues to develop therapeutics for clinical applications. PMID:26997759

  3. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

    PubMed Central

    2012-01-01

    It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers. PMID:22747645

  4. Taxonomic applicability of inflammatory cytokines in adverse outcome pathway (AOP) development.

    PubMed

    Angrish, Michelle M; Pleil, Joachim D; Stiegel, Matthew A; Madden, Michael C; Moser, Virginia C; Herr, David W

    2016-01-01

    Cytokines, low-molecular-weight messenger proteins that act as intercellular immunomodulatory signals, have become a mainstream preclinical marker for assessing the systemic inflammatory response to external stressors. The challenge is to quantitate from healthy subjects cytokine levels that are below or at baseline and relate those dynamic and complex cytokine signatures of exposures with the inflammatory and repair pathways. Thus, highly sensitive, specific, and precise analytical and statistical methods are critically important. Investigators at the U.S. Environmental Protection Agency (EPA) have implemented advanced technologies and developed statistics for evaluating panels of inflammatory cytokines in human blood, exhaled breath condensate, urine samples, and murine biological media. Advanced multiplex, bead-based, and automated analytical platforms provided sufficient sensitivity, precision, and accuracy over the traditional enzyme-linked immunosorbent assay (ELISA). Thus, baseline cytokine levels can be quantified from healthy human subjects and animals and compared to an in vivo exposure response from an environmental chemical. Specifically, patterns of cytokine responses in humans exposed to environmental levels of ozone and diesel exhaust, and in rodents exposed to selected pesticides (such as fipronil and carbaryl), were used as case studies to generally assess the taxonomic applicability of cytokine responses. The findings in this study may aid in the application of measureable cytokine markers in future adverse outcome pathway (AOP)-based toxicity testing. Data from human and animal studies were coalesced and the possibility of using cytokines as key events (KE) to bridge species responses to external stressors in an AOP-based framework was explored.

  5. The TSC-mTOR signaling pathway regulates the innate inflammatory response.

    PubMed

    Weichhart, Thomas; Costantino, Giuseppina; Poglitsch, Marko; Rosner, Margit; Zeyda, Maximilian; Stuhlmeier, Karl M; Kolbe, Thomas; Stulnig, Thomas M; Hörl, Walter H; Hengstschläger, Markus; Müller, Mathias; Säemann, Marcus D

    2008-10-17

    The innate inflammatory immune response must be tightly controlled to avoid damage to the host. Here, we showed that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Inhibition of mTOR by rapamycin promoted production of proinflammatory cytokines via the transcription factor NF-kappaB but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift. Rapamycin-hyperactivated monocytes displayed a strong T helper 1 (Th1) cell- and Th17 cell-polarizing potency. Inhibition of mTOR in vivo regulated the inflammatory response and protected genetically susceptible mice against lethal Listeria monocytogenes infection. These data identify the TSC2-mTOR pathway as a key regulator of innate immune homeostasis with broad clinical implications for infectious and autoimmune diseases, vaccination, cancer, and transplantation.

  6. Picroside II protects myocardium from ischemia/reperfusion-induced injury through inhibition of the inflammatory response

    PubMed Central

    Li, Jian-Zhe; Xie, Mei-Qing; Mo, Dan; Zhao, Xiao-Fang; Yu, Shu-Yi; Liu, Li-Juan; Wu, Cheng; Yang, Yang

    2016-01-01

    The inflammatory response is important in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Picroside II, the primary active constituent of Picrorhizae, has been reported to protect the myocardium from I/R-induced injury, however, the exact mechanism underlying these protective effects remains unclear. The aim of the present study was to investigate the mechanism underlying the protective effects of picroside II on I/R-induced myocardial injury. Adult male Sprague-Dawley rats underwent 1 h left coronary artery occlusion followed by 3 h reperfusion. Picroside II was administered (10 mg/kg) via the tail vein 30 min prior to left coronary artery occlusion. The results revealed that pretreatment of picroside II could significantly alleviate I/R-induced myocardial injury concomitantly with a decrease in inflammatory factor production. In addition, picroside II was also able to decrease high mobility group box 1 (HMGB1) expression, and release and downregulate the expression of the receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-2 and TLR-4. Furthermore, picroside II was able to inhibit nuclear factor-κB (NF-κB) activation. The results indicated that the protective effect of picroside II on I/R-induced myocardial injury was associated, at least partly, with inhibition of the inflammatory response by suppressing the HMGB1-RAGE/TLR-2/TLR-4-NF-κB signaling pathway. PMID:28105084

  7. Platelets protect lung from injury induced by systemic inflammatory response

    PubMed Central

    Luo, Shuhua; Wang, Yabo; An, Qi; Chen, Hao; Zhao, Junfei; Zhang, Jie; Meng, Wentong; Du, Lei

    2017-01-01

    Systemic inflammatory responses can severely injure lungs, prompting efforts to explore how to attenuate such injury. Here we explored whether platelets can help attenuate lung injury in mice resulting from extracorporeal circulation (ECC)-induced systemic inflammatory responses. Mice were subjected to ECC for 30 min, then treated with phosphate-buffered saline, platelets, the GPIIb/IIIa inhibitor Tirofiban, or the combination of platelets and Tirofiban. Blood and lung tissues were harvested 60 min later, and lung injury and inflammatory status were assessed. As expected, ECC caused systemic inflammation and pulmonary dysfunction, and platelet transfusion resulted in significantly milder lung injury and higher lung function. It also led to greater numbers of circulating platelet-leukocyte aggregates and greater platelet accumulation in the lung. Platelet transfusion was associated with higher production of transforming growth factor-β and as well as lower levels of tumour necrosis factor-α and neutrophil elastase in plasma and lung. None of these platelet effects was observed in the presence of Tirofiban. Our results suggest that, at least under certain conditions, platelets can protect lung from injury induced by systemic inflammatory responses. PMID:28155889

  8. Mast Cell Proteases as Protective and Inflammatory Mediators

    PubMed Central

    Caughey, George H.

    2014-01-01

    Proteases are the most abundant class of proteins produced by mast cells. Many of these are stored in membrane-enclosed intracellular granules until liberated by degranulating stimuli, which include cross-linking of high affinity IgE receptor FcεRI by IgE bound to multivalent allergen. Understanding and separating the functions of the proteases is important because expression differs among mast cells in different tissue locations. Differences between laboratory animals and humans in protease expression also influence the degree of confidence with which results obtained in animal models of mast cell function can be extrapolated to humans. The inflammatory potential of mast cell proteases was the first aspect of their biology to be explored and has received the most attention, in part because some of them—notably tryptases and chymases—are biomarkers of local and systemic mast cell degranulation and anaphylaxis. Although some of the proteases indeed augment allergic inflammation and are potential targets for inhibition to treat asthma and related allergic disorders, they are protective and even anti-inflammatory in some settings. For example, mast cell tryptases may protect from serious bacterial lung infections and may limit the “rubor” component of inflammation caused by vasodilating neuropeptides in the skin. Chymases help to maintain intestinal barrier function and to expel parasitic worms, and may support blood pressure during anaphylaxis by generating angiotensin II. In other life-or-death examples, carboxypeptidase A3 and other mast cell peptidases limit systemic toxicity of endogenous peptides like endothelin and neurotensin during septic peritonitis, and inactivate venom-associated peptides. On the other hand, mast cell peptidase-mediated destruction of protective cytokines, like IL-6, can enhance mortality from sepsis. Peptidases released from mast cells also influence non-mast cell proteases, such as by activating matrix metalloproteinase cascades

  9. The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease.

    PubMed

    Schuck, Robert N; Zha, Weibin; Edin, Matthew L; Gruzdev, Artiom; Vendrov, Kimberly C; Miller, Tricia M; Xu, Zhenghong; Lih, Fred B; DeGraff, Laura M; Tomer, Kenneth B; Jones, H Michael; Makowski, Liza; Huang, Leaf; Poloyac, Samuel M; Zeldin, Darryl C; Lee, Craig R

    2014-01-01

    Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase) exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted.

  10. Cross-talk between bone morphogenetic proteins and inflammatory pathways.

    PubMed

    van der Kraan, Peter M; Davidson, Esmeralda N Blaney

    2015-11-23

    Pro-inflammatory cytokines and bone morphogenetic proteins are generally studied separately and considered to be elements of different worlds, immunology and developmental biology. Varas and colleagues report that these factors show cross-talk in rheumatoid arthritis synoviocytes. They show that pro-inflammatory cytokines not only stimulate the production of bone morphogenetic proteins but that these endogenously produced bone morphogenetic proteins interfere with the effects of pro-inflammatory cytokines on synoviocytes.

  11. Emodin Combined with Nanosilver Inhibited Sepsis by Anti-inflammatory Protection.

    PubMed

    Li, Hong; Yang, Tian; Zhou, Hong; Du, Juan; Zhu, Bo; Sun, Zhongmin

    2016-01-01

    Background: Emodin is the main active component of rhubarb, which has demonstrated many beneficial effects against inflammation. Nanosilver is an effective antimicrobial agent. The present study was designed to observe the effects of Emodin combined with silver nanoparticles (E/S) on sepsis protection and related mechanism. Methods: E/S was prepared by loading different concentrations of Emodin on nanosilver and cytotoxicity of E/S were determined by suphorhodamine B assays. Anti-microbial activities of E/S were assayed by direct interaction with various common pathogens and anti-adhesive activites of E/S on leukocytes with endothelial cells were assayed by biochemical analysis. Next, inflammatory cell enumeration, inflammatory mediators in bronchoalveolar lavage fluid (BALF) and endothelial cell function were analyzed on a clinically relevant model of sepsis induced by cecal ligation and puncture (CLP) after E/S administration. The effects of E/S on NF-κB and p38 were also examined by western blot. Results: E/S exhibited little cytotoxicity action on endothelial cells and significant inhibitory activities against all tested common microorganisms and adherence between leukocyte and endothelial cells. E/S induced anti-sepsis protection mainly mediated by inhibition of inflammatory cells infiltration, down-regulation of TNF-alpha, IL-8 and lactic dehydrogenase (LDH), and inhibition of NF-κB and p38 pathways in mice 24 h post-CLP. Conclusion: Our data suggest that E/S has strong anti-sepsis effects, which was related with anti-inflammatory protection and thereby promote survival following sepsis challenge.

  12. Emodin Combined with Nanosilver Inhibited Sepsis by Anti-inflammatory Protection

    PubMed Central

    Li, Hong; Yang, Tian; Zhou, Hong; Du, Juan; Zhu, Bo; Sun, Zhongmin

    2017-01-01

    Background: Emodin is the main active component of rhubarb, which has demonstrated many beneficial effects against inflammation. Nanosilver is an effective antimicrobial agent. The present study was designed to observe the effects of Emodin combined with silver nanoparticles (E/S) on sepsis protection and related mechanism. Methods: E/S was prepared by loading different concentrations of Emodin on nanosilver and cytotoxicity of E/S were determined by suphorhodamine B assays. Anti-microbial activities of E/S were assayed by direct interaction with various common pathogens and anti-adhesive activites of E/S on leukocytes with endothelial cells were assayed by biochemical analysis. Next, inflammatory cell enumeration, inflammatory mediators in bronchoalveolar lavage fluid (BALF) and endothelial cell function were analyzed on a clinically relevant model of sepsis induced by cecal ligation and puncture (CLP) after E/S administration. The effects of E/S on NF-κB and p38 were also examined by western blot. Results: E/S exhibited little cytotoxicity action on endothelial cells and significant inhibitory activities against all tested common microorganisms and adherence between leukocyte and endothelial cells. E/S induced anti-sepsis protection mainly mediated by inhibition of inflammatory cells infiltration, down-regulation of TNF-alpha, IL-8 and lactic dehydrogenase (LDH), and inhibition of NF-κB and p38 pathways in mice 24 h post-CLP. Conclusion: Our data suggest that E/S has strong anti-sepsis effects, which was related with anti-inflammatory protection and thereby promote survival following sepsis challenge. PMID:28119611

  13. The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway.

    PubMed

    Denaës, Timothé; Lodder, Jasper; Chobert, Marie-Noële; Ruiz, Isaac; Pawlotsky, Jean-Michel; Lotersztajn, Sophie; Teixeira-Clerc, Fatima

    2016-06-27

    Kupffer cells, the resident macrophages of the liver, play a major role in the pathogenesis of alcoholic liver disease. We have previously demonstrated that CB2 receptor protects against alcoholic liver disease by inhibiting alcohol-induced inflammation and steatosis via the regulation of Kupffer cell activation. Here, we explored the mechanism underlying these effects and hypothesized that the anti-inflammatory properties of CB2 receptor in Kupffer cells rely on activation of autophagy. For this purpose, mice invalidated for CB2 receptor (CB2(Mye-/-) mice) or for the autophagy gene ATG5 (ATG5(Mye-/-) mice) in the myeloid lineage, and their littermate wild-type mice were subjected to chronic-plus-binge ethanol feeding. CB2(Mye-/-) mice showed exacerbated alcohol-induced pro-inflammatory gene expression and steatosis. Studies in cultured macrophages demonstrated that CB2 receptor activation by JWH-133 stimulated autophagy via a heme oxygenase-1 dependent pathway. Moreover, JWH-133 reduced the induction of inflammatory genes by lipopolysaccharide in wild-type macrophages, but not in ATG5-deficient cells. The CB2 agonist also protected from alcohol-induced liver inflammation and steatosis in wild-type mice, but not in ATG5(Mye-/-) mice demonstrating that macrophage autophagy mediates the anti-inflammatory and anti-steatogenic effects of CB2 receptor. Altogether these results demonstrate that CB2 receptor activation in macrophages protects from alcohol-induced steatosis by inhibiting hepatic inflammation through an autophagy-dependent pathway.

  14. Protective effects of leucine against lipopolysaccharide-induced inflammatory response in Labeo rohita fingerlings.

    PubMed

    Giri, Sib Sankar; Sen, Shib Sankar; Jun, Jin Woo; Sukumaran, Venkatachalam; Park, Se Chang

    2016-05-01

    The present study investigated the protective effects of leucine against lipopolysaccharide (LPS)-induced inflammatory responses in Labeo rohita (rohu) in vivo and in vitro. Primary hepatocytes, isolated from the hepatopancreas, were exposed to different concentrations of LPS for 24 h to induce an inflammatory response, and the protective effects of leucine against LPS-induced inflammation were studied. Finally, we investigated the efficiency of dietary leucine supplementation in attenuating an immune challenge induced by LPS in vivo. Exposure of cells to 10-25 μg mL(-1) of LPS for 24 h resulted in a significant production of nitric oxide and release of lactate dehydrogenase to the medium, whereas cell viability and protein content were reduced (p < 0.05). LPS exposure (10 μg mL(-1)) increased mRNA levels of the pro-inflammatory cytokines TNF-α, IL-1β and IL-8 in vitro (p < 0.05). However, pretreatment with leucine prevented the LPS-induced upregulation of TNF-α, IL-1β and IL-8 mRNAs by downregulating TLR4, MyD88, NF-κBp65, and MAPKp38 mRNA expression. Interestingly, mRNA expression of the anti-inflammatory cytokine, IL-10, which was increased by LPS treatment, was further enhanced (p < 0.05) by leucine pretreatment. The enhanced expression of IL-10 might inhibit the production of other pro-inflammatory cytokines. It was found that leucine pretreatment attenuated the excessive activation of LPS-induced TLR4-MyD88 signaling as manifested by lower level of TLR4, MyD88, MAPKp38, NF-κBp65 and increased level of IκB-α protein in leucine pre-treatment group. In vivo experiments demonstrated that leucine pre-supplementation could protect fish against LPS-induced inflammation through an attenuation of TLR4-MyD88 signaling pathway. Taken together, we propose that leucine pre-supplementation decreases LPS-induced immune damage in rohu by enhancing the expression of IL-10 and by regulating the TLR4-MyD88 signaling pathways.

  15. Anti-inflammatory therapies of amyotrophic lateral sclerosis guided by immune pathways

    PubMed Central

    Lam, Larry; Halder, Ramesh C; Montoya, Dennis J; Rubbi, Liudmilla; Rinaldi, Arturo; Sagong, Bien; Weitzman, Sarah; Rubattino, Rachel; Singh, Ram Raj; Pellegrini, Matteo; Fiala, Milan

    2015-01-01

    Sporadic ALS patients display heterogeneous immune pathways in peripheral blood mononuclear cells (PBMCs). We tested nine sALS patients and one unaffected identical twin of an index case by RNA-Seq of PBMCs. The inflammatory patients (n = 3) clustered into a subset with an inflammatory Th1/Th17 signature and the non-inflammatory patients (n = 7) into another subset with a B cell signature. The inflammatory subset was remarkable for granulocyte and agranulocyte diapedesis, hepatic fibrosis, roles of cytokines and metalloproteases. The non-inflammatory subset was highlighted by degradation of vitamin E, serotonin and nucleotides, altered T cell and B cell signaling, agranulocyte diapedesis, and up regulation of B cell genes. Identification of these differentially regulated pathways in sALS patients may guide the choice of anti-inflammatory therapies. PMID:26807342

  16. Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway.

    PubMed

    Xu, Sheng; Liu, Xingguang; Bao, Yan; Zhu, Xuhui; Han, Chaofeng; Zhang, Peng; Zhang, Xuemin; Li, Weihua; Cao, Xuetao

    2012-04-22

    The molecular mechanisms that fine-tune Toll-like receptor (TLR)-triggered innate inflammatory responses remain to be fully elucidated. Major histocompatibility complex (MHC) molecules can mediate reverse signaling and have nonclassical functions. Here we found that constitutively expressed membrane MHC class I molecules attenuated TLR-triggered innate inflammatory responses via reverse signaling, which protected mice from sepsis. The intracellular domain of MHC class I molecules was phosphorylated by the kinase Src after TLR activation, then the tyrosine kinase Fps was recruited via its Src homology 2 domain to phosphorylated MHC class I molecules. This led to enhanced Fps activity and recruitment of the phosphatase SHP-2, which interfered with TLR signaling mediated by the signaling molecule TRAF6. Thus, constitutive MHC class I molecules engage in crosstalk with TLR signaling via the Fps-SHP-2 pathway and control TLR-triggered innate inflammatory responses.

  17. Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway

    SciTech Connect

    Li, Yanyan; Gao, Chao; Shi, Yanru; Tang, Yuhan; Liu, Liang; Xiong, Ting; Du, Min; Xing, Mingyou; Liu, Liegang; Yao, Ping

    2013-11-15

    Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0 g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100 mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8 mg/kg for mice or 20 μmol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin. The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals. - Highlights: • CO alleviated ethanol-derived liver oxidative and inflammatory stress in mice. • CO eased ethanol and inflammatory factor-induced oxidative damage in hepatocytes. • The p38 MAPK is a key signaling mechanism for the protective function of CO in ALD.

  18. Forsythoside B protects against experimental sepsis by modulating inflammatory factors.

    PubMed

    Jiang, Wang-Lin; Yong-Xu; Zhang, Shu-Ping; Zhu, Hai-Bo; Jian-Hou

    2012-07-01

    The present study investigated the effects of Forsythoside B on an experimental model of sepsis induced by caecal ligation and puncture (CLP) in rats and elucidated the potential mechanism in cultured RAW 264.7 cells. Results showed that Forsythoside B concentration-dependently down-regulated the levels of TNF-α, IL-6 and high-mobility group-box 1 protein (HMGB1) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, inhibited the IκB kinase (IKK) pathway and modulated nuclear factor (NF)- κB. Intravenous injection (i.v.) of Forsythoside B alone or plus Imipenem reduced serum levels of TNF-α, IL-6, HMGB1, triggering receptor expressed on myeloid cells (TREM-1) and endotoxin, while the serum level of IL-10 was up-regulated and myeloperoxidase (MPO) in lung, liver and small intestine was reduced. Meanwhile, i.v. of Forsythoside B alone or plus Imipenem reduced CLP-induced lethality in rats. These data indicated that the antisepsis effect of Forsythoside B is mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. Its antisepsis mechanism may be that Forsythoside B binds to LPS and reduces the biological activity of serum LPS, and inhibits NF-κB activition. Our studies enhance the case for the use of Forsythoside B in sepsis. Forsythoside B itself has promise as a therapy for the treatment of sepsis in humans.

  19. Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway

    PubMed Central

    Zhang, Shuang; Yu, Min; Guo, Qiang; Li, Rongpeng; Li, Guobo; Tan, Shirui; Li, Xuefeng; Wei, Yuquan; Wu, Min

    2015-01-01

    Lipopolysaccharide (LPS) derived from Gram-negative bacteria activates plasma membrane signaling via Toll-like receptor 4 (TLR4) on host cells and triggers innate inflammatory responses, but the underlying mechanisms remain to be fully elucidated. Here we reveal a role for annexin A2 (AnxA2) in host defense against infection as anxa2−/− mice were highly susceptible to Gram-negative bacteria-induced sepsis with enhanced inflammatory responses. Computing analysis and biochemical experiments identified that constitutive AnxA2 expression facilitated TLR4 internalization and its subsequent translocation into early endosomal membranes. It activated the TRAM-dependent endosomal signaling, leading to the release of anti-inflammatory cytokines. Importantly, AnxA2 deficiency prolonged TLR4-mediated signaling from the plasma membrane, which was attributable to pro-inflammatory cytokine production (IL-6, TNFα and IL-1β). Thus, AnxA2 directly exerted negative regulation of inflammatory responses through TLR4-initiated TRAM-TRIF pathway occurring on endosomes. This study reveals AnxA2 as a critical regulator in infection-initiated inflammation, which protects the host from excessive inflammatory damage. PMID:26527544

  20. Cockroach induces inflammatory responses through protease-dependent pathways.

    PubMed

    Wada, Kota; Matsuwaki, Yoshinori; Moriyama, Hiroshi; Kita, Hirohito

    2011-01-01

    Exposure to cockroaches is a major risk factor for asthma. Products from cockroaches may contain proteases and ligands for pattern recognition receptors. These molecules may activate airway inflammatory cells, such as eosinophils, that are involved in asthma. Among inner-city children, cockroach allergens play an especially important role in increasing asthma morbidity. The molecular mechanism for this association between cockroach exposure and asthma is not fully understood. Enzymatic activities from cockroaches activate inflammatory cells in the airways and may also exacerbate certain human airway diseases, such as asthma. We recently reported that cockroach extracts contain pepstatin A-sensitive proteases that activate PAR-2 and induce activation and degranulation of human eosinophils. This review focuses on the effects of cockroach on various inflammatory cells, including eosinophils, epithelial cells, fibroblasts, dendritic cells, and T cells, in allergic reactions.

  1. Glycosaminoglycan sulodexide modulates inflammatory pathways in chronic venous disease.

    PubMed

    Mannello, F; Ligi, D; Raffetto, J D

    2014-06-01

    Inflammation represents an important epiphenomenon in the etiopathogenesis of chronic venous disease, a worldwide debilitating condition affecting millions of subjects. The pathophysiology of chronic venous disease (CVD) is based on the hemodynamic abnormalities in conjunction to alterations in cellular and extracellular matrix biocompounds. The endothelial dysfunction results from early perturbation in the endothelium linked to glycocalyx injury and promoted by inflammatory cells and mediators (such as matrix metalloproteinases and interleukins), which lead to progressive dilation of the vein resulting in chronic venous insufficiency. Activated leukocytes during the inflammatory process release enzymes, free radicals, chemokines and inflammatory cytokines in the vessel microenvironment, which are responsible for the changes of the venous wall and venous valve, reflux and venous hypertension, and the development/progression of tissue destruction and skin changes. Sulodexide, a highly purified mixture of glycosaminoglycans composed by 80% fast moving heparin and 20% of dermatan sulphate, exhibits anti-thrombotic and profibrinolytic properties, restoring also the essential endothelial glycocalyx. Glycosaminoglycan sulodexide has been also characterized to reduce the release of inflammatory cytokines/chemokines and to inhibit the matrix metalloproteinases-related proteolytic cascades, counteracting endothelial dysfunctions. The pleiotropic effects of sulodexide set the basis for a very promising agent in treating the spectrum of CVD.

  2. Fluoride-Induced Oxidative and Inflammatory Stress in Osteosarcoma Cells: Does It Affect Bone Development Pathway?

    PubMed

    Gandhi, Deepa; Naoghare, Pravin K; Bafana, Amit; Kannan, Krishnamurthi; Sivanesan, Saravanadevi

    2017-01-01

    Oxidative stress is reported to negatively affect osteoblast cells. Present study reports oxidative and inflammatory signatures in fluoride-exposed human osteosarcoma (HOS) cells, and their possible association with the genes involved in osteoblastic differentiation and bone development pathways. HOS cells were challenged with sublethal concentration (8 mg/L) of sodium fluoride for 30 days and analyzed for transcriptomic expression. In total, 2632 transcripts associated with several biological processes were found to be differentially expressed. Specifically, genes involved in oxidative stress, inflammation, osteoblastic differentiation, and bone development pathways were found to be significantly altered. Variation in expression of key genes involved in the abovementioned pathways was validated through qPCR. Expression of serum amyloid A1 protein, a key regulator of stress and inflammatory pathways, was validated through western blot analysis. This study provides evidence that chronic oxidative and inflammatory stress may be associated with the fluoride-induced impediment in osteoblast differentiation and bone development.

  3. Interleukin-34 sustains inflammatory pathways in the gut.

    PubMed

    Franzè, Eleonora; Monteleone, Ivan; Cupi, Maria Laura; Mancia, Pamela; Caprioli, Flavio; Marafini, Irene; Colantoni, Alfredo; Ortenzi, Angela; Laudisi, Federica; Sica, Giuseppe; Sileri, PierPaolo; Pallone, Francesco; Monteleone, Giovanni

    2015-08-01

    IBD (inflammatory bowel disease)-related tissue damage occurs in areas which are massively infiltrated with monocytes/macrophages. These cells respond to inflammatory stimuli with enhanced production of cytokines/chemokines. In the present study, we analysed the expression and role of IL (interleukin)-34, a regulator of monocyte/macrophage differentiation, survival and function, in IBD. A significant increase in IL-34 mRNA and protein expression was seen in inflamed mucosa of patients with CD (Crohn's disease) and patients with UC (ulcerative colitis) compared with the uninvolved areas of the same patients and normal controls. IL-34 was up-regulated in LPMCs (lamina propria mononuclear cells) isolated from normal colon by TNF-α (tumour necrosis factor α) and TLR (Toll-like receptor) ligands and was down-regulated in intestinal biopsies and LPMCs of IBD patients upon treatment with infliximab. Treatment of normal LPMCs with IL-34 increased TNF-α expression in an ERK1/2 (extracellular-signal-regulated kinase 1/2)-dependent fashion and neutralization of IL-34 in IBD mucosal explants reduced TNF-α and IL-6 synthesis. In conclusion, our results indicate that IL-34 is up-regulated in IBD and suggest a role for this cytokine in sustaining the inflammatory responses in this disease.

  4. Lactobacillus casei and Lactobacillus acidophilus regulate inflammatory pathway and improve antioxidant status in collagen-induced arthritic rats.

    PubMed

    Amdekar, Sarika; Singh, Vinod; Kumar, Avnish; Sharma, Poonam; Singh, Rambir

    2013-01-01

    In view of well-established immunomodulatory properties of Lactobacillus, present investigation was carried out to evaluate antioxidant and anti-inflammatory potential of Lactobacillus casei and Lactobacillus acidophilus, against inflammatory pathway and oxidative stress developed in an experimental model of arthritis. Collagen-induced arthritis (CIA) model was used. Oral administration of L. casei, L. acidophilus, standard antiarthritic drug indomethacin, and vehicle were started after induced arthritis and continued up to day 28. Interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, IL-17, IL-4, and IL-10 levels were estimated in serum. In parallel, oxidative stress parameters were also measured from synovial effsuate. All rats were graded for arthritis score at the end of each week. L. casei, L. acidophilus, and indomethacin treatment significantly downregulated proinflammatory and upregulated anti-inflammatory cytokines at P<0.0001. They have significantly decreased oxidative stress in synovial effsuate (P<0.0001) and also arthritis score (P<0.05). Protection provided by L. casei and L. acidophilus was more pronounced than that of indomethacin. These lines of evidence suggest that L. casei and L. acidophilus exert potent protective effect against CIA. It further establishes effective anti-inflammatory and antioxidant properties of Lactobacillus. However, additional clinical investigations are needed to prove the efficacy of Lactobacillus in treatment/management of rheumatoid arthritis.

  5. Potential of flavonoids as anti-inflammatory agents: modulation of pro-inflammatory gene expression and signal transduction pathways.

    PubMed

    Tuñón, M J; García-Mediavilla, M V; Sánchez-Campos, S; González-Gallego, J

    2009-03-01

    Flavonoids are a large class of naturally occurring compounds widely present in fruits, vegetables, and beverages derived from plants. Reports have suggested that these compounds might be useful for the prevention of a number of diseases, partly due to their anti-inflammatory properties. It has been demonstrated that flavonoids are able to inhibit expression of isoforms of inducible nitric oxide synthase, ciclooxygenase and lipooxygenase, which are responsible for the production of a great amount of nitric oxide, prostanoids and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines or adhesion molecules. Modulation of the cascade of molecular events leading to the over-expression of those mediators include inhibition of transcription factors such as nuclear factor kappa B, activator protein 1, signal transducers and activators of transcription, CCAAT/enhancer binding protein and others. Effects on the binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen activated protein kinases. Although the numerous studies published with in vitro approaches allow identifying molecular mechanisms of flavonoid effects, the limited bioavailability of these molecules makes necessary validation in humans. Whatever the case, the data available make clear the potential utility of dietary flavonoids or new flavonoid-based agents for the possible treatment of inflammatory diseases. The present review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by flavonoids and the effects on cell signaling pathways responsible for their anti-inflammatory activity.

  6. Pathogenesis of Endometriosis: Roles of Retinoids and Inflammatory Pathways

    PubMed Central

    Taylor, Robert N.; Kane, Maureen A.; Sidell, Neil

    2016-01-01

    Endometriosis is a nonmalignant, but potentially metastatic, gynecological condition manifested by the extrauterine growth of inflammatory endometrial implants. Ten percent of reproductive-age women are affected and commonly suffer pelvic pain and/ or infertility. The theories of endometriosis histogenesis remain controversial, but retrograde menstruation and metaplasia each infer mechanisms that explain the immune cell responses observed around the ectopic lesions. Recent findings from our laboratories and others suggest that retinoic acid metabolism and action are fundamentally flawed in endometriotic tissues and even generically in women with endometriosis. The focus of our ongoing research is to develop medical therapies as adjuvants or alternatives to the surgical excision of these lesions. On the basis of concepts put forward in this review, we predict that the pharmacological actions and anticipated low side-effect profiles of retinoid supplementation might provide a new treatment option for the long-term management of this chronic and debilitating gynecological disease. PMID:26132929

  7. Pilose antler peptide protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling.

    PubMed

    Chunhui, Yang; Wenjun, Cai; Hui, Wen; Liquan, Sha; Changwei, Zhao; Tianzhu, Zhang; Wenhai, Zhao

    2017-02-16

    Epidermal growth factor (EGF)/EFG receptor (EGFR) signaling plays an important role in the osteoblastogenesis. The potential effects of pilose antler peptide (PAP) on osteoblast cell damages was investigated in our present study through EGF/EGFR signaling. In MC3T3-E1 osteoblastic cells, PAP treatment significantly inhibited the production of inflammatory cytokines by decreasing the levels of serum proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). PAP treatment also alleviated the oxidative responses as indicated by increased activities of catalase (SOD) and decreased levels of malondialdehyde (MDA). EGF inhibition, by siRNA knockdown, almost abolished PAP-induced osteoblast cytoprotection against inflammation and oxidant stress. Further, our results showed that PAP stimulated the nuclear erythroid factor 2-related factor 2 (Nrf2)2/heme oxygenase-1(HO-1) signaling, and inhibited the activation of uclear factor kappa B (NF-κB) pathway in MC3T3-E1 cells. On the other hand, EGF siRNA knockdown inhibited PAP-induced cytoprotection, which decreased the expression of Nrf-2, HO-1 and increased the level of p-NF-κBp65, p-IκBα in MC3T3-E1 cells. Thus, our research demonstrated that PAP protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling.

  8. Inflammatory signaling pathways in self-renewing breast cancer stem cells.

    PubMed

    Hinohara, Kunihiko; Gotoh, Noriko

    2010-12-01

    Cancer stem cells (CSCs), which make up only a small proportion of heterogeneous tumor cells, may possess greater ability to maintain tumorigenesis than do other tumor cell types. Breast cancer tissue is reported to contain cancer stem-like cells. In order to eradicate tumor cells, various approaches have been taken to identify the critical molecules and signaling pathways in breast CSCs. Recent findings suggest that inflammatory signaling pathways are important for the maintenance of breast CSCs. Here, we review the current understanding of the role of inflammatory pathways in these cells and discuss future perspectives of the research on and the possibility of targeting the molecules involved in these pathways for developing treatments for breast cancer.

  9. Resveratrol Attenuates Acute Inflammatory Injury in Experimental Subarachnoid Hemorrhage in Rats via Inhibition of TLR4 Pathway

    PubMed Central

    Zhang, Xiang-Sheng; Li, Wei; Wu, Qi; Wu, Ling-Yun; Ye, Zhen-Nan; Liu, Jing-Peng; Zhuang, Zong; Zhou, Meng-Liang; Zhang, Xin; Hang, Chun-Hua

    2016-01-01

    Toll-like receptor 4 (TLR4) has been proven to play a critical role in neuroinflammation and to represent an important therapeutic target following subarachnoid hemorrhage (SAH). Resveratrol (RSV), a natural occurring polyphenolic compound, has a powerful anti-inflammatory property. However, the underlying molecular mechanisms of RSV in protecting against early brain injury (EBI) after SAH remain obscure. The purpose of this study was to investigate the effects of RSV on the TLR4-related inflammatory signaling pathway and EBI in rats after SAH. A prechiasmatic cistern SAH model was used in our experiment. The expressions of TLR4, high-mobility group box 1 (HMGB1), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) were evaluated by Western blot and immunohistochemistry. The expressions of Iba-1 and pro-inflammatory cytokines in brain cortex were determined by Western blot, immunofluorescence staining, or enzyme-linked immunosorbent assay. Neural apoptosis, brain edema, and neurological function were further evaluated to investigate the development of EBI. We found that post-SAH treatment with RSV could markedly inhibit the expressions of TLR4, HMGB1, MyD88, and NF-κB. Meanwhile, RSV significantly reduced microglia activation, as well as inflammatory cytokines leading to the amelioration of neural apoptosis, brain edema, and neurological behavior impairment at 24 h after SAH. However, RSV treatment failed to alleviate brain edema and neurological deficits at 72 h after SAH. These results indicated that RSV treatment could alleviate EBI after SAH, at least in part, via inhibition of TLR4-mediated inflammatory signaling pathway. PMID:27529233

  10. Contemporary views on inflammatory pain mechanisms: TRPing over innate and microglial pathways

    PubMed Central

    Guan, Zhonghui; Hellman, Judith; Schumacher, Mark

    2016-01-01

    Tissue injury, whether by trauma, surgical intervention, metabolic dysfunction, ischemia, or infection, evokes a complex cellular response (inflammation) that is associated with painful hyperalgesic states. Although in the acute stages it is necessary for protective reflexes and wound healing, inflammation may persist well beyond the need for tissue repair or survival. Prolonged inflammation may well represent the greatest challenge mammalian organisms face, as it can lead to chronic painful conditions, organ dysfunction, morbidity, and death. The complexity of the inflammatory response reflects not only the inciting event (infection, trauma, surgery, cancer, or autoimmune) but also the involvement of heterogeneous cell types including neuronal (primary afferents, sensory ganglion, and spinal cord), non-neuronal (endothelial, keratinocytes, epithelial, and fibroblasts), and immune cells. In this commentary, we will examine 1.) the expression and regulation of two members of the transient receptor potential family in primary afferent nociceptors and their activation/regulation by products of inflammation, 2.) the role of innate immune pathways that drive inflammation, and 3.) the central nervous system’s response to injury with a focus on the activation of spinal microglia driving painful hyperalgesic states. PMID:27781082

  11. Exploiting the Annexin A1 pathway for the development of novel anti-inflammatory therapeutics

    PubMed Central

    Perretti, Mauro; Dalli, Jesmond

    2009-01-01

    The appreciation that the inflammatory reaction does not ‘spontaneously’ finish, but rather that inflammatory resolution is an active phenomenon brought about by endogenous anti-inflammatory agonists opens multiple opportunities for a reassessment of the complexity of inflammation and its main mediators. This review dwells on one of these pathways, the one centred around the glucocorticoid-regulated protein Annexin A1 and its G protein-coupled receptor. In recent years, much of the knowledge detailing the processes by which Annexin A1 expresses its anti-inflammatory role on innate immunity has been produced. Moreover, the generation of the Annexin A1 null mouse colony has provided important proof-of-concept experiments demonstrating the inhibitory properties of this mediator in the context of inflammatory and/or tissue-injury models. Therefore, Annexin A1 acts as a pivotal homeostatic mediator, where if absent, inflammation would overshoot and be prolonged. This new understanding scientific information could guide us onto the exploitation of the biological properties of Annexin A1 and its receptor to instigate novel drug discovery programmes for anti-inflammatory therapeutics. This line of research relies on the assumption that anti-inflammatory drugs designed upon endogenous anti-inflammatory mediators would be burdened by a lower degree of secondary effects as these agonists would be mimicking specific pathways activated in our body for safe disposal of inflammation. We believe that the next few years will produce examples of such new drugs and the validity of this speculation could then be assessed. This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 PMID:19845684

  12. Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways.

    PubMed

    Maes, Michael; Kubera, Marta; Obuchowiczwa, Ewa; Goehler, Lisa; Brzeszcz, Joanna

    2011-01-01

    There is now evidence that depression, as characterized by melancholic symptoms, anxiety, and fatigue and somatic (F&S) symptoms, is the clinical expression of peripheral cell-mediated activation, inflammation and induction of oxidative and nitrosative stress (IO&NS) pathways and of central microglial activation, decreased neurogenesis and increased apoptosis. This review gives an explanation for the multiple "co-morbidities" between depression and a large variety of a) brain disorders related to neurodegeneration, e.g. Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis and stroke; b) medical disorders, such as cardiovascular disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, leaky gut, diabetes type 1 and 2, obesity and the metabolic syndrome, and HIV infection; and c) conditions, such as hemodialysis, interferon-α-based immunotherapy, the postnatal period and psychosocial stressors. The common denominator of all those disorders/conditions is the presence of microglial activation and/or activation of peripheral IO&NS pathways. There is evidence that shared peripheral and / or central IO&NS pathways underpin the pathophysiology of depression and the previously mentioned disorders and that activation of these IO&NS pathways contributes to shared risk. The IO&NS pathways function as a smoke sensor that detect threats in the peripheral and central parts of the body and signal these threats as melancholic, anxiety, and fatigue and somatic (F&S) symptoms. The presence of concomitant depression is strongly associated with a lower quality of life and increased morbidity and mortality in medical disorders. This may be explained since depression contributes to increased (neuro)inflammatory burden and may therefore drive the inflammatory and degenerative progression. It is concluded that the activation of peripheral

  13. Block of the Mevalonate Pathway Triggers Oxidative and Inflammatory Molecular Mechanisms Modulated by Exogenous Isoprenoid Compounds

    PubMed Central

    Tricarico, Paola Maura; Kleiner, Giulio; Valencic, Erica; Campisciano, Giuseppina; Girardelli, Martina; Crovella, Sergio; Knowles, Alessandra; Marcuzzi, Annalisa

    2014-01-01

    Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines’ release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD. PMID:24758928

  14. Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds.

    PubMed

    Tricarico, Paola Maura; Kleiner, Giulio; Valencic, Erica; Campisciano, Giuseppina; Girardelli, Martina; Crovella, Sergio; Knowles, Alessandra; Marcuzzi, Annalisa

    2014-04-22

    Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines' release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

  15. PPARγ regulates inflammatory reaction by inhibiting the MAPK/NF-κB pathway in C2C12 skeletal muscle cells.

    PubMed

    Kim, Jeong-Seok; Lee, Young-Hee; Chang, Yong-Uoo; Yi, Ho-Keun

    2017-02-01

    Excessive exercise induces an inflammatory response caused by oxidative stress, which delays recovery of damaged muscle fibers. The reduction of inflammatory response is important for skeletal muscle homeostasis. Peroxisome proliferator-activated receptor gamma (PPARγ) is an anti-inflammatory molecule, but the role of PPARγ in skeletal muscle as anti-inflammatory activity is not clear. Thus, this study examined the anti-inflammatory role of PPARγ against H2O2-induced oxidative stress in skeletal muscle. Sprague Dawley (SD) rats were exercised on a treadmill to induce oxidative stress. In vitro oxidative stress was evaluated in differentiated C2C12 cells stimulated using 200 μM H2O2. Inflammation-related molecules were determined by immunohistochemistry and Western blot analysis. Expressions of the inflammatory molecules tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-2 (MMP-2) in muscles of the acute exercise group were highly increased. PPARγ was also highly expressed in these muscles. These inflammatory molecules were also markedly increased in C2C12 cells with H2O2 stimulation. However, PPARγ overexpression in C2C12 transfected by Ad/PPARγ dramatically reduced the inflammatory molecules. PPARγ also enhanced the anti-oxidants molecules like Cu/Zn-SOD, Mn-SOD, and hemeoxygenase-1 by reducing the generation of ROS, even in the presence of H2O2. PPARγ displayed dual anti-inflammatory and anti-oxidant roles by inhibiting the mitogen-activated protein kinase (MAPK) pathway and translocation of nuclear transcriptional factor-κB (NF-κB) from the cytosol to the nucleus. These results demonstrate a potential role of PPARγ in protecting muscle fibers against oxidative stress caused by excessive acute exercise due to its anti-inflammatory and anti-oxidant activity exerted by inhibition of the MAPK/NF-κB pathway.

  16. The bright side of plasmonic gold nanoparticles; activation of Nrf2, the cellular protective pathway

    NASA Astrophysics Data System (ADS)

    Goldstein, Alona; Soroka, Yoram; Frušić-Zlotkin, Marina; Lewis, Aaron; Kohen, Ron

    2016-06-01

    Plasmonic gold nanoparticles (AuNPs) are widely investigated for cancer therapy, due to their ability to strongly absorb light and convert it to heat and thus selectively destroy tumor cells. In this study we shed light on a new aspect of AuNPs and their plasmonic excitation, wherein they can provide anti-oxidant and anti-inflammatory protection by stimulating the cellular protective Nrf2 pathway. Our study was carried out on cells of the immune system, macrophages, and on skin cells, keratinocytes. A different response to AuNPs was noted in the two types of cells, explained by their distinct uptake profiles. In keratinocytes, the exposure to AuNPs, even at low concentrations, was sufficient to activate the Nrf2 pathway, without any irradiation, due to the presence of free AuNPs inside the cytosol. In contrast, in macrophages, the plasmonic excitation of the AuNPs by a low, non-lethal irradiation dose was required for their release from the constraining vesicles. The mechanism by which AuNPs activate the Nrf2 pathway was studied. Direct and indirect activation were suggested, based on the inherent ability of the AuNPs to react with thiol groups and to generate reactive oxygen species, in particular, under plasmonic excitation. The ability of AuNPs to directly activate the Nrf2 pathway renders them good candidates for treatment of disorders in which the up-regulation of Nrf2 is beneficial, specifically for topical treatment of inflammatory skin diseases.

  17. Update on biologic pathways in inflammatory bowel disease and their therapeutic relevance

    PubMed Central

    Snapper, Scott B.; Blumberg, Richard S.

    2015-01-01

    Results of recent genetic and immunologic studies have brought to the forefront several biologic pathways that allow for a better understanding of the mechanisms of tissue homeostasis, on the one hand, and inflammatory bowel disease (IBD) on the other. The explosion of research activity as a result of these newly identified targets is bringing the pathogenesis of these complex disorders into focus as well as creating new therapeutic opportunities. The greatest advances with perhaps the largest impact on our understanding of the etiology of Crohn’s disease are those related to bacterial sensing, such as through nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and its relationships to autophagy and the unfolded protein response as a consequence of endoplasmic reticulum stress. Interestingly, it appears as though these pathways, which are rooted in microbial sensing and regulation, are interrelated. Genetic studies have also renewed interest in previously studied pathways in IBD, such as the formation and function of the inflammasome and its relationship to interleukin (IL) 1-beta signaling. With the recent success of therapeutic agents designed to block tumor necrosis factor, the IL-12/23 pathways, and lymphocyte homing, insights have been gained into the biologic relevance and impact of these various inflammatory pathways in IBD. In this review, the exciting recent advances in these biologic pathways of IBD are discussed, particularly in light of their therapeutic relevance. PMID:22215058

  18. Oxymatrine lightened the inflammatory response of LPS-induced mastitis in mice through affecting NF-κB and MAPKs signaling pathways.

    PubMed

    Yang, Zhengtao; Yin, Ronglan; Cong, Yunfeng; Yang, Zhanqing; Zhou, Ershun; Wei, Zhengkai; Liu, Zhicheng; Cao, Yongguo; Zhang, Naisheng

    2014-12-01

    Mastitis, an inflammatory reaction of the mammary gland, is recognized as one of the most costly diseases in dairy cattle. Oxymatrine, one of the alkaloids extracted from Chinese herb Sophora flavescens Ait, has been reported to have many biological activities, such as anti-inflammatory, anti-virus, and anti-hepatic fibrosis properties. The aim of this study was to investigate the protective effect and the anti-inflammatory mechanism of oxymatrine on lipopolysaccharide (LPS)-induced mastitis in mice. The mouse mastitis was induced by 10 μg of LPS for 24 h. Oxymatrine was intraperitoneally administered with the dose of 30, 60, and 120 mg/kg 1 h before and 12 h after LPS induction. The results showed that oxymatrine significantly attenuated the damage of the mammary gland induced by LPS. Oxymatrine inhibited the phosphorylation of NF-κB p65 and IκB in NF-κB signal pathway and reduced the phosphorylation of p38, ERK, and JNK in mitogen-activated protein kinase (MAPKs) signal pathway. The results showed that oxymatrine had a protective effect on LPS-induced mastitis, and the anti-inflammatory mechanism of oxymatrine was related to the inhibition of NF-κB and MAPKs signal pathways.

  19. Exploring the anti-inflammatory activity of a novel 2-phenylquinazoline analog with protection against inflammatory injury.

    PubMed

    Chatterjee, Nabanita; Das, Subhadip; Bose, Dipayan; Banerjee, Somenath; Das, Sujata; Chattopadhyay, Debprasad; Saha, Krishna Das

    2012-10-15

    Inflammation is a protective immune response against harmful stimuli whose long time continuation results in host disease. Quinazolinones are nitrogen containing heterocyclic compounds with wide spectrum of biological activities. The anticancer effect of a 3-(arylideneamino)-phenylquinazoline-4(3H)-one derivative was reported earlier. The anti-inflammatory effect of these quinazolinone derivatives has now been examined in endotoxin stimulated macrophages and in different in vivo models of inflammation by measuring the proinflammatory cytokines (TNF-α, IL-1β and IL-6), mediators NO and NF-κB (by ELISA and western blot), and translocation of the nuclear factor kB (by immunocytochemical analysis). To elucidate the in vivo effect, mice endotoxin model was and the various levels of edema, inflammatory pain and vascular permeability were studied. One of the quinazolinone derivatives showed significant anti-inflammatory activity in stimulated macrophage cells by inhibiting the expression of TNF-α, IL-1β, IL-6, iNOS, COX-2, p-IκB and NF-κBp65. Significant (P<0.01) improvement was observed in the mortality of endotoxemic mice. The carrageenan and formalin-induced paw edema thicknesses were found to be reduced significantly (P<0.01) along with the reduction of pain, vascular permeability and edema induced by complete Freund's adjuvant (P<0.01). These findings indicate that 3-(arylideneamino)-phenylquinazoline-4(3H)-one derivative as a potential anti-inflammatory agent.

  20. Protective Effect of Strawberry Extract against Inflammatory Stress Induced in Human Dermal Fibroblasts.

    PubMed

    Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Y; Giampieri, Francesca; Afrin, Sadia; Mezzetti, Bruno; Quiles, Josè L; Bompadre, Stefano; Battino, Maurizio

    2017-01-21

    A protracted pro-inflammatory state is a major contributing factor in the development, progression and complication of the most common chronic pathologies. Fruit and vegetables represent the main sources of dietary antioxidants and their consumption can be considered an efficient tool to counteract inflammatory states. In this context an evaluation of the protective effects of strawberry extracts on inflammatory stress induced by E. coli LPS on human dermal fibroblast cells was performed in terms of viability assays, ROS and nitrite production and biomarkers of oxidative damage of the main biological macromolecules. The results demonstrated that strawberry extracts exerted an anti-inflammatory effect on LPS-treated cells, through an increase in cell viability, and the reduction of ROS and nitrite levels, and lipid, protein and DNA damage. This work showed for the first time the potential health benefits of strawberry extract against inflammatory and oxidative stress in LPS-treated human dermal fibroblast cells.

  1. Mediators, Receptors, and Signalling Pathways in the Anti-Inflammatory and Antihyperalgesic Effects of Acupuncture

    PubMed Central

    McDonald, John L.; Cripps, Allan W.; Smith, Peter K.

    2015-01-01

    Acupuncture has been used for millennia to treat allergic diseases including both intermittent rhinitis and persistent rhinitis. Besides the research on the efficacy and safety of acupuncture treatment for allergic rhinitis, research has also investigated how acupuncture might modulate immune function to exert anti-inflammatory effects. A proposed model has previously hypothesized that acupuncture might downregulate proinflammatory neuropeptides, proinflammatory cytokines, and neurotrophins, modulating transient receptor potential vallinoid (TRPV1), a G-protein coupled receptor which plays a central role in allergic rhinitis. Recent research has been largely supportive of this model. New advances in research include the discovery of a novel cholinergic anti-inflammatory pathway activated by acupuncture. A chemokine-mediated proliferation of opioid-containing macrophages in inflamed tissues, in response to acupuncture, has also been demonstrated for the first time. Further research on the complex cross talk between receptors during inflammation is also helping to elucidate the mediators and signalling pathways activated by acupuncture. PMID:26339274

  2. Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses

    PubMed Central

    Aho, Vilma; Ollila, Hanna M.; Kronholm, Erkki; Bondia-Pons, Isabel; Soininen, Pasi; Kangas, Antti J.; Hilvo, Mika; Seppälä, Ilkka; Kettunen, Johannes; Oikonen, Mervi; Raitoharju, Emma; Hyötyläinen, Tuulia; Kähönen, Mika; Viikari, Jorma S.A.; Härmä, Mikko; Sallinen, Mikael; Olkkonen, Vesa M.; Alenius, Harri; Jauhiainen, Matti; Paunio, Tiina; Lehtimäki, Terho; Salomaa, Veikko; Orešič, Matej; Raitakari, Olli T.; Ala-Korpela, Mika; Porkka-Heiskanen, Tarja

    2016-01-01

    Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases. PMID:27102866

  3. Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells.

    PubMed

    Kim, Sun Ae; Choi, Hyoung Chul

    2012-09-07

    Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2mM) and inhibited by compound C (10 μM) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-α) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-κB. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-κB activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-α. Taken together, PTEN could be a possible downstream regulator of AMPK, and the AMPK-PTEN pathway might be important in the regulation of the inflammatory response in VSMCs.

  4. Right Cervical Vagotomy Aggravates Viral Myocarditis in Mice Via the Cholinergic Anti-inflammatory Pathway

    PubMed Central

    Li-Sha, Ge; Xing-Xing, Chen; Lian-Pin, Wu; De-Pu, Zhou; Xiao-Wei, Li; Jia-Feng, Lin; Yue-Chun, Li

    2017-01-01

    The autonomic nervous system dysfunction with increased sympathetic activity and withdrawal of vagal activity may play an important role in the pathogenesis of viral myocarditis. The vagus nerve can modulate the immune response and control inflammation through a ‘cholinergic anti-inflammatory pathway’ dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Although the role of β-adrenergic stimulation on viral myocarditis has been investigated in our pervious studies, the direct effect of vagal tone in this setting has not been yet studied. Therefore, in the present study, we investigated the effects of cervical vagotomy in a murine model of viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of right cervical vagotomy and nAChR agonist nicotine on echocardiography, myocardial histopathology, viral RNA, and proinflammatory cytokine levels were studied. We found that right cervical vagotomy inhibited the cholinergic anti-inflammatory pathway, aggravated myocardial lesions, up-regulated the expression of TNF-α, IL-1β, and IL-6, and worsened the impaired left ventricular function in murine viral myocarditis, and these changes were reversed by co-treatment with nicotine by activating the cholinergic anti-inflammatory pathway. These results indicate that vagal nerve plays an important role in mediating the anti-inflammatory effect in viral myocarditis, and that cholinergic stimulation with nicotine also plays its peripheral anti-inflammatory role relying on α7nAChR, without requirement for the integrity of vagal nerve in the model. The findings suggest that vagus nerve stimulation mediated inhibition of the inflammatory processes likely provide important benefits in myocarditis treatment. PMID:28197102

  5. Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models

    SciTech Connect

    Lee, Wonhwa; Kim, Tae Hoon; Ku, Sae-Kwang; Min, Kyoung-jin; Lee, Hyun-Shik; Kwon, Taeg Kyu; Bae, Jong-Sup

    2012-07-01

    Withaferin A (WFA), an active compound from Withania somnifera, is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In this study, we first investigated the possible barrier protective effects of WFA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice induced by high mobility group box 1 protein (HMGB1) and the associated signaling pathways. The barrier protective activities of WFA were determined by measuring permeability, leukocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs. We found that WFA inhibited lipopolysaccharide (LPS)-induced HMGB1 release and HMGB1-mediated barrier disruption, expression of cell adhesion molecules (CAMs) and adhesion/transendothelial migration of leukocytes to human endothelial cells. WFA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Further studies revealed that WFA suppressed the production of interleukin 6, tumor necrosis factor-α (TNF-α) and activation of nuclear factor-κB (NF-κB) by HMGB1. Collectively, these results suggest that WFA protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases. -- Highlights: ► Withaferin A inhibited LPS induced HMGB1 release. ► Withaferin A reduced HMGB1-mediated hyperpermeability. ► Withaferin A inhibited HMGB1-mediated adhesion and migration of leukocytes. ► Withaferin A inhibited HMGB1-mediated activation of NF-κB, IL-6 and TNF-α.

  6. Dung biomass smoke activates inflammatory signaling pathways in human small airway epithelial cells.

    PubMed

    McCarthy, Claire E; Duffney, Parker F; Gelein, Robert; Thatcher, Thomas H; Elder, Alison; Phipps, Richard P; Sime, Patricia J

    2016-12-01

    Animal dung is a biomass fuel burned by vulnerable populations who cannot afford cleaner sources of energy, such as wood and gas, for cooking and heating their homes. Exposure to biomass smoke is the leading environmental risk for mortality, with over 4,000,000 deaths each year worldwide attributed to indoor air pollution from biomass smoke. Biomass smoke inhalation is epidemiologically associated with pulmonary diseases, including chronic obstructive pulmonary disease (COPD), lung cancer, and respiratory infections, especially in low and middle-income countries. Yet, few studies have examined the mechanisms of dung biomass smoke-induced inflammatory responses in human lung cells. Here, we tested the hypothesis that dung biomass smoke causes inflammatory responses in human lung cells through signaling pathways involved in acute and chronic lung inflammation. Primary human small airway epithelial cells (SAECs) were exposed to dung smoke at the air-liquid interface using a newly developed, automated, and reproducible dung biomass smoke generation system. The examination of inflammatory signaling showed that dung biomass smoke increased the production of several proinflammatory cytokines and enzymes in SAECs through activation of the activator protein (AP)-1 and arylhydrocarbon receptor (AhR) but not nuclear factor-κB (NF-κB) pathways. We propose that the inflammatory responses of lung cells exposed to dung biomass smoke contribute to the development of respiratory diseases.

  7. Multifaceted pathways protect human skin from UV radiation.

    PubMed

    Natarajan, Vivek T; Ganju, Parul; Ramkumar, Amrita; Grover, Ritika; Gokhale, Rajesh S

    2014-07-01

    The recurrent interaction of skin with sunlight is an intrinsic constituent of human life, and exhibits both beneficial and detrimental effects. The apparent robust architectural framework of skin conceals remarkable mechanisms that operate at the interface between the surface and environment. In this Review, we discuss three distinct protective mechanisms and response pathways that safeguard skin from deleterious effects of ultraviolet (UV) radiation. The unique stratified epithelial architecture of human skin along with the antioxidant-response pathways constitutes the important defense mechanisms against UV radiation. The intricate pigmentary system and its intersection with the immune-system cytokine axis delicately balance tissue homeostasis. We discuss the relationship among these networks in the context of an unusual depigmenting disorder, vitiligo. The elaborate tunable mechanisms, elegant multilayered architecture and evolutionary selection pressures involved in skin and sunlight interaction makes this a compelling model to understand biological complexity.

  8. Titanium dioxide nanoparticles activate IL8-related inflammatory pathways in human colonic epithelial Caco-2 cells

    NASA Astrophysics Data System (ADS)

    Krüger, Kristin; Cossais, François; Neve, Horst; Klempt, Martin

    2014-05-01

    Nanosized titanium dioxide (TiO2) particles are widely used as food additive or coating material in products of the food and pharmaceutical industry. Studies on various cell lines have shown that TiO2 nanoparticles (NPs) induced the inflammatory response and cytotoxicity. However, the influences of TiO2 NPs' exposure on inflammatory pathways in intestinal epithelial cells and their differentiation have not been investigated so far. This study demonstrates that TiO2 NPs with particle sizes ranging between 5 and 10 nm do not affect enterocyte differentiation but cause an activation of inflammatory pathways in the human colon adenocarcinoma cell line Caco-2. 5 and 10 nm NPs' exposures transiently induce the expression of ICAM1, CCL20, COX2 and IL8, as determined by quantitative PCR, whereas larger particles (490 nm) do not. Further, using nuclear factor (NF)-κB reporter gene assays, we show that NP-induced IL8 mRNA expression occurs, in part, through activation of NF-κB and p38 mitogen-activated protein kinase pathways.

  9. EGCG Attenuates Uric Acid-Induced Inflammatory and Oxidative Stress Responses by Medicating the NOTCH Pathway

    PubMed Central

    Xie, Hua; Sun, Jianqin; Chen, Yanqiu; Zong, Min; Li, Shijie; Wang, Yan

    2015-01-01

    Background. The aim of this study is to investigate whether (-)-epigallocatechin-3-gallate (EGCG) can prevent the UA-induced inflammatory effect of human umbilical vein endothelial cells (HUVEC) and the involved mechanisms in vitro. Methods. HUVEC were subjected to uric acid (UA) with or without EGCG treatment. RT-PCR and western blots were performed to determine the level of inflammation marker. The antioxidant activity was evaluated by measuring scavenged reactive oxygen species (ROS). Functional studies of the role of Notch-1 in HUVEC lines were performed using RNA interference analyses. Results. UA significantly increased the expressions of IL-6, ICAM-1, TNF-α, and MCP-1 and the production of ROS in HUVEC. Meanwhile, the expression of Notch-1 and its downstream effects significantly increased. Using siRNA, inhibition of Notch-1 signaling significantly impeded the expressions of inflammatory cytokines under UA treatment. Interestingly, EGCG suppressed the expressions of inflammatory cytokines and the generation of ROS. Western blot analysis of Notch-1 showed that EGCG significantly decreased the expressions of inflammatory cytokines through Notch-1 signaling pathways. Conclusions. In summary, our findings indicated that Notch-1 plays an important role in the UA-induced inflammatory response, and the downregulation of Notch-1 by EGCG could be an effective approach to decrease inflammation and oxidative stress induced by UA. PMID:26539255

  10. Physalis angulata extract exerts anti-inflammatory effects in rats by inhibiting different pathways.

    PubMed

    Bastos, G N T; Silveira, A J A; Salgado, C G; Picanço-Diniz, D L W; do Nascimento, J L M

    2008-07-23

    Physalis angulata is a popular medicine used in Brazil due to its anti-inflammatory effects, but the pharmacological mechanisms underlying these actions remain to be better understood. In the present work, lyophilized aqueous extract from the roots of Physalis angulata Linneu (AEPa) was used to control the inflammatory response induced by the injection of 1% carrageenan into subcutaneous rat's air pouches. Adenosine deaminase (ADA) activity, nitrite level, and prostaglandin E(2) (PGE(2)) level were used to evaluate the action of inflammatory mediators. Tumor growth factor-beta (TGF-beta) level was used as a bioindicator of immunomodulatory response. Rats were injected with vehicle, indomethacin, or AEPa (0.5 mg/kg, 1 mg/kg, and 5 mg/kg i.p.), 1h before carrageenan administration. AEPa at 0.5 mg/kg had no effect. However, 1mg/kg of AEPa showed significant anti-inflammatory effects, decreasing exudate volume, total number of inflammatory cells, ADA activity, nitrite level, and PGE(2) level in 50%, 41%, 20%, 60%, and 41%, respectively. The anti-inflammatory effects of 5 mg/kg AEPa appeared to be more effective than those of 1 mg/kg AEPa (84%, 80%, 43%, 70%, and 75%, respectively). In addition, TGF-beta level was upregulated to 9700 pg/ml after 5mg/kg AEPa, in comparison with 160 pg/ml in the vehicle-treated group, and 137 pg/ml in the indomethacin-treated group. The results indicate that AEPa exerts powerful anti-inflammatory and immunomodulatory activities, interfering with the cyclooxygenase pathway, lymphocyte proliferation, NO, and TGF-beta production.

  11. Cellular prion protein protects from inflammatory and neuropathic pain.

    PubMed

    Gadotti, Vinicius M; Zamponi, Gerald W

    2011-08-16

    Cellular prion protein (PrPC) inhibits N-Methyl-D-Aspartate (NMDA) receptors. Since NMDA receptors play an important role in the transmission of pain signals in the dorsal horn of spinal cord, we thus wanted to determine if PrPC null mice show a reduced threshold for various pain behaviours.We compared nociceptive thresholds between wild type and PrPC null mice in models of inflammatory and neuropathic pain, in the presence and the absence of a NMDA receptor antagonist. 2-3 months old male PrPC null mice exhibited an MK-801 sensitive decrease in the paw withdrawal threshold in response both mechanical and thermal stimuli. PrPC null mice also exhibited significantly longer licking/biting time during both the first and second phases of formalin-induced inflammation of the paw, which was again prevented by treatment of the mice with MK-801, and responded more strongly to glutamate injection into the paw. Compared to wild type animals, PrPC null mice also exhibited a significantly greater nociceptive response (licking/biting) after intrathecal injection of NMDA. Sciatic nerve ligation resulted in MK-801 sensitive neuropathic pain in wild-type mice, but did not further augment the basal increase in pain behaviour observed in the null mice, suggesting that mice lacking PrPC may already be in a state of tonic central sensitization. Altogether, our data indicate that PrPC exerts a critical role in modulating nociceptive transmission at the spinal cord level, and fit with the concept of NMDA receptor hyperfunction in the absence of PrPC.

  12. Exploring the anti-inflammatory activity of a novel 2-phenylquinazoline analog with protection against inflammatory injury

    SciTech Connect

    Chatterjee, Nabanita; Das, Subhadip; Bose, Dipayan; Banerjee, Somenath; Das, Sujata; Chattopadhyay, Debprasad; Saha, Krishna Das

    2012-10-15

    Inflammation is a protective immune response against harmful stimuli whose long time continuation results in host disease. Quinazolinones are nitrogen containing heterocyclic compounds with wide spectrum of biological activities. The anticancer effect of a 3-(arylideneamino)‐phenylquinazoline-4(3H)-one derivative was reported earlier. The anti-inflammatory effect of these quinazolinone derivatives has now been examined in endotoxin stimulated macrophages and in different in vivo models of inflammation by measuring the proinflammatory cytokines (TNF-α, IL-1β and IL-6), mediators NO and NF-κB (by ELISA and western blot), and translocation of the nuclear factor kB (by immunocytochemical analysis). To elucidate the in vivo effect, mice endotoxin model was and the various levels of edema, inflammatory pain and vascular permeability were studied. One of the quinazolinone derivatives showed significant anti-inflammatory activity in stimulated macrophage cells by inhibiting the expression of TNF-α, IL-1β, IL-6, iNOS, COX-2, p-IκB and NF-κBp65. Significant (P < 0.01) improvement was observed in the mortality of endotoxemic mice. The carrageenan and formalin-induced paw edema thicknesses were found to be reduced significantly (P < 0.01) along with the reduction of pain, vascular permeability and edema induced by complete Freund's adjuvant (P < 0.01). These findings indicate that 3-(arylideneamino)‐phenylquinazoline-4(3H)-one derivative as a potential anti-inflammatory agent. -- Highlights: ► 2-phenylquinazoline analog suppresses the cytokines in stimulated macrophages. ► 2-phenylquinazoline analog down regulated NF-kB P65 translocation. ► Role of 2-phenylquinazoline analog in endotoximia and peripheral inflammations.

  13. Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis.

    PubMed

    Kanashiro, Alexandre; Sônego, Fabiane; Ferreira, Raphael G; Castanheira, Fernanda V S; Leite, Caio A; Borges, Vanessa F; Nascimento, Daniele C; Cólon, David F; Alves-Filho, José Carlos; Ulloa, Luis; Cunha, Fernando Q

    2017-03-01

    Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called "cholinergic anti-inflammatory pathway", suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.

  14. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers

    PubMed Central

    Saadi, Amel; Shannon, Nicholas B.; Lao-Sirieix, Pierre; O’Donovan, Maria; Walker, Elaine; Clemons, Nicholas J.; Hardwick, James S.; Zhang, Chunsheng; Das, Madhumita; Save, Vicki; Novelli, Marco; Balkwill, Frances; Fitzgerald, Rebecca C.

    2010-01-01

    The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett’s esophagus (BE) is an ideal research model. Supervised clustering of gene expression profiles from microdissected stroma identified a gene signature that could distinguish between BE metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). EAC patients overexpressing any of the five genes (TMEPAI, JMY, TSP1, FAPα, and BCL6) identified from this stromal signature had a significantly poorer outcome. Gene ontology analysis identified a strong inflammatory component in BE disease progression, and key pathways included cytokine–cytokine receptor interactions and TGF-β. Increased protein levels of inflammatory-related genes significantly up-regulated in EAC compared with preinvasive stages were confirmed in the stroma of independent samples, and in vitro assays confirmed functional relevance of these genes. Gene set enrichment analysis of external datasets demonstrated that the stromal signature was also relevant in the preinvasive to invasive transition of the stomach, colon, and pancreas. These data implicate inflammatory pathways in the genesis of gastrointestinal tract cancers, which can affect prognosis. PMID:20080664

  15. Hydrogen Sulfide Delays LPS-Induced Preterm Birth in Mice via Anti-Inflammatory Pathways

    PubMed Central

    Liu, Weina; Xu, Chen; You, Xingji; Olson, David M.; Chemtob, Sylvain; Gao, Lu; Ni, Xin

    2016-01-01

    A major cause of preterm labor in pregnant women is intra-amniotic infection, which is mediated by an inflammatory process. Hydrogen sulfide (H2S), a gaseous transmitter, has been implicated to be involved in inflammatory responses. We sought to investigate whether H2S affects infectious preterm birth using the mouse model of lipopolysaccharides (LPS)-induced preterm birth. Administration of LPS at 0.4 mg/kg with two injections intraperitoneally (i.p.) on gestational day 14.5 induced preterm labor. LPS significantly increased leukocyte infiltration in uterus, stimulated the expression of pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), CCL2 and CXCL15 in myometrium. Administration of NaHS (i.p.) delayed the onset of labor induced by LPS in a dose-dependent manner. NaHS prevented leukocyte infiltration into intrauterine tissues and inhibited the production of pro-inflammatory cytokines in myometrium and decreased the levels of these cytokines in maternal circulation. H2S also decreased LPS-activated extracellular signal-regulated kinase (ERK) 1/2/ nuclear factor (NF)-κB signaling pathways in myometrium. This study provides new in vivo evidence for the roles of H2S in attenuating inflammation, and a potential novel therapeutic strategy for infection-related preterm labor. PMID:27035826

  16. Hydrogen Sulfide Delays LPS-Induced Preterm Birth in Mice via Anti-Inflammatory Pathways.

    PubMed

    Liu, Weina; Xu, Chen; You, Xingji; Olson, David M; Chemtob, Sylvain; Gao, Lu; Ni, Xin

    2016-01-01

    A major cause of preterm labor in pregnant women is intra-amniotic infection, which is mediated by an inflammatory process. Hydrogen sulfide (H2S), a gaseous transmitter, has been implicated to be involved in inflammatory responses. We sought to investigate whether H2S affects infectious preterm birth using the mouse model of lipopolysaccharides (LPS)-induced preterm birth. Administration of LPS at 0.4 mg/kg with two injections intraperitoneally (i.p.) on gestational day 14.5 induced preterm labor. LPS significantly increased leukocyte infiltration in uterus, stimulated the expression of pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), CCL2 and CXCL15 in myometrium. Administration of NaHS (i.p.) delayed the onset of labor induced by LPS in a dose-dependent manner. NaHS prevented leukocyte infiltration into intrauterine tissues and inhibited the production of pro-inflammatory cytokines in myometrium and decreased the levels of these cytokines in maternal circulation. H2S also decreased LPS-activated extracellular signal-regulated kinase (ERK) 1/2/ nuclear factor (NF)-κB signaling pathways in myometrium. This study provides new in vivo evidence for the roles of H2S in attenuating inflammation, and a potential novel therapeutic strategy for infection-related preterm labor.

  17. HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

    PubMed Central

    2011-01-01

    Background Although the high mobility group A1 (HMGA1) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. HMGA1 functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, HMGA1 is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from HMGA1a transgenic mice at different stages in tumorigenesis. Results RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors. Conclusions We found that HMGA1 induces inflammatory pathways early in

  18. Endogenous hydrogen sulfide regulates inflammatory response by activating the ERK pathway in polymicrobial sepsis.

    PubMed

    Zhang, Huili; Moochhala, Shabbir M; Bhatia, Madhav

    2008-09-15

    Hydrogen sulfide (H(2)S) up-regulates inflammatory response in several inflammatory diseases. However, to date, little is known about the molecular mechanism by which H(2)S provokes the inflammatory response in sepsis. Thus, the aim of this study was to investigate the signaling pathway underlying the proinflammatory role of H(2)S in cecal ligation and puncture (CLP)-induced sepsis. Male Swiss mice were subjected to CLP and treated with dl-propargylglycine (PAG; 50 mg/kg i.p., an inhibitor of H(2)S formation), NaHS (10 mg/kg, i.p., an H(2)S donor), or saline. PAG was administered 1 h before CLP, whereas NaHS was given at the time of CLP. CLP-induced sepsis resulted in a time-dependent increase in the synthesis of endogenous H(2)S. Maximum phosphorylation of ERK1/2 and degradation of IkappaBalpha in lung and liver were observed 4 h after CLP. Inhibition of H(2)S formation by PAG significantly reduced the phosphorylation of ERK1/2 in lung and liver 4 h after CLP, coupled with decreased degradation of IkappaBalpha and activation of NF-kappaB. In contrast, injection of NaHS significantly enhanced the activation of ERK1/2 in lung and liver, therefore leading to a further rise in tissue NF-kappaB activity. As a result, pretreatment with PAG significantly reduced the production of cytokines and chemokines in sepsis, whereas exogenous H(2)S greatly increased it. In addition, pretreatment with PD98059, an inhibitor of ERK kinase (MEK-1), significantly prevented NaHS from aggravating systemic inflammation in sepsis. In conclusion, the present study shows for the first time that H(2)S may regulate systemic inflammatory response in sepsis via ERK pathway.

  19. Isorhamnetin protects against cardiac hypertrophy through blocking PI3K-AKT pathway.

    PubMed

    Gao, Lu; Yao, Rui; Liu, Yuzhou; Wang, Zheng; Huang, Zhen; Du, Binbin; Zhang, Dianhong; Wu, Leiming; Xiao, Lili; Zhang, Yanzhou

    2017-02-07

    Isorhamnetin, a flavonoid compound extracted from the Chinese herb Hippophae rhamnoides L., is well known for its anti-inflammatory, anti-oxidative, anti-adipogenic, anti-proliferative, and anti-tumor activities. However, the role of isorhamnetin in cardiac hypertrophy has not been reported. The aims of the present study were to find whether isorhamnetin could alleviate cardiac hypertrophy and to define the underlying molecular mechanisms. Here, we investigated the effects of isorhamnetin (100 mg/kg/day) on cardiac hypertrophy induced by aortic banding in mice. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. Our data demonstrated that isorhamnetin could inhibit cardiac hypertrophy and fibrosis 8 weeks after aortic banding. The results further revealed that the effect of isorhamnetin on cardiac hypertrophy was mediated by blocking the activation of phosphatidylinositol 3-kinase-AKT signaling pathway. In vitro studies performed in neonatal rat cardiomyocytes confirmed that isorhamnetin could attenuate cardiomyocyte hypertrophy induced by angiotensin II, which was associated with phosphatidylinositol 3-kinase-AKT signaling pathway. In conclusion, these data indicate for the first time that isorhamnetin has protective potential for targeting cardiac hypertrophy by blocking the phosphatidylinositol 3-kinase-AKT signaling pathway. Thus, our study suggests that isorhamnetin may represent a potential therapeutic strategy for the treatment of cardiac hypertrophy and heart failure.

  20. Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

    SciTech Connect

    Kim, Sun Ae; Choi, Hyoung Chul

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK

  1. The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases

    PubMed Central

    Raker, Verena Katharina; Becker, Christian; Steinbrink, Kerstin

    2016-01-01

    Nucleotide signaling molecules contribute to the regulation of cellular pathways. In the immune system, cyclic adenosine monophosphate (cAMP) is well established as a potent regulator of innate and adaptive immune cell functions. Therapeutic strategies to interrupt or enhance cAMP generation or effects have immunoregulatory potential in autoimmune and inflammatory disorders. Here, we provide an overview of the cyclic AMP axis and its role as a regulator of immune functions and discuss the clinical and translational relevance of interventions with these processes. PMID:27065076

  2. Photorespiration: metabolic pathways and their role in stress protection.

    PubMed Central

    Wingler, A; Lea, P J; Quick, W P; Leegood, R C

    2000-01-01

    Photorespiration results from the oxygenase reaction catalysed by ribulose-1,5-bisphosphate carboxylase/oxygenase. In this reaction glycollate-2-phosphate is produced and subsequently metabolized in the photorespiratory pathway to form the Calvin cycle intermediate glycerate-3-phosphate. During this metabolic process, CO2 and NH3 are produced and ATP and reducing equivalents are consumed, thus making photorespiration a wasteful process. However, precisely because of this inefficiency, photorespiration could serve as an energy sink preventing the overreduction of the photosynthetic electron transport chain and photoinhibition, especially under stress conditions that lead to reduced rates of photosynthetic CO2 assimilation. Furthermore, photorespiration provides metabolites for other metabolic processes, e.g. glycine for the synthesis of glutathione, which is also involved in stress protection. In this review we describe the use of photorespiratory mutants to study the control and regulation of photorespiratory pathways. In addition, we discuss the possible role of photorespiration under stress conditions, such as drought, high salt concentrations and high light intensities encountered by alpine plants. PMID:11128005

  3. Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer

    PubMed Central

    Yadav, Vivek R.; Prasad, Sahdeo; Sung, Bokyung; Kannappan, Ramaswamy; Aggarwal, Bharat B.

    2010-01-01

    Traditional medicine and diet has served mankind through the ages for prevention and treatment of most chronic diseases. Mounting evidence suggests that chronic inflammation mediates most chronic diseases, including cancer. More than other transcription factors, nuclear factor-kappaB (NF-κB) and STAT3 have emerged as major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Thus, agents that can inhibit NF-κB and STAT3 activation pathways have the potential to both prevent and treat cancer. In this review, we examine the potential of one group of compounds called triterpenes, derived from traditional medicine and diet for their ability to suppress inflammatory pathways linked to tumorigenesis. These triterpenes include avicins, betulinic acid, boswellic acid, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, and withanolide. This review thus supports the famous adage of Hippocrates, “Let food be thy medicine and medicine be thy food”. PMID:22069560

  4. IGF-1, the Cross Road of the Nutritional, Inflammatory and Hormonal Pathways to Frailty

    PubMed Central

    Maggio, Marcello; De Vita, Francesca; Lauretani, Fulvio; Buttò, Valeria; Bondi, Giuliana; Cattabiani, Chiara; Nouvenne, Antonio; Meschi, Tiziana; Dall’Aglio, Elisabetta; Ceda, Gian Paolo

    2013-01-01

    The decline in functional capacity is a heterogeneous phenomenon in the elderly. An accelerated ageing determines a frail status. It results in an increased vulnerability to stressors for decreased physiological reserves. The early identification of a frail status is essential for preventing loss of functional capacity, and its clinical consequences. Frailty and mobility limitation result from an interplay of different pathways including multiple anabolic deficiency, inflammation, oxidative stress, and a poor nutritional status. However, the age-related decline in insulin-like growth factor 1 (IGF-1) bioactivity deserves special attention as it could represent the ideal crossroad of endocrine, inflammatory, and nutritional pathways to frailty. Several minerals, namely magnesium, selenium, and zinc, appear to be important determinants of IGF-1 bioactivity. This review aims to provide an overview of the potential usefulness of nutrients modulating IGF-1 as potential therapeutic targets in the prevention of mobility limitation occurring in frail older subjects. PMID:24152751

  5. The Th17 Pathway and Inflammatory Diseases of the Intestines, Lungs and Skin

    PubMed Central

    Weaver, Casey T.; Elson, Charles O.; Fouser, Lynette A.; Kolls, Jay K.

    2014-01-01

    The recent emergence of a new CD4+ T cell subset, Th17, has transformed our understanding of the pathogenetic basis of an increasing number of chronic immune-mediated diseases. Particularly in tissues that interface with the microbial environment — such as the intestinal and respiratory tracts, and skin — where most of the Th17 cells present in the body reside, dysregulated immunity to self, or the extended “self,” the diverse microbiota that normally colonize these tissues, can result in chronic inflammatory disease. In this review, we focus on recent advances in the biology of the Th17 pathway and genome-wide association studies (GWAS) implicating this immune pathway in human disease that are providing new insights into disease mechanisms in these and other tissues. PMID:23157335

  6. Lycopene protects pancreatic acinar cells against severe acute pancreatitis by abating the oxidative stress through JNK pathway.

    PubMed

    Lv, J C; Wang, G; Pan, S H; Bai, X W; Sun, B

    2015-02-01

    This study investigated the anti-oxidative and anti-inflammatory effects of lycopene on severe acute pancreatitis (SAP) in both in vivo and in vitro models. Utilizing a rat model, we found that lycopene administration protected against SAP, as indicated by the decreased levels of serum amylase and C-reactive protein. Pathological changes were alleviated by pretreatment with lycopene. The serum levels of tumor necrosis factor-α, interleukin-6, macrophage inflammatory protein-1α, and monocyte chemotactic protein-1 were decreased by lycopene. The decreased reactive oxygen species (ROS) content in the pancreatic tissues of the lycopene-treated group were indirectly evaluated by measuring the levels of myeloperoxidase, lipid peroxidase, and superoxide dismutase. Lycopene protected acinar cells against necrosis and apoptosis by relieving the mitochondrial and endoplasmic stress caused by ROS which was shown in electron microscopy and immunohistochemistry staining of active nuclear factor-κB p65. The protective effect was also observed in a simulated SAP model in a rat acinar cell line. ROS and apoptotic staining were compared between groups. Lycopene exerts protective effects against SAP in rats that may be related to its anti-inflammatory property through inhibiting the expression of damage-associated molecular patterns, and anti-oxidative property which can thus maintain cellular homeostasis and prevent the phosphorylation of JNK pathway.

  7. Effect of pulsed electromagnetic field on inflammatory pathway markers in RAW 264.7 murine macrophages.

    PubMed

    Ross, Christina L; Harrison, Benjamin S

    2013-01-01

    In the treatment of bacterial infections, antibiotics have proven to be very effective, but the way in which antibiotics are dosed can create a lag time between the administration of the drug and its absorption at the site of insult. The time it takes an antibiotic to reach therapeutic levels can often be significantly increased if the vascular system is compromized. Bacteria can multiply pending the delivery of the drug, therefore, developing treatments that can inhibit the inflammatory response while waiting for antibiotics to take effect could help prevent medical conditions such as septic shock. The aim of this study was to examine the effect of a pulsed electromagnetic field on the production of inflammatory markers tumor necrosis factor (TNF), transcription factor nuclear factor kappa B (NFkB), and the expression of the A20 (tumor necrosis factor-alpha-induced protein 3), in an inflamed-cell model. Lipopolysaccharide-challenged cells were exposed to a pulsed electromagnetic field at various frequencies in order to determine which, if any, frequency would affect the TNF-NFkB-A20 inflammatory response pathway. Our study revealed that cells continuously exposed to a pulsed electromagnetic field at 5 Hz demonstrated significant changes in the downregulation of TNF-α and NFkB and also showed a trend in the down regulation of A20, as compared with controls. This treatment could be beneficial in modulating the immune response, in the presence of infection.

  8. Effect of pulsed electromagnetic field on inflammatory pathway markers in RAW 264.7 murine macrophages

    PubMed Central

    Ross, Christina L; Harrison, Benjamin S

    2013-01-01

    In the treatment of bacterial infections, antibiotics have proven to be very effective, but the way in which antibiotics are dosed can create a lag time between the administration of the drug and its absorption at the site of insult. The time it takes an antibiotic to reach therapeutic levels can often be significantly increased if the vascular system is compromized. Bacteria can multiply pending the delivery of the drug, therefore, developing treatments that can inhibit the inflammatory response while waiting for antibiotics to take effect could help prevent medical conditions such as septic shock. The aim of this study was to examine the effect of a pulsed electromagnetic field on the production of inflammatory markers tumor necrosis factor (TNF), transcription factor nuclear factor kappa B (NFkB), and the expression of the A20 (tumor necrosis factor-alpha-induced protein 3), in an inflamed-cell model. Lipopolysaccharide-challenged cells were exposed to a pulsed electromagnetic field at various frequencies in order to determine which, if any, frequency would affect the TNF-NFkB-A20 inflammatory response pathway. Our study revealed that cells continuously exposed to a pulsed electromagnetic field at 5 Hz demonstrated significant changes in the downregulation of TNF-α and NFkB and also showed a trend in the down regulation of A20, as compared with controls. This treatment could be beneficial in modulating the immune response, in the presence of infection. PMID:23576877

  9. Cardiac dysfunction, mitochondrial architecture, energy production, and inflammatory pathways: Interrelated aspects in endotoxemia and sepsis.

    PubMed

    Alvarez, Silvia; Vico, Tamara; Vanasco, Virginia

    2016-12-01

    Septic patients with myocardial dysfunction have a 3-fold increase in mortality compared with patients without cardiovascular impairment, and usually show myocarditis, disruption of the contractile apparatus, increased amounts of interstitial collagen, and damaged mitochondria. The presence of nitric oxide and cytokines in cardiac tissue constitute the molecular markers and the intracellular messengers of inflammatory conditions in the heart due to the onset of sepsis and endotoxemia, derived from the nuclear factor-κB pathway activation and proinflammatory gene transcription. Sepsis occurs with an exacerbated inflammatory response that damages tissue mitochondria and impaired bioenergetic processes. The heart consumes 20-30 times its own weight in adenosine triphosphate every day, and 90% of this molecule is derived from mitochondrial oxidative phosphorylation. Cardiac energy management is comprised in sepsis and endotoxemia; both a deficit in energy production and alterations in the source of energy substrates are believed to be involved in impaired cardiac function. Although several hypotheses try to explain the molecular mechanisms underlying the complex condition of sepsis and endotoxemia, the current view is that these syndromes are the result of an intricate balance between prevailing levels of mitochondrial stress, biogenesis/autophagy signaling and mitochondria quality control processes, rather on a single factor. The aim of this review is to discuss current hypothesis of cardiac dysfunction related to energy metabolism and mitochondrial function in experimental models of sepsis and endotoxemia, and to introduce the importance of lipids (mainly cardiolipin) in the mechanism of cardiac energy mismanagement in these inflammatory conditions.

  10. Downregulating p22phox ameliorates inflammatory response in Angiotensin II-induced oxidative stress by regulating MAPK and NF-κB pathways in ARPE-19 cells

    PubMed Central

    Qiu, Yiguo; Tao, Lifei; Lei, Chunyan; Wang, Jiaming; Yang, Peizeng; Li, Qiuhong; Lei, Bo

    2015-01-01

    Oxidative stress and inflammation are two interrelated biological events implicated in the pathogenesis of many diseases. Reactive oxygen species (ROS) produced under oxidative stress play a key role in pathological conditions. Inhibition of p22phox, an indispensable component of the NADPH oxidase (NOX) complex comprising the main source of ROS, plays a protective role in many ocular conditions by inhibiting the activation of NOXs and the generation of ROS. However, little is understood regarding the role of p22phox in oxidative stress-related inflammation in the eye. We used a p22phox small interfering RNA (siRNA) to transfect the retinal pigment epithelium (RPE)-derived cell line ARPE-19, and human primary RPE (hRPE) cells, then stimulated with Ang II. We observed a potent anti-inflammatory effect and studied the underlying mechanism. Downregulating p22phox resulted in decreased ROS generation, a reduction of NOXs (NOX1, 2, 4) and a decrease in inflammatory cytokine. In addition, p22phox downregulation reduced the activation of the MAPK and NF-κB signaling pathways. We conclude that inhibition of p22phox has an anti-inflammatory effect in Ang II-induced oxidative stress. Suppressing the MAPK and NF-κB pathways is involved in this protective effect. These results suggest that p22phox may provide a promising therapeutic target for oxidative stress-induced ocular inflammation PMID:26415877

  11. Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds.

    PubMed

    Bisht, Kavita; Wagner, Karl-Heinz; Bulmer, Andrew C

    2010-11-28

    Numerous dietary compounds, ubiquitous in fruits, vegetables and spices have been isolated and evaluated during recent years for their therapeutic potential. These compounds include flavonoid and non-flavonoid polyphenols, which describe beneficial effects against a variety of ailments. The notion that these plant products have health promoting effects emerged because their intake was related to a reduced incidence of cancer, cardiovascular, neurological, respiratory, and age-related diseases. Exposure of the body to a stressful environment challenges cell survival and increases the risk of chronic disease developing. The polyphenols afford protection against various stress-induced toxicities through modulating intercellular cascades which inhibit inflammatory molecule synthesis, the formation of free radicals, nuclear damage and induce antioxidant enzyme expression. These responses have the potential to increase life expectancy. The present review article focuses on curcumin, resveratrol, and flavonoids and seeks to summarize their anti-inflammatory, cytoprotective and DNA-protective properties.

  12. 15-Oxoeicosatetraenoic acid is a 15-hydroxyprostaglandin dehydrogenase-derived electrophilic mediator of inflammatory signaling pathways.

    PubMed

    Snyder, Nathaniel W; Golin-Bisello, Franca; Gao, Yang; Blair, Ian A; Freeman, Bruce A; Wendell, Stacy Gelhaus

    2015-06-05

    Bioactive lipids govern cellular homeostasis and pathogenic inflammatory processes. Current dogma holds that bioactive lipids, such as prostaglandins and lipoxins, are inactivated by 15-hydroxyprostaglandin dehydrogenase (15PGDH). In contrast, the present results reveal that catabolic "inactivation" of hydroxylated polyunsaturated fatty acids (PUFAs) yields electrophilic α,β-unsaturated ketone derivatives. These endogenously produced species are chemically reactive signaling mediators that induce tissue protective events. Electrophilic fatty acids diversify the proteome through post-translational alkylation of nucleophilic cysteines in key transcriptional regulatory proteins and enzymes that govern cellular metabolic and inflammatory homeostasis. 15PGDH regulates these processes as it is responsible for the formation of numerous electrophilic fatty acids including the arachidonic acid metabolite, 15-oxoeicosatetraenoic acid (15-oxoETE). Herein, the role of 15-oxoETE in regulating signaling responses is reported. In cell cultures, 15-oxoETE activates Nrf2-regulated antioxidant responses (AR) and inhibits NF-κB-mediated pro-inflammatory responses via IKKβ inhibition. Inhibition of glutathione S-transferases using ethacrynic acid incrementally increased the signaling capacity of 15-oxoETE by decreasing 15-oxoETE-GSH adduct formation. This work demonstrates that 15PGDH plays a role in the regulation of cell and tissue homeostasis via the production of electrophilic fatty acid signaling mediators.

  13. ACTIVATION OF COMMON ANTIVIRAL PATHWAYS CAN POTENTIATE INFLAMMATORY RESPONSES TO SEPTIC SHOCK

    PubMed Central

    Doughty, Lesley A.; Carlton, Stacey; Galen, Benjamin; Cooma-Ramberan, Indranie; Chung, Chung-Shiang; Ayala, Alfred

    2006-01-01

    Induction of the antiviral cytokine interferon α/β (IFN-α/β) is common in many viral infections. The impact of ongoing antiviral responses on subsequent bacterial infection is not well understood. In human disease, bacterial superinfection complicating a viral infection can result in significant morbidity and mortality. We injected mice with polyinosinic-polycytidylic (PIC) acid, a TLR3 ligand and known IFN-α/β inducer as well as nuclear factor κB (NF-κB) activator to simulate very early antiviral pathways. We then challenged mice with an in vivo septic shock model characterized by slowly evolving bacterial infection to simulate bacterial superinfection early during a viral infection. Our data demonstrated robust induction of IFN-α in serum within 24 h of PIC injection with IFN-α/β–dependent major histocompatibility antigen class II up-regulation on peritoneal macrophages. PIC pretreatment before septic shock resulted in augmented tumor necrosis factor alpha and interleukins 6 and 10 and heightened lethality compared with septic shock alone. Intact IFN-α/β signaling was necessary for augmentation of the inflammatory response to in vivo septic shock and to both TLR2 and TLR4 agonists in vitro. To assess the NF-κB contribution to PIC-modulated inflammatory responses to septic shock, we treated with parthenolide an NF-κB inhibitor before PIC and septic shock. Parthenolide did not inhibit IFN-α induction by PIC. Inhibition of NF-κB by parthenolide did reduce IFN-α–mediated potentiation of the cytokine response and lethality from septic shock. Our data demonstrate that pathways activated early during many viral infections can have a detrimental impact on the outcome of subsequent bacterial infection. These pathways may be critical to understanding the heightened morbidity and mortality from bacterial superinfection after viral infection in human disease. PMID:16878028

  14. Polymorphisms in key pulmonary inflammatory pathways and the development of acute respiratory distress syndrome

    PubMed Central

    Brown, Samuel M.; Grissom, Colin K.; Rondina, Matthew T.; Hoidal, John R.; Scholand, Mary Beth; Wolff, Roger K.; Morris, Alan H.; Paine, Robert

    2015-01-01

    Purpose/Aim Acute Respiratory Distress Syndrome (ARDS) is an important clinical and public health problem. Why some at-risk individuals develop ARDS and others do not is unclear but may be related to differences in inflammatory and cell signaling systems. The Receptor for Advanced Glycation Endproducts (RAGE) and Granulocyte-Monocyte Stimulating Factor (GM-CSF) pathways have recently been implicated in pulmonary pathophysiology; whether genetic variation within these pathways contributes to ARDS risk or outcome is unknown. Materials and Methods We studied 842 patients from three centers in Utah and 14 non-Utah ARDS Network centers. We studied patients at risk for ARDS and patients with ARDS to determine whether Single Nucleotide Polymorphisms (SNPs) in the RAGE and GM-CSF pathways were associated with development of ARDS. We studied 29 SNPs in 5 genes within the two pathways and controlled for age, sepsis as ARDS risk factor, and severity of illness, while targeting a false discovery rate of ≤5%. In a secondary analysis we evaluated associations with mortality. Results Of 842 patients, 690 had ARDS, and 152 were at-risk. Sepsis was the risk factor for ARDS in 250 (30%) patients. When controlling for age, APACHE III score, sepsis as risk factor, and multiple comparisons, no SNPs were significantly associated with ARDS. In a secondary analysis, only rs743564 in CSF2 approached significance with regard to mortality (OR 2.17, unadjusted p = 0.005, adjusted p = 0.15). Conclusions Candidate SNPs within 5 genes in the RAGE and GM-CSF pathways were not significantly associated with development of ARDS in this multi-centric cohort. PMID:25513711

  15. Anti-inflammatory and protective effects of 2-methacryloyloxyethyl phosphorylcholine polymer on oral epithelial cells.

    PubMed

    Yumoto, Hiromichi; Hirota, Katsuhiko; Hirao, Kouji; Miyazaki, Tsuyoshi; Yamamoto, Nobuyuki; Miyamoto, Koji; Murakami, Keiji; Fujiwara, Natsumi; Matsuo, Takashi; Miyake, Yoichiro

    2015-02-01

    Periodontitis is a chronic inflammatory disease initiated by a microbial biofilm formed in the periodontal pocket. Gingival epithelium plays important roles as the first physical barrier to bacterial invasion and in orchestrating the innate immune reaction via toll-like receptors (TLRs), which recognize various bacterial products, and maintaining its function. Newly developed oral care products to inhibit bacterial adherence, subsequent inflammatory reaction and protect the gingival epithelium are expected. We previously reported that 2-methacryloyloxyethyl phosphorylcholine (MPC)-polymer coating decreased bacterial adhesion to human oral keratinocytes, RT-7, and mouth-rinsing with MPC-polymer inhibited the increase of oral bacteria. In this study, regarding the possibility of MPC-polymer application for preventing the adherence of periodontal pathogen, subsequent inflammatory reaction and protection of gingival epithelium, we examined the effects of MPC-polymer on the adherence of Porphyromonas gingivalis, major periodontitis-related pathogen, and TLR2 ligand to RT-7 and subsequent interleukin (IL)-8 production. MPC-polymer treatment significantly reduced P. gingivalis adherence by 44% and TLR2-mediated IL-8 production by blocking the binding of its specific-ligand in a concentration-dependent manner. Furthermore, MPC-polymer pretreatment protected RT-7 from injury by chemical irritants, cetylpyridinium chloride. These findings suggest that MPC-polymer is potentially useful for oral care to prevent oral infection and to maintain oral epithelial function.

  16. Chemopreventive action of non-steroidal anti-inflammatory drugs on the inflammatory pathways in colon cancer.

    PubMed

    Ghanghas, Preety; Jain, Shelly; Rana, Chandan; Sanyal, S N

    2016-03-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development by cellular proliferation and by promoting apoptosis. Inflammation is principal cause of colon carcinogenesis. A missing link between inflammation and cancer could be the activation of NF-κB, which is a hallmark of inflammatory response, and is commonly detected in malignant tumors. Therefore, targeting pro-inflammatory cyclooxygenase enzymes and transcription factors will be profitable as a mechanism to inhibit tumor growth. In the present study, we have studied the role of various pro-inflammatory enzymes and transcription factors in the development of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer and also observed the role of three NSAIDs, viz., Celecoxib, Etoricoxib and Diclofenac. Carcinogenic changes were observed in morphological and histopathological studies, whereas protein regulations of various biomolecules were identified by immunofluorescence analysis. Apoptotic studies was done by TUNEL assay and Hoechst/PI co-staining of the isolated colonocytes. It was found that DMH-treated animals were having an over-expression of pro-inflammatory enzymes, aberrant nuclear localization of activated cell survival transcription factor, NF-κB and suppression of anti-inflammatory transcription factor PPAR-γ, thereby suggesting a marked role of inflammation in the tumor progression. However, co-administration of NSAIDs has significantly reduced the inflammatory potential of the growing neoplasm.

  17. VEGF and LPS synergistically silence inflammatory response to Plasmodium berghei infection and protect against cerebral malaria

    PubMed Central

    Canavese, Miriam; Dottorini, Tania

    2015-01-01

    Malaria infection induces, alongside endothelial damage and obstruction hypoxia, a potent inflammatory response similar to that observed in other systemic diseases caused by bacteria and viruses. Accordingly, it is increasingly recognised that cerebral malaria (CM), the most severe and life threatening complication of Plasmodium falciparum infection, bears a number of similarities with sepsis, an often fatal condition associated with a misregulated inflammatory response triggered by systemic microbial infections. Using a Plasmodium berghei ANKA mouse model, histology, immunohistochemistry and gene expression analysis, we showed that lipopolysaccharide S (LPS), at doses that normally induce inflammation tolerance, protects P. berghei infected mice against experimental CM (ECM). Vascular endothelial growth factor (VEGF) preserved blood vessel integrity, and the combination with LPS resulted in a strong synergistic effect. Treated mice did not develop ECM, showed a prolonged survival and failed to develop a significant inflammatory response and splenomegaly in spite of normal parasite loads. The protective role of VEGF was further confirmed by the observation that the treatment of P. berghei infected C57BL/6 and Balb/c mice with the VEGF receptor inhibitor axitinib exacerbates cerebral pathology and aggravates the course of infection. Infected mice treated with VEGF and LPS showed an induction of the anti-inflammatory genes Nrf2 and HO-1 and a suppression to basal levels of the genes IFN-γ and TNF-α. These results provide the rationale for developing new therapeutic approaches against CM and shed new light on how the inflammatory process can be modulated in the presence of systemic infectious diseases. PMID:26392042

  18. Vitamin D receptor pathway is required for probiotic protection in colitis.

    PubMed

    Wu, Shaoping; Yoon, Sonia; Zhang, Yong-Guo; Lu, Rong; Xia, Yinglin; Wan, Jiandi; Petrof, Elaine O; Claud, Erika C; Chen, Di; Sun, Jun

    2015-09-01

    Low expression of vitamin D receptor (VDR) and dysfunction of vitamin D/VDR signaling are reported in patients with inflammatory bowel disease (IBD); therefore, restoration of VDR function to control inflammation in IBD is desirable. Probiotics have been used in the treatment of IBD. However, the role of probiotics in the modulation of VDR signaling to effectively reduce inflammation is unknown. We identified a novel role of probiotics in activating VDR activity, thus inhibiting inflammation, using cell models and VDR knockout mice. We found that the probiotics Lactobacillus rhamnosus strain GG (LGG) and Lactobacillus plantarum (LP) increased VDR protein expression in both mouse and human intestinal epithelial cells. Using the VDR luciferase reporter vector, we detected increased transcriptional activity of VDR after probiotic treatment. Probiotics increased the expression of the VDR target genes, such as antimicrobial peptide cathelicidin, at the transcriptional level. Furthermore, the role of probiotics in regulating VDR signaling was tested in vivo using a Salmonella-colitis model in VDR knockout mice. Probiotic treatment conferred physiological and histologic protection from Salmonella-induced colitis in VDR(+/+) mice, whereas probiotics had no effects in the VDR(-/-) mice. Probiotic treatment also enhanced numbers of Paneth cells, which secrete AMPs for host defense. These data indicate that the VDR pathway is required for probiotic protection in colitis. Understanding how probiotics enhance VDR signaling and inhibit inflammation will allow probiotics to be used effectively, resulting in innovative approaches to the prevention and treatment of chronic inflammation.

  19. Dexmedetomidine controls systemic cytokine levels through the cholinergic anti-inflammatory pathway.

    PubMed

    Xiang, Hui; Hu, Bo; Li, Zhifeng; Li, Jianguo

    2014-10-01

    Previous studies have shown that dexmedetomidine exerted anti-inflammatory effect on several animal models with inflammation, but the mechanism is not clear. This study intends to elucidate the anti-inflammatory mechanism of dexmedetomidine through the cholinergic anti-inflammatory pathway. To investigate this therapeutic potential of dexmedetomidine, a murine model of endotoxemia was established induced by lipopolysaccharide (LPS). Animals were assigned to one of four protocols. Protocol one: animals were randomly assigned to control group, dexmedetomidine group, and sterile saline group (n=20 each), and these animals were used for survival analysis. The survival rate was assessed up to 120 h after endotoxin injection. Protocol two: animals were randomly assigned to one of four groups (n=16 each): group 1 (group Saline), treated with sterile saline 15 min prior to endotoxin treatment (10 mg kg(-1) over 2 min); group 2 (group Dex), treated with dexmedetomidine 15 min prior to endotoxin treatment; group 3 (group αBGT+Dex), treated with alpha-7 nicotinic acetylcholine receptors (α7nAChR) antagonist alpha-bungarotoxin (αBGT, 1 μg/kg) 15 min prior to dexmedetomidine treatment; group 4 (group saline+Dex), treated with equivalent sterile saline 15 min prior to dexmedetomidine treatment. Protocol three: animals were randomly assigned to one of two groups (n=16 each): vagotomy group (group VNX+Dex), right cervical vagus nerve was exposed and transected; sham-operated group (group SHAM+Dex), the cervical vagus nerve was visualized, but was neither isolated from the surrounding tissues nor transected. Protocol four: animals were treated with dexmedetomidine (40 μg/kg) and sterile saline to observe the discharge activity of cervical vagus nerves by using BL-420F data acquisition and analysis system (n=16 each). In the survival analysis groups, the survival rate of dexmedetomidine group was significantly higher than that of the endotoxemia group (65 versus 25 %, P<0

  20. Actual concepts in rhinosinusitis: a review of clinical presentations, inflammatory pathways, cytokine profiles, remodeling, and management.

    PubMed

    Eloy, Philippe; Poirrier, Anne Lise; De Dorlodot, Clotilde; Van Zele, Thibaut; Watelet, Jean Baptiste; Bertrand, Bernard

    2011-04-01

    Rhinosinusitis (RS) is a heterogeneous group of diseases. It is a significant and increasing health problem that affects about 15% of the population in Western countries. It has a substantial impact on patients' health-related quality of life and daily functioning and represents a huge financial burden to society and the health care system as a result of the direct and indirect costs. In addition, RS is not well-understood, and little is known about the etiology and pathophysiology. In the past decade, many papers have been published that have changed our understanding of RS. RS is commonly classified into acute and chronic RS based on symptom duration. In acute RS, an inflammatory reaction initiated by a viral infection characterizes most uncomplicated, mild to moderate cases. Therefore, the first line of treatment for these cases are intranasal steroids and not antibiotics. In severe and complicated cases, antibiotics combined with topical steroids remain the treatment of choice. On the other hand, chronic RS is actually subdivided into two distinct entities (chronic rhinosinusitis with and without polyps), as growing evidence indicates that these entities have specific inflammatory pathways and cytokine profiles. The authors review recent data regarding the clinical presentations, cytokine profiles, tissue remodeling, and modalities of treatment for each form of RS.

  1. Protein-kinase inhibitors: A new treatment pathway for autoimmune and inflammatory diseases?

    PubMed

    Hernández-Flórez, Diana; Valor, Lara

    2016-01-01

    Although advances in biological medicine have seen significant progress in the treatment of autoimmune and inflammatory disease, many patients do not experience a satisfactory response. Hence, there are two challenges facing the medical research community. The first is to continue development in the field of existing biological therapies, such as monoclonal antibodies. The second is to open new frontiers of research and explore treatment alternatives for non-responders to other therapies. Attention has increasingly turned to the therapeutic potential of small molecule weight kinase inhibitors (SMKIs), currently used extensively in oncology and haematology. Initial research into the therapeutic value of SMKIs for autoimmune and inflammatory diseases has been encouraging. SMKIs are taken orally, which reduces cost for the health provider, and could increase compliance for the patient. This is why research is now focusing increasingly on SMKIs as a new generation line of treatment in these diseases. Tofacitinib, an inhibitor of Janus-kinase, is currently the only drug approved for the treatment of rheumatoid arthritis by FDA. However, much more needs to be done to understand the intracellular signalling pathways and how these might affect disease progression before solid conclusions can be drawn.

  2. Hydrogen sulfide attenuates lipopolysaccharide-induced cognitive impairment: a pro-inflammatory pathway in rats.

    PubMed

    Gong, Qi-Hai; Wang, Qian; Pan, Li-Long; Liu, Xin-Hua; Huang, Hui; Zhu, Yi-Zhun

    2010-07-01

    The present study investigated the effect of sodium hydrosulfide (NaHS), a H(2)S donor, on cognitive impairment and neuroinflammatory changes induced by bilateral intracerebroventricular injections of LPS at a dose of 10mug/rat. Rats received 5mg/kg NaHS or volume-matched vehicle administration by intraperitoneal injection 3days before LPS injection then for 9days once daily. Morris water maze was used to detect the cognitive function. Compared to the sham-treated rats, LPS injection significantly prolonged the mean escape latency in the navigation test (P<0.05) and shortened the adjusted escape latency by approximately 30% (P<0.05). Meanwhile, LPS injection decreased H(2)S level but increased pro-inflammatory mediators (i.e., TNF-alpha, TNFR1, degradation of IkappaB-alpha and thereafter activation of NF-kappaB) in hippocampus. However, these effects of LPS were significantly ameliorated with NaHS treatment (P<0.05 vs vehicle-treated group). The present data suggest that H(2)S attenuates LPS-induced cognitive impairment through reducing the overproduction of pro-inflammatory mediators via inhibition of NF-kappaB pathways in rats. This study sets the stage for exploring a novel H(2)S releasing agent for preventing or retarding the development or progression of neurological disorders such as Alzheimer's disease.

  3. Exploring New Inflammatory Biomarkers and Pathways during LPS-Induced M1 Polarization.

    PubMed

    Cunha, Carolina; Gomes, Cátia; Vaz, Ana Rita; Brites, Dora

    2016-01-01

    Identification of mediators triggering microglia activation and transference of noncoding microRNA (miRNA) into exosomes are critical to dissect the mechanisms underlying neurodegeneration. We used lipopolysaccharide- (LPS-) induced N9 microglia activation to explore new biomarkers/signaling pathways and to identify inflammatory miRNA (inflamma-miR) in cells and their derived exosomes. Upregulation of iNOS and MHC-II (M1-markers) and downregulation of arginase 1, FIZZ1 (M2-markers), and CX3CR1 (M0/M2 polarization) confirmed the switch of N9 LPS-treated cells into the M1 phenotype, as described for macrophages/microglia. Cells showed increased proliferation, activated TLR4/TLR2/NF-κB pathway, and enhanced phagocytosis, further corroborated by upregulated MFG-E8. We found NLRP3-inflammasome activation in these cells, probably accounting for the increased extracellular content of the cytokine HMGB1 and of the MMP-9 we have observed. We demonstrate for the first time that the inflamma-miR profiling (upregulated miR-155 and miR-146a plus downregulated miR-124) in M1 polarized N9 cells, noticed by others in activated macrophages/microglia, was replicated in their derived exosomes, likely regulating the inflammatory response of recipient cells and dissemination processes. Data show that LPS-treated N9 cells behave like M1 polarized microglia/macrophages, while providing new targets for drug discovery. In particular, the study yields novel insights into the exosomal circulating miRNA during neuroinflammation important for emerging therapeutic approaches targeting microglia activation.

  4. Exploring New Inflammatory Biomarkers and Pathways during LPS-Induced M1 Polarization

    PubMed Central

    2016-01-01

    Identification of mediators triggering microglia activation and transference of noncoding microRNA (miRNA) into exosomes are critical to dissect the mechanisms underlying neurodegeneration. We used lipopolysaccharide- (LPS-) induced N9 microglia activation to explore new biomarkers/signaling pathways and to identify inflammatory miRNA (inflamma-miR) in cells and their derived exosomes. Upregulation of iNOS and MHC-II (M1-markers) and downregulation of arginase 1, FIZZ1 (M2-markers), and CX3CR1 (M0/M2 polarization) confirmed the switch of N9 LPS-treated cells into the M1 phenotype, as described for macrophages/microglia. Cells showed increased proliferation, activated TLR4/TLR2/NF-κB pathway, and enhanced phagocytosis, further corroborated by upregulated MFG-E8. We found NLRP3-inflammasome activation in these cells, probably accounting for the increased extracellular content of the cytokine HMGB1 and of the MMP-9 we have observed. We demonstrate for the first time that the inflamma-miR profiling (upregulated miR-155 and miR-146a plus downregulated miR-124) in M1 polarized N9 cells, noticed by others in activated macrophages/microglia, was replicated in their derived exosomes, likely regulating the inflammatory response of recipient cells and dissemination processes. Data show that LPS-treated N9 cells behave like M1 polarized microglia/macrophages, while providing new targets for drug discovery. In particular, the study yields novel insights into the exosomal circulating miRNA during neuroinflammation important for emerging therapeutic approaches targeting microglia activation. PMID:28096568

  5. Dehydroepiandrosterone Protects Endothelial Cells against Inflammatory Events Induced by Urban Particulate Matter and Titanium Dioxide Nanoparticles

    PubMed Central

    Huerta-García, Elizabeth; Montiél-Dávalos, Angélica; Alfaro-Moreno, Ernesto; Gutiérrez-Iglesias, Gisela; López-Marure, Rebeca

    2013-01-01

    Particulate matter (PM) and nanoparticles (NPs) induce activation and dysfunction of endothelial cells characterized by inhibition of proliferation, increase of adhesion and adhesion molecules expression, increase of ROS production, and death. DHEA has shown anti-inflammatory and antioxidant properties in HUVEC activated with proinflammatory agents. We evaluated if DHEA could protect against some inflammatory events produced by PM10 and TiO2 NPs in HUVEC. Adhesion was evaluated by a coculture with U937 cells, proliferation by crystal violet staining, and oxidative stress through DCFDA and Griess reagent. PM10 and TiO2 NPs induced adhesion and oxidative stress and inhibited proliferation of HUVEC; however, when particles were added in combination with DHEA, the effects previously observed were abolished independently from the tested concentrations and the time of addition of DHEA to the cultures. These results indicate that DHEA exerts significant anti-inflammatory and antioxidative effects on the damage induced by particles in HUVEC, suggesting that DHEA could be useful to counteract the harmful effects and inflammatory diseases induced by PM and NPs. PMID:23484113

  6. Protective effect of taraxasterol against rheumatoid arthritis by the modulation of inflammatory responses in mice.

    PubMed

    Jiang, Shu-Hua; Ping, Li-Feng; Sun, Feng-Yan; Wang, Xiao-Lei; Sun, Zhi-Juan

    2016-12-01

    Taraxasterol is an effective component of dandelion that has anti-inflammatory effects in vivo and in vitro. The present study was performed to explore whether taraxasterol exhibits a protective effect against rheumatoid arthritis through the modulation of inflammatory responses in mice. Eight-week-old CCR9-deficient mice were injected with a collagen II monoclonal antibody cocktail to create a rheumatoid arthritis model. In the experimental group, arthritic model mice were treated with 10 mg/kg taraxasterol once per day for 5 days. Treatment with taraxasterol significantly increased the pain thresholds and reduced the clinical arthritic scores of the mice in the experimental group compared with those of the model group. Furthermore, treatment with taraxasterol significantly suppressed tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and nuclear factor-κB protein expression levels compared with those in the rheumatoid arthritis model mice. Taraxasterol treatment also significantly reduced nitric oxide, prostaglandin E2 and cyclooxygenase-2 levels compared with those in the rheumatoid arthritis model group. These observations indicate that the protective effect of taraxasterol against rheumatoid arthritis is mediated via the modulation of inflammatory responses in mice.

  7. Protective effect of taraxasterol against rheumatoid arthritis by the modulation of inflammatory responses in mice

    PubMed Central

    Jiang, Shu-Hua; Ping, Li-Feng; Sun, Feng-Yan; Wang, Xiao-Lei; Sun, Zhi-Juan

    2016-01-01

    Taraxasterol is an effective component of dandelion that has anti-inflammatory effects in vivo and in vitro. The present study was performed to explore whether taraxasterol exhibits a protective effect against rheumatoid arthritis through the modulation of inflammatory responses in mice. Eight-week-old CCR9-deficient mice were injected with a collagen II monoclonal antibody cocktail to create a rheumatoid arthritis model. In the experimental group, arthritic model mice were treated with 10 mg/kg taraxasterol once per day for 5 days. Treatment with taraxasterol significantly increased the pain thresholds and reduced the clinical arthritic scores of the mice in the experimental group compared with those of the model group. Furthermore, treatment with taraxasterol significantly suppressed tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and nuclear factor-κB protein expression levels compared with those in the rheumatoid arthritis model mice. Taraxasterol treatment also significantly reduced nitric oxide, prostaglandin E2 and cyclooxygenase-2 levels compared with those in the rheumatoid arthritis model group. These observations indicate that the protective effect of taraxasterol against rheumatoid arthritis is mediated via the modulation of inflammatory responses in mice. PMID:28101182

  8. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

    PubMed Central

    Morris, Gerwyn; Maes, Michael

    2014-01-01

    Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) has been classified as a disease of the central nervous system by the WHO since 1969. Many patients carrying this diagnosis do demonstrate an almost bewildering array of biological abnormalities particularly the presence of oxidative and nitrosative stress (O&NS) and a chronically activated innate immune system. The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS. Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels. Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism (e.g. compromised ATP production) and dysfunctional intracellular signaling pathways. The interplay between all of these factors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory and autoimmune pathways which may sustain the disease. PMID:24669210

  9. Cholesterol Crystals Induce Inflammatory Cytokines Expression in nARPE-19 Cells by Activating the NF-κB Pathway

    PubMed Central

    Hu, Yijun; Lin, Haijiang; Dib, Bernard; Atik, Alp; Bouzika, Peggy; Lin, Christopher; Yan, Yueran; Tang, Shibo; Miller, Joan W.; Vavvas, Demetrios G.

    2015-01-01

    Purpose To investigate the expression of inflammatory cytokines in ARPE-19 cells after stimulation with cholesterol crystals. Methods APRE-19 cells were cultured, primed with IL-1α, and treated with cholesterol crystals under different concentrations. Inflammatory cytokines (mature-IL-1β, IL-6, and IL-8) in supernatant and inflammatory cytokines (pro-IL-1β, IL-18) in cell lysate were detected by western blot. The NF-κB pathway inhibitor BAY 11-7082 was used to determine the pathway of cytokine expression. Results Cholesterol crystals did not induce the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, but did increase pro-IL-1β expression in ARPE-19 cells. Cholesterol crystals increased pro-IL-1β expression by activating the NF-κB pathway. Cholesterol crystal activation of the NF-κB pathway also leads to increased IL-6 and IL-8 expression. Conclusion Cholesterol crystals can induce inflammatory cytokine expression in ARPE-19 cells by activating the NF-κB pathway. PMID:25091484

  10. Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharide-induced lipolysis in human adipocytes.

    PubMed

    Grisouard, Jean; Bouillet, Elisa; Timper, Katharina; Radimerski, Tanja; Dembinski, Kaethi; Frey, Daniel M; Peterli, Ralph; Zulewski, Henryk; Keller, Ulrich; Müller, Beat; Christ-Crain, Mirjam

    2012-02-01

    High fat diet-induced endotoxaemia triggers low-grade inflammation and lipid release from adipose tissue. This study aims to unravel the cellular mechanisms leading to the lipopolysaccharide (LPS) effects in human adipocytes. Subcutaneous pre-adipocytes surgically isolated from patients were differentiated into mature adipocytes in vitro. Lipolysis was assessed by measurement of glycerol release and mRNA expression of pro-inflammatory cytokines were evaluated by real-time PCR. Treatment with LPS for 24 h induced a dose-dependent increase in interleukin (IL)-6 and IL-8 mRNA expression. At 1 µg/ml LPS, IL-6 and IL-8 were induced to 19.5 ± 1.8-fold and 662.7 ± 91.5-fold (P < 0.01 vs basal), respectively. From 100 ng/ml to 1 µg/ml, LPS-induced lipolysis increased to a plateau of 3.1-fold above basal level (P < 0.001 vs basal). Co-treatment with inhibitors of inhibitory kappa B kinase kinase beta (IKKβ) or NF-κB inhibited LPS-induced glycerol release. Co-treatment with the protein kinase A (PKA) inhibitor H-89, the lipase inhibitor orlistat or the hormone-sensitive lipase (HSL) inhibitor CAY10499 abolished the lipolytic effects of LPS. Co-treatment with the MAPK inhibitor, U0126 also reduced LPS-induced glycerol release. Inhibition of lipolysis by orlistat or CAY10499 reduced LPS-induced IL-6 and IL-8 mRNA expression. Induction of lipolysis by the synthetic catecholamine isoproterenol or the phosphodiesterase type III inhibitor milrinone did not alter basal IL-6 and IL-8 mRNA expression after 24 treatments whereas these compounds enhanced LPS-induced IL-6 and IL-8 mRNA expression. Both the inflammatory IKKβ/NF-κB pathway and the lipolytic PKA/HSL pathways mediate LPS-induced lipolysis. In turn, LPS-induced lipolysis reinforces the expression of pro-inflammatory cytokines and, thereby, triggers its own lipolytic activity.

  11. Puerarin protects brain tissue against cerebral ischemia/reperfusion injury by inhibiting the inflammatory response

    PubMed Central

    Zhou, Feng; Wang, Liang; Liu, Panpan; Hu, Weiwei; Zhu, Xiangdong; Shen, Hong; Yao, Yuanyuan

    2014-01-01

    Puerarin, a traditional Chinese medicine, exerts a powerful neuroprotective effect in cerebral ischemia/reperfusion injury, but its mechanism is unknown. Here, we established rat models of middle cerebral artery ischemia/reperfusion injury using the suture method. Puerarin (100 mg/kg) was administered intraperitoneally 30 minutes before middle cerebral artery occlusion and 8 hours after reperfusion. Twenty-four hours after reperfusion, we found that puerarin significantly improved neurological deficit, reduced infarct size and brain water content, and notably diminished the expression of Toll-like receptor-4, myeloid differentiation factor 88, nuclear factor kappa B and tumor necrosis factor-α in the ischemic region. These data indicate that puerarin exerts an anti-inflammatory protective effect on brain tissue with ischemia/reperfusion damage by downregulating the expression of multiple inflammatory factors. PMID:25657724

  12. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease

    PubMed Central

    Scaldaferri, Franco; Sans, Miquel; Vetrano, Stefania; Graziani, Cristina; De Cristofaro, Raimondo; Gerlitz, Bruce; Repici, Alessandro; Arena, Vincenzo; Malesci, Alberto; Panes, Julian; Grinnell, Brian W.; Danese, Silvio

    2007-01-01

    Endothelial protein C receptor (EPCR) and thrombomodulin (TM) are expressed at high levels in the resting microvasculature and convert protein C (PC) into its activated form, which is a potent anticoagulant and antiinflammatory molecule. Here we provide evidence that in Crohn disease (CD) and ulcerative colitis (UC), the 2 major forms of inflammatory bowel disease (IBD), there was loss of expression of endothelial EPCR and TM, which in turns caused impairment of PC activation by the inflamed mucosal microvasculature. In isolated human intestinal endothelial cells, administration of recombinant activated PC had a potent antiinflammatory effect, as demonstrated by downregulated cytokine-dependent cell adhesion molecule expression and chemokine production as well as inhibited leukocyte adhesion. In vivo, administration of activated PC was therapeutically effective in ameliorating experimental colitis as evidenced by reduced weight loss, disease activity index, and histological colitis scores as well as inhibited leukocyte adhesion to the inflamed intestinal vessels. The results suggest that the PC pathway represents a new system crucially involved in governing intestinal homeostasis mediated by the mucosal microvasculature. Restoring the PC pathway may represent a new therapeutic approach to suppress intestinal inflammation in IBD. PMID:17557119

  13. Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response.

    PubMed

    Powell, Timothy R; Schalkwyk, Leonard C; Heffernan, Andrew L; Breen, Gerome; Lawrence, Timothy; Price, Tom; Farmer, Anne E; Aitchison, Katherine J; Craig, Ian W; Danese, Andrea; Lewis, Cathryn; McGuffin, Peter; Uher, Rudolf; Tansey, Katherine E; D'Souza, Ursula M

    2013-09-01

    Converging evidence suggests that the activation of the inflammatory cytokine pathway is important in the pathophysiology of unipolar depression. Antidepressants have anti-inflammatory properties and evidence suggests that inter-individual variability in response to antidepressants may reflect genetic differences in the inflammatory cytokine pathway. In particular, protein levels of Tumor Necrosis Factor (TNF) and the SNPs rs1126757 in interleukin-11 (IL11), and rs7801617 in interleukin-6 (IL6), have previously been implicated in the clinical response to the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram. This study investigated the transcription of TNF, IL11 and IL6 as well as genes in the wider inflammatory cytokine pathway both at baseline and after escitalopram treatment in depressed patients who were either clinical "responders" (n=25) or "non-responders" (n=21). Samples were obtained as a subset of the Genome-Based Therapeutic Drugs for Depression (GENDEP) project and response status is based on changes in the Montgomery-Asberg Depression Rating Scores over a 12 wk treatment period. Binary logistic regressions revealed significant expression differences at baseline between responders and non-responders in TNF, and after escitalopram treatment in TNF and IL11. Differences in IL11 after treatment were found to be driven by drug-induced allele-specific expression differences relating to rs1126757. Top hits in the wider inflammatory cytokine pathway at both baseline and after escitalopram treatment were found to be targets of TNF. The current study adds substantial support for the role of the inflammatory cytokine pathway in mediating response to the SSRI escitalopram, and is the first to identify TNF and its targets as putative transcriptomic predictors of clinical response.

  14. A Novel Chromone Derivative with Anti-Inflammatory Property via Inhibition of ROS-Dependent Activation of TRAF6-ASK1-p38 Pathway

    PubMed Central

    Liu, Hailiang; Xu, Rui; Feng, Lili; Guo, Wenjie; Cao, Ning; Qian, Cheng; Teng, Peng; Wang, Lu; Wu, Xuefeng; Sun, Yang; Li, Jianxin; Shen, Yan; Xu, Qiang

    2012-01-01

    The p38 MAPK signaling pathway plays a pivotal role in inflammation. Targeting p38 MAPK may be a potential strategy for the treatment of inflammatory diseases. In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK. Moreover, DCO-6 specifically inhibited TLR4-dependent p38 activation without directly inhibiting its kinase activity. LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex. Administering DCO-6 significantly protected mice from LPS-induced septic shock in parallel with the inhibition of p38 activation and ROS production. Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway. Blockade of the upstream events required for p38 MAPK action by DCO-6 may provide a new therapeutic option in the treatment of inflammatory diseases. PMID:22720096

  15. Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies

    PubMed Central

    Patial, Sonika; Curtis, Alan D.; Lai, Wi S.; Stumpo, Deborah J.; Hill, Georgette D.; Flake, Gordon P.; Mannie, Mark D.; Blackshear, Perry J.

    2016-01-01

    Tristetraprolin (TTP) is an inducible, tandem zinc-finger mRNA binding protein that binds to adenylate-uridylate–rich elements (AREs) in the 3′-untranslated regions (3′UTRs) of specific mRNAs, such as that encoding TNF, and increases their rates of deadenylation and turnover. Stabilization of Tnf mRNA and other cytokine transcripts in TTP-deficient mice results in the development of a profound, chronic inflammatory syndrome characterized by polyarticular arthritis, dermatitis, myeloid hyperplasia, and autoimmunity. To address the hypothesis that increasing endogenous levels of TTP in an intact animal might be beneficial in the treatment of inflammatory diseases, we generated a mouse model (TTPΔARE) in which a 136-base instability motif in the 3′UTR of TTP mRNA was deleted in the endogenous genetic locus. These mice appeared normal, but cultured fibroblasts and macrophages derived from them exhibited increased stability of the otherwise highly labile TTP mRNA. This resulted in increased TTP protein expression in LPS-stimulated macrophages and increased levels of TTP protein in mouse tissues. TTPΔARE mice were protected from collagen antibody-induced arthritis, exhibited significantly reduced inflammation in imiquimod-induced dermatitis, and were resistant to induction of experimental autoimmune encephalomyelitis, presumably by dampening the excessive production of proinflammatory mediators in all cases. These data suggest that increased systemic levels of TTP, secondary to increased stability of its mRNA throughout the body, can be protective against inflammatory disease in certain models and might be viewed as an attractive therapeutic target for the treatment of human inflammatory diseases. PMID:26831084

  16. The Immune Protective Effect of the Mediterranean Diet against Chronic Low-grade Inflammatory Diseases

    PubMed Central

    Casas, Rosa; Sacanella, Emilio; Estruch, Ramon

    2016-01-01

    Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. The Mediterranean Diet (MedDiet) is a nutritional model inspired by the traditional dietary pattern of some of the countries of the Mediterranean basin. This dietary pattern is characterized by the abundant consumption of olive oil, high consumption of plant foods (fruits, vegetables, pulses, cereals, nuts and seeds); frequent and moderate intake of wine (mainly with meals); moderate consumption of fish, seafood, yogurt, cheese, poultry and eggs; and low consumption of red meat, processed meat products and seeds. Several epidemiological studies have evaluated the effects of a Mediterranean pattern as protective against several diseases associated with chronic low-grade inflammation such as cancer, diabetes, obesity, atherosclerosis, metabolic syndrome and cognition disorders. The adoption of this dietary pattern could counter the effects of several inflammatory markers, decreasing, for example, the secretion of circulating and cellular biomarkers involved in the atherosclerotic process. Thus, the aim of this review was to consider the current evidence about the effectiveness of the MedDiet in these chronic inflammatory diseases due to its antioxidant and anti-inflammatory properties, which may not only act on classical risk factors but also on inflammatory biomarkers such as adhesion molecules, cytokines or molecules related to the stability of atheromatic plaque. PMID:25244229

  17. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways.

    PubMed

    Bhasin, Manoj K; Dusek, Jeffery A; Chang, Bei-Hung; Joseph, Marie G; Denninger, John W; Fricchione, Gregory L; Benson, Herbert; Libermann, Towia A

    2013-01-01

    The relaxation response (RR) is the counterpart of the stress response. Millennia-old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal) genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS) as top upregulated critical molecules (focus hubs) and NF-κB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-κB-associated upstream and downstream targets that mitigates stress.

  18. Relaxation Response Induces Temporal Transcriptome Changes in Energy Metabolism, Insulin Secretion and Inflammatory Pathways

    PubMed Central

    Joseph, Marie G.; Denninger, John W.; Fricchione, Gregory L.; Benson, Herbert; Libermann, Towia A.

    2013-01-01

    The relaxation response (RR) is the counterpart of the stress response. Millennia-old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal) genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS) as top upregulated critical molecules (focus hubs) and NF-κB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-κB-associated upstream and downstream targets that mitigates stress. PMID:23650531

  19. Protective effects of ethanol extract from Portulaca oleracea L on dextran sulphate sodium-induced mice ulcerative colitis involving anti-inflammatory and antioxidant

    PubMed Central

    Yang, Xiaohang; Yan, Yongmei; Li, Jiankang; Tang, Zhishu; Sun, Jing; Zhang, Huan; Hao, Siyang; Wen, Aidong; Liu, Li

    2016-01-01

    Portulaca oleracea L., (POL) is one of commonly used medicine-food herbs and has a cosmopolitan distribution in many countries. Many studies showed that POL exhibited a wide range of pharmacological effects such as anti-inflammatory and liver complaints. In the clinical studies, POL was usually used for the treatment of UC disease and the clinical efficacy was well, but the mechanism and scientific intension was still unknown. In the present study, we studied the protective effects of the ethanol extract from POL on dextran sulphate sodium-induced UC in C57BL/6 mice model through oxidative stress and inflammatory pathway. The results demonstrated that the ethanol extract from POL could exhibit the effective protection for the DSS induced UC by increasing the colon length, decreasing body weight loss and the disease activity index score, inhibiting oxidative stress response through the MDA, NO, SOD activities, reducing the mRNA expressions of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and the protein expressions of TNF-α and NF-kB p65. These results may prove that POL could be considered as a useful and effective botanical compound from the edible plant to be used in UC through the oxidative stress and inflammatory activities. PMID:27347321

  20. Nickel chloride (NiCl2)-caused inflammatory responses via activation of NF-κB pathway and reduction of anti-inflammatory mediator expression in the kidney

    PubMed Central

    Cui, Hengmin; Peng, Xi; Fang, Jing; Zuo, Zhicai; Deng, Junliang; Wang, Xun; Wu, Bangyuan; Chen, Kejie

    2015-01-01

    Nickel (Ni) or Ni compounds target a number of organs and produce multiple toxic effects. Kidney is the major organ for Ni accumulation and excretion. There are no investigations on the Ni- or Ni compounds-induced renal inflammatory responses in human beings and animals at present. Therefore, we determined NiCl2-caused alteration of inflammatory mediators, and functional damage in the broiler's kidney by the methods of biochemistry, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Dietary NiCl2 in excess of 300 mg/kg caused the renal inflammatory responses that characterized by increasing mRNA expression levels of the pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-18 (IL-18) via the activation of nucleic factor κB (NF-κB), and decreasing mRNA expression levels of the anti-inflammatory mediators including interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-13 (IL-13). Concurrently, NiCl2 caused degeneration, necrosis and apoptosis of the tubular cells, which was consistent with the alteration of renal function parameters including elevated alkaline phosphatase (AKP) activity, and reduced activities of sodium-potassium adenosine triphosphatase (Na+/K+-ATPase), calcium adenosine triphosphatase (Ca2+-ATPase), lactic dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) in the kidney. The above-mentioned results present that the activation of NF-κB pathway and reduction of anti-inflammatory mediator expression are main mechanisms of NiCl2-caused renal inflammatory responses and that the renal function is decreased or impaired after NiCl2-treated. PMID:26417933

  1. Rapamycin protects neurons from brain contusion-induced inflammatory reaction via modulation of microglial activation

    PubMed Central

    SONG, QI; XIE, DUJIANG; PAN, SHIYONG; XU, WEIJUN

    2015-01-01

    The inflammatory reaction is important in secondary injury following traumatic brain injury (TBI). Rapamycin has been demonstrated as a neuroprotective agent in a mouse model of TBI, however, there is a lack of data regarding the effects of rapamycin on the inflammatory reaction following TBI. Therefore, the present study was designed to assess the effects of treatment with rapamycin on inflammatory reactions and examine the possible involvement of microglial activation following TBI. Male imprinting control region mice were randomly divided into four groups: Sham group (n=23), TBI group (n=23), TBI + dimethyl sulfoxide (DMSO) group (n=31) and TBI + rapamycin group (n=31). Rapamycin was dissolved in DMSO (50 mg/ml) and injected 30 min after TBI (2 mg/Kg; intraperitoneally). A weight-drop model of TBI was induced, and the brain tissues were harvested 24 h after TBI. The findings indicated that the administration of rapamycin following TBI was associated with decreased levels of activated microglia and neuron degeneration at the peri-injury site, reduced levels of proinflammatory cytokines and increased neurobehavioral function, possibly mediated by inactivation of the mammalian target of rapamycin pathway. The results of the present study offer novel insight into the mechanisms responsible for the anti-neuroinflammatory effects of rapamycin, possibly involving the modulation of microglial activation. PMID:26458361

  2. Stem cells on fire: inflammatory signaling in HSC emergence.

    PubMed

    Veldman, Matthew B; Lin, Shuo

    2014-12-08

    Inflammatory pathways protect the body from infection and promote healing following injury. Recent reports demonstrate the surprising involvement of these pathways during hematopoietic stem cell emergence from the hemogenic endothelium in both zebrafish and mice.

  3. Cross-talk between TLR4 and PPARγ pathways in the arachidonic acid-induced inflammatory response in pancreatic acini.

    PubMed

    Mateu, A; Ramudo, L; Manso, M A; De Dios, I

    2015-12-01

    Arachidonic acid (AA) is generally associated with inflammation in different settings. We assess the molecular mechanisms involved in the inflammatory response exerted by AA on pancreatic acini as an approach to acute pancreatitis (AP). Celecoxib (COX-2 inhibitor), TAK-242 (TLR4 inhibitor) and 15d-PGJ2 (PPARγ agonist) were used to ascertain the signaling pathways. In addition, we examine the effects of TAK-242 and 15d-PGJ2 on AP induced in rats by bile-pancreatic duct obstruction (BPDO). To carry out in vitro studies, acini were isolated from pancreas of control rats. Generation of PGE2 and TXB2, activation of pro-inflammatory pathways (MAPKs, NF-κB, and JAK/STAT3) and overexpression of CCL2 and P-selectin was found in AA-treated acini. In addition, AA up-regulated TLR4 and down-regulated PPARγ expression. Celecoxib prevented the up-regulation of CCL2 and P-selectin but did not show any effect on the AA-mediated changes in TLR4 and PPARγ expression. TAK-242, reduced the generation of AA metabolites and repressed both the cascade of pro-inflammatory events which led to CCL2 and P-selectin overexpression as well as the AA-induced PPARγ down-regulation. Thus, TLR4 acts as upstream activating pro-inflammatory and inhibiting anti-inflammatory pathways. 15d-PGJ2 down-regulated TLR4 expression and hence prevented the synthesis of AA metabolites and the inflammatory response mediated by them. Reciprocal negative cross-talk between TLR4 and PPARγ pathways is evidenced. In vivo experiments showed that TAK-242 and 15d-PGJ2 treatments reduced the inflammatory response in BPDO-induced AP. We conclude that through TLR4-dependent mechanisms, AA up-regulated CCL2 and P-selectin in pancreatic acini, partly mediated by the generation of PGE2 and TXB2, which activated pro-inflammatory pathways, but also directly by down-regulating PPARγ expression with anti-inflammatory activity. In vitro and in vivo studies support the role of TLR4 in AP and the use of TLR4 inhibitors and

  4. Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways

    PubMed Central

    Zeng, Hui; Wu, Huixia; Sloane, Valerie; Jones, Rheinallt; Yu, Yimin; Lin, Patricia; Gewirtz, Andrew T.; Neish, Andrew S.

    2015-01-01

    Flagellin, the primary structural component of bacterial flagella, is recognized by Toll-like receptor 5 (TLR5) present on the basolateral surface of intestinal epithelial cells. Utilizing biochemical assays of proinflammatory signaling pathways and mRNA expression profiling, we found that purified flagellin could recapitulate the human epithelial cell proinflammatory responses activated by flagellated pathogenic bacteria. Flagellin-induced proinflammatory activation showed similar kinetics and gene specificity as that induced by the classical endogenous proinflammatory cytokine TNF-α, although both responses were more rapid than that elicited by viable flagellated bacteria. Flagellin, like TNF-α, activated a number of antiapoptotic mediators, and pretreatment of epithelial cells with this bacterial protein could protect cells from subsequent bacterially mediated apoptotic challenge. However, when NF-κB-mediated or phosphatidylinositol 3-kinase/Akt proinflammatory signaling was blocked, flagellin could induce programmed cell death. Consistently, we demonstrate that flagellin and viable flagellate Salmonella induces both the extrinsic and intrinsic caspase activation pathways, with the extrinsic pathway (caspase 8) activated by purified flagellin in a TLR5-dependant fashion. We conclude that interaction of flagellin with epithelial cells induces caspase activation in parallel with proinflammatory responses. Such intertwining of proinflammatory and apoptotic signaling mediated by bacterial products suggests roles for host programmed cell death in the pathogenesis of enteric infections. PMID:16179598

  5. Anti-inflammatory effects of apigenin in lipopolysaccharide-induced inflammatory in acute lung injury by suppressing COX-2 and NF-kB pathway.

    PubMed

    Wang, Jing; Liu, Yu-Tao; Xiao, Lu; Zhu, Lingpeng; Wang, Qiujuan; Yan, Tianhua

    2014-12-01

    This study aims to evaluate the possible mechanisms responsible for the anti-inflammatory effects of apigenin lipopolysaccharide (LPS)-induced inflammatory in acute lung injury. In this study, the anti-inflammatory effects of apigenin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible mechanisms involved in this protection were investigated. Pretreatment with apigenin prior to the administration of intratracheal LPS significantly induced a decrease in lung wet weight/dry weight ratio in total leukocyte number and neutrophil percent in the bronchoalveolar lavage fluid (BALF) and in IL-6 and IL-1β, the tumor neurosis factor-α (TNF-α) in the BALF. These results showed that anti-inflammatory effects of apigenin against the LPS-induced ALI may be due to its ability of primary inhibition of cyclooxygenase-2 (COX-2) gene expression and nuclear factor kB (NF-kB) gene expression of lung. The results presented here suggest that the protective mechanism of apigenin may be attributed partly to decreased production of proinflammatory cytokines through the inhibition of COX-2 and NF-kB activation. The results support that use of apigenin is beneficial in the treatment of ALI.

  6. Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways.

    PubMed

    Martin-Subero, Marta; Anderson, George; Kanchanatawan, Buranee; Berk, Michael; Maes, Michael

    2016-04-01

    The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut-brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when "comorbid" with depression.

  7. Thymoquinone Modulates Blood Coagulation in Vitro via Its Effects on Inflammatory and Coagulation Pathways

    PubMed Central

    Muralidharan-Chari, Vandhana; Kim, Jaehan; Abuawad, Ahlam; Naeem, Mubeena; Cui, Huadong; Mousa, Shaker A.

    2016-01-01

    Thymoquinone (THQ) is a major component of black seeds. Given that both THQ and black seeds exhibit anti-cancer and anti-inflammatory activities, we hypothesized that THQ will affect cancer-associated thrombosis (CAT), which is primarily triggered by tissue factor (TF) and inflammation. The effect of both black seed-extracted and purchased (“pure”) THQ on normal blood coagulation was tested with in vitro thromboelastography (TEG) and activated partial thromboplastin time (aPTT) coagulation assays. The effect of pure THQ on CAT was tested with aPTT assay using pancreatic cancer cell lines that are either positive or negative for TF, and with TEG assay using lipopolysaccharide as an inflammatory trigger. Additionally, the direct effect of THQ on the inactivation of factors IIa and Xa was assessed. Since TNF-α facilitates crosstalk between inflammation and thrombosis by triggering the NF-κB pathway, we tested THQ’s ability to interfere with this communication with a luciferase assay. Both extracted and pure THQ had minimal effects on normal blood coagulation. Pure THQ reversed CAT initiated by both TF and inflammation to basal levels (p < 0.001). Mechanistically, while THQ had minimal to no effect on factor IIa and Xa inactivation, it strongly reduced the effects of TNF-α on NF-κB elements (p < 0.001). THQ has a minimal effect on basal coagulation and can reverse CAT in vitro, possibly by interfering with the crosstalk between inflammation and coagulation. This study suggests the utility of THQ as a preventative anticoagulant and/or as a supplement to existing chemotherapies and anticoagulant therapies. PMID:27043539

  8. Sesamin inhibits IL-1β-stimulated inflammatory response in human osteoarthritis chondrocytes by activating Nrf2 signaling pathway.

    PubMed

    Kong, Pengyu; Chen, Guanghua; Jiang, Anlong; Wang, Yufu; Song, Chengchao; Zhuang, Jinpeng; Xi, Chunyang; Wang, Guangxi; Ji, Ye; Yan, Jinglong

    2016-12-13

    Sesamin, a bioactive component extracted from sesame, has been reported to exert anti-inflammatory and anti-oxidant effects. In this study, we evaluated the anti-inflammatory effects of sesamin on IL-1β-stimulated human osteoarthritis chondrocytes and investigated the possible mechanism. Results demonstrated that sesamin treatment significantly inhibited PGE2 and NO production induced by IL-1β. Sesamin inhibited MMP1, MMP3, and MMP13 production in IL-1β-stimulated chondrocytes. Sesamin also inhibited IL-1β-induced phosphorylation of NF-κB p65 and IκBα. Meanwhile, sesamin was found to up-regulate the expression of Nrf2 and HO-1. However, Nrf2 siRNA reversed the anti-inflammatory effects of sesamin. In conclusion, our results suggested that sesamin showed anti-inflammatory effects in IL-1β-stimulated chondrocytes by activating Nrf2 signaling pathway.

  9. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD.

    PubMed

    Busso, Nathalie; Karababa, Mahir; Nobile, Massimo; Rolaz, Aline; Van Gool, Frédéric; Galli, Mara; Leo, Oberdan; So, Alexander; De Smedt, Thibaut

    2008-05-21

    Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFalpha levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders.

  10. Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.

    PubMed

    Jones, Simon P; Franco, Nunzio F; Varney, Bianca; Sundaram, Gayathri; Brown, David A; de Bie, Josien; Lim, Chai K; Guillemin, Gilles J; Brew, Bruce J

    2015-01-01

    The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.

  11. Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease

    PubMed Central

    Jones, Simon P.; Franco, Nunzio F.; Varney, Bianca; Sundaram, Gayathri; Brown, David A.; de Bie, Josien; Lim, Chai K.; Guillemin, Gilles J.; Brew, Bruce J.

    2015-01-01

    The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes. PMID:26114426

  12. Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis

    PubMed Central

    Norling, Lucy V.; Headland, Sarah E.; Arnardottir, Hildur H.; Haworth, Oliver; Jones, Hefin R.; Serhan, Charles N.

    2016-01-01

    Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which — once applied to human neutrophils — attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE2 biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor–deficient mice termed ALX/fpr2/3–/–. These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA. PMID:27158677

  13. Mechanisms of the beneficial effect of NHE1 inhibitor in traumatic hemorrhage: inhibition of inflammatory pathways.

    PubMed

    Wu, Dongmei; Qi, Jiansong

    2012-06-01

    This study evaluated the effects of sodium-hydrogen exchanger (NHE1) inhibition on enhancing fluid resuscitation outcomes in traumatic hemorrhagic shock, and examined the mechanisms related to NHE1 inhibitor-induced protection and recovery from hemorrhagic shock. Traumatic hemorrhage was modeled in anesthetized pigs by producing tibia fractures followed by hemorrhage of 25 ml/kg for 20 min, and then a 4mm hepatic arterial tear with surgical repair after 20 min. Animals then underwent low volume fluid resuscitation with either hextend (n=6) or 3mg/kg BIIB513 (NHE1 inhibitor)+hextend (n=6). The experiment was terminated 6h after the beginning of resuscitation. In association with traumatic hemorrhagic shock, there was a decrease in cardiac index, stimulation of the inflammatory response, myocardial, liver and kidney injury. The administration of the NHE1 inhibitor at the time of resuscitation attenuated shock-resuscitation-induced myocardial hypercontracture and resulted in a significant increase in stroke volume index, compared to vehicle-treated controls. NHE1 inhibition also reduced the inflammatory response, and lessened myocardial, liver and kidney injury. In addition, NHE1 inhibition reduced NF-κB activation and iNOS expression, and attenuated of ERK1/2 phosphorylation. Results from the present study indicate that NHE1 inhibition prevents multiple organ injury by attenuating shock-resuscitation-induced myocardial hypercontracture and by inhibiting NF-κB activation and neutrophil infiltration, reducing iNOS expression and ERK1/2 phosphorylation, thereby, reducing systemic inflammation and thus multi-organ injury.

  14. Leonurine exerts anti-inflammatory effect by regulating inflammatory signaling pathways and cytokines in LPS-induced mouse mastitis.

    PubMed

    Song, Xiaojing; Wang, Tiancheng; Zhang, Zecai; Jiang, Haichao; Wang, Wei; Cao, Yongguo; Zhang, Naisheng

    2015-02-01

    Bovine mastitis is defined as the inflammation of mammary gland and is the most multiple diseases in dairy cattle. There is still no effective treatment now. Leonurine, extracted from Leonurus cardiaca, has been proved to have anti-inflammatory effect. In the present study, we utilized a mouse mastitis model to study the effect of leonurine on LPS-induced mastitis. Leonurine was administered three times during the 24 h after inducing infection in the mammary gland. The results showed that leonurine significantly alleviated LPS-induced histopathological changes, downregulated the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), upregulated the level of anti-inflammatory cytokine interleukin-10 (IL-10), and inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Further study revealed that leonurine inhibited the expression of Toll-like receptor 4 (TLR4) and the activation of nuclear factor-kappaB (NF-κB) and the phosphorylation of p38, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK). Therefore, the results demonstrated that leonurine could downregulate the expression of TNF-α, IL-6, iNOS, and COX-2 and upregulate the expression of IL-10 mainly by inhibiting the expression of TLR4 and the activation of NF-κB and the phosphorylation of p38, ERK, and JNK. Leonurine may be a potential agent for mastitis therapy.

  15. Oral contraceptives, Chlamydia trachomatis infection, and pelvic inflammatory disease. A word of caution about protection.

    PubMed

    Washington, A E; Gove, S; Schachter, J; Sweet, R L

    1985-04-19

    Management of pelvic inflammatory disease (PID) and decisions about contraception are being influenced by reports that oral contraceptives decrease the risk of PID. To evaluate the validity of this association, we have examined published epidemiologic evidence and reviewed relevant information from other disciplines. Current information does not permit the generalization that oral contraceptives protect against all forms of PID. Most studies conducted (1) have been limited to hospitalized women, who represent less than 25% of all PID cases and are likely to have relatively severe forms of the disease, and (2) have failed to distinguish between gonococcal and nongonococcal PID. While oral contraceptives may provide some protection against gonococcal PID, no basis exists for assuming similar protection is provided against chlamydial PID. In fact, epidemiologic and biologic evidence suggests that infection with Chlamydia trachomatis, the leading cause of nongonococcal PID, is enhanced by oral contraceptives. We judge the conclusion that oral contraceptives protect against all PID to be premature, and urge caution in its application in health policy and clinical decisions.

  16. Inhibition of inflammatory mediators contributes to the anti-inflammatory activity of KYKZL-1 via MAPK and NF-κB pathway.

    PubMed

    Xu, Guang-Lin; Du, Yi-Fang; Cheng, Jing; Huan, Lin; Chen, Shi-Cui; Wei, Shao-Hua; Gong, Zhu-Nan; Cai, Jie; Qiu, Ting; Wu, Hao; Sun, Ting; Ao, Gui-Zhen

    2013-10-01

    KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the anti-inflammatory activity test focusing on its modulation of inflammatory mediators as well as intracellular MAPK and NF-κB signaling pathways. In acute ear edema model, pretreatment with KYKZL-1 (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice with a higher inhibition than diclofenac. In a three-day TPA-induced inflammation, KYKZL-1 also showed significant anti-inflammatory activity with inhibition ranging between 20% and 64%. In gastric lesion test, KYKZL-1 elicited markedly fewer stomach lesions with a low index of ulcer as compared to diclofenac in rats. In further studies, KYKZL-1 was found to significantly inhibit the production of NO, PGE2, LTB4 in LPS challenged RAW264.7, which is parallel to its attenuation of the expression of iNOS, COX-2, 5-LOX mRNAs or proteins and inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. Taken together, our data indicate that KYKZL-1 comprises dual inhibition of COX and 5-LOX and exerts an obvious anti-inflammatory activity with an enhanced gastric safety profile via simultaneous inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB.

  17. Osteoimmunology: Major and Costimulatory Pathway Expression Associated with Chronic Inflammatory Induced Bone Loss

    PubMed Central

    Crotti, Tania N.; Dharmapatni, Anak A. S. S. K.; Alias, Ekram; Haynes, David R.

    2015-01-01

    The field of osteoimmunology has emerged in response to the range of evidences demonstrating the close interrelationship between the immune system and bone metabolism. This is pertinent to immune-mediated diseases, such as rheumatoid arthritis and periodontal disease, where there are chronic inflammation and local bone erosion. Periprosthetic osteolysis is another example of chronic inflammation with associated osteolysis. This may also involve immune mediation when occurring in a patient with rheumatoid arthritis (RA). Similarities in the regulation and mechanisms of bone loss are likely to be related to the inflammatory cytokines expressed in these diseases. This review highlights the role of immune-related factors influencing bone loss particularly in diseases of chronic inflammation where there is associated localized bone loss. The importance of the balance of the RANKL-RANK-OPG axis is discussed as well as the more recently appreciated role that receptors and adaptor proteins involved in the immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway play. Although animal models are briefly discussed, the focus of this review is on the expression of ITAM associated molecules in relation to inflammation induced localized bone loss in RA, chronic periodontitis, and periprosthetic osteolysis, with an emphasis on the soluble and membrane bound factor osteoclast-associated receptor (OSCAR). PMID:26064999

  18. Anti-inflammatory activity of flavonoids in Nepalese propolis is attributed to inhibition of the IL-33 signaling pathway.

    PubMed

    Funakoshi-Tago, Megumi; Okamoto, Kazuhi; Izumi, Rika; Tago, Kenji; Yanagisawa, Ken; Narukawa, Yuji; Kiuchi, Fumiyuki; Kasahara, Tadashi; Tamura, Hiroomi

    2015-03-01

    Propolis has been used in folk medicine to improve health and prevent inflammatory diseases; however, the components that exhibit its anti-inflammatory activity remain unknown. We herein investigated the effects of flavonoids isolated from Nepalese propolis on the IL-33 signaling pathway to clarify the anti-inflammatory mechanism involved. Of the 8 types of flavonoids isolated from Nepalese propolis, 4 types of compounds, such as 3',4'-dihydroxy-4-methoxydalbergione, 4-methoxydalbergion, cearoin, and chrysin, markedly inhibited the IL-33-induced mRNA expression of inflammatory genes including IL-6, TNFα and IL-13 in bone marrow-derived mast cells (BMMC). These four flavonoids also inhibited the IL-33-induced activation of nuclear factor κB (NF-κB), which was consistent with their inhibitory effects on cytokine expression. The effects of these flavonoids are attributed to inhibition of IL-33-induced activation of IKK, which leads to the degradation of IκBα and nuclear localization of NF-κB. On the other hand, other flavonoids isolated from Nepalese propolis, such as isoliquiritigenin, plathymenin, 7-hydroxyflavanone, and (+)-medicarpin, had no effect on the IL-33 signaling pathway or cytokine expression. Therefore, these results indicate that 3',4'-dihydroxy-4-methoxydalbergione, 4-methoxydalbergion, cearoin, and chrysin are the substances responsible for the anti-inflammatory activity of Nepalese propolis.

  19. Inflammatory landscape of human brain tumors reveals an NFκB dependent cytokine pathway associated with mesenchymal glioblastoma.

    PubMed

    Zanotto-Filho, Alfeu; Gonçalves, Rosângela Mayer; Klafke, Karina; de Souza, Priscila Oliveira; Dillenburg, Fabiane Cristine; Carro, Luigi; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca

    2017-04-01

    The tumor microenvironment is being increasingly recognized as a key factor in cancer aggressiveness. In this study, we characterized the inflammatory gene signatures altered in glioma cell lines and tumor specimens of differing histological and molecular subtypes. The results showed that glioblastoma multiforme (GBM) shows upregulation of a subset of inflammatory genes when compared to astrocytomas and oligodendrogliomas. With molecular subtypes of GBM, the expression of inflammatory genes is heterogeneous, being enriched in mesenchymal and downregulated in Proneural/GCIMP. Other inflammation-associated processes such as tumor-associated macrophage (TAM) signatures are upregulated in mesenchymal, and a subset of 33 mesenchymal-enriched inflammatory and TAM markers showed correlation with poor survival. We found that various GBM tumor-upregulated genes such as IL6, IL8 and CCL2 are also actively expressed in glioma cell lines, playing differential and cooperative roles in promoting proliferation, invasion, angiogenesis and macrophage polarization in vitro. These genes can be stimulated by pathways typically altered in GBM, including the EGFR, PDGFR, MEK1/2-ERK1/2, PI3K/Akt and NFκB cascades. Taken together, the results presented herein depict some inflammatory pathways altered in gliomas and highlight potentially relevant targets to therapy improvement.

  20. HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway

    SciTech Connect

    Luo, Ying; Li, Shu-Jun; Yang, Jian; Qiu, Yuan-Zhen; Chen, Fang-Ping

    2013-09-06

    Highlights: •Mechanisms of inflammatory response induced by HMGB1 are incompletely understood. •We found that endoplasmic reticulum stress mediate the inflammatory response induced by HMGB1. •RAGE-mediated ERS pathways are involved in those processes. •We reported a new mechanism for HMGB1 induced inflammatory response. -- Abstract: The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulum stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01–1 μg/ml) for 24 h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway.

  1. Naphthazarin protects against glutamate-induced neuronal death via activation of the Nrf2/ARE pathway

    SciTech Connect

    Son, Tae Gen; Kawamoto, Elisa M.; Yu, Qian-Sheng; Greig, Nigel H.; Mattson, Mark P.; Camandola, Simonetta

    2013-04-19

    Highlights: •Naphthazarin activates the Nrf2/ARE pathway. •Naphthazarin induces Nrf2-driven genes in neurons and astrocytes. •Naphthazarin protects neurons against excitotoxicity. -- Abstract: Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. We previously screened several natural phytochemicals and identified plumbagin as a novel activator of the Nrf2/ARE pathway that can protect neurons against ischemic injury. Here we extended our studies to natural and synthetic derivatives of plumbagin. We found that 5,8-dimethoxy-1,4-naphthoquinone (naphthazarin) is a potent activator of the Nrf2/ARE pathway, up-regulates the expression of Nrf2-driven genes in primary neuronal and glial cultures, and protects neurons against glutamate-induced excitotoxicity.

  2. Pathogenic Lifestyles of E. coli Pathotypes in a Standardized Epithelial Cell Model Influence Inflammatory Signaling Pathways and Cytokines Secretion

    PubMed Central

    Sanchez-Villamil, Javier; Tapia-Pastrana, Gabriela; Navarro-Garcia, Fernando

    2016-01-01

    Inflammatory response is key for the host defense against diarrheagenic Escherichia coli and contributes to the pathogenesis of the disease but there is not a comparative study among different diarrheagenic pathotypes. We analyzed the inflammatory response induced by five diarrheagenic pathotypes in a HT-29 cell infection model. The model was unified to reproduce the pathogenesis of each pathotype. To compare the inflammatory responses we evaluated: (i) nuclear NF-κB and ERK1/2 translocation by confocal microscopy; (ii) kinetics of activation by each pathway detecting p65 and ERK1/2 phosphorylation by Western blotting; (iii) pathways modulation through bacterial infections with or without co-stimulation with TNF-α or EGF; (iv) cytokine profile induced by each pathotype with and without inhibitors of each pathway. EHEC but mainly EPEC inhibited translocation and activation of p65 and ERK1/2 pathways, as well as cytokines secretion; inhibition of p65 and ERK1/2 phosphorylation prevailed in the presence of TNF-α and EGF, respectively. Intracellular strains, EIEC/Shigella flexneri, caused a strong translocation, activation, and cytokines secretion but they could not inhibit TNF-α and EGF stimulation. ETEC and mainly EAEC caused a moderate translocation, but a differential activation, and high cytokines secretion; interestingly TNF-α and EGF stimulation did no modify p65 and ERK1/2 activation. The use of inhibitors of NF-κB and/or ERK1/2 showed that NF-κB is crucial for cytokine induction by the different pathotypes; only partially depended on ERK1/2 activation. Thus, in spite of their differences, the pathotypes can also be divided in three groups according to their inflammatory response as those (i) that inject effectors to cause A/E lesion, which are able to inhibit NF-κB and ERK1/2 pathways, and cytokine secretion; (ii) with fimbrial adherence and toxin secretion with a moderate inhibition of both pathways but high cytokines secretion through autocrine

  3. Inhibition of inflammatory mediators contributes to the anti-inflammatory activity of KYKZL-1 via MAPK and NF-κB pathway

    SciTech Connect

    Xu, Guang-Lin; Du, Yi-Fang; Cheng, Jing; Huan, Lin; Chen, Shi-Cui; Wei, Shao-Hua; Gong, Zhu-Nan; Cai, Jie; Qiu, Ting; Wu, Hao; Sun, Ting; Ao, Gui-Zhen

    2013-10-01

    KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the anti-inflammatory activity test focusing on its modulation of inflammatory mediators as well as intracellular MAPK and NF-κB signaling pathways. In acute ear edema model, pretreatment with KYKZL-1 (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice with a higher inhibition than diclofenac. In a three-day TPA-induced inflammation, KYKZL-1 also showed significant anti-inflammatory activity with inhibition ranging between 20% and 64%. In gastric lesion test, KYKZL-1 elicited markedly fewer stomach lesions with a low index of ulcer as compared to diclofenac in rats. In further studies, KYKZL-1 was found to significantly inhibit the production of NO, PGE{sub 2}, LTB{sub 4} in LPS challenged RAW264.7, which is parallel to its attenuation of the expression of iNOS, COX-2, 5-LOX mRNAs or proteins and inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. Taken together, our data indicate that KYKZL-1 comprises dual inhibition of COX and 5-LOX and exerts an obvious anti-inflammatory activity with an enhanced gastric safety profile via simultaneous inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. - Highlights: • KYKZL-1 is designed to exhibit COX/5-LOX dual inhibition. • KYKZL-1 inhibits NO, PGE{sub 2} and LTB{sub 4} and iNOS, COX-2 and 5-LOX mRNAs and MAPKs. • KYKZL-1 inhibits phosphorylation of MAPKs. • KYKZL-1 inactivates NF-κB pathway.

  4. IL-10 Protects Neurites in Oxygen-Glucose-Deprived Cortical Neurons through the PI3K/Akt Pathway.

    PubMed

    Lin, Longzai; Chen, Hongbin; Zhang, Yixian; Lin, Wei; Liu, Yong; Li, Tin; Zeng, Yongping; Chen, Jianhao; Du, Houwei; Chen, Ronghua; Tan, Yi; Liu, Nan

    2015-01-01

    IL-10, as a cytokine, has an anti-inflammatory cascade following various injuries, but it remains blurred whether IL-10 protects neurites of cortical neurons after oxygen-glucose deprivation injury. Here, we reported that IL-10, in a concentration-dependent manner, reduced neuronal apoptosis and increased neuronal survival in oxygen-glucose-deprived primary cortical neurons, producing an optimal protective effect at 20ng/ml. After staining NF-H and GAP-43, we found that IL-10 significantly protected neurites in terms of axon length and dendrite number by confocal microscopy. Furthermore, it induced the phosphorylation of AKT, suppressed the activation of caspase-3, and up-regulated the protein expression of GAP-43. In contrast, LY294002, a specific inhibitor of PI3K/AKT, reduced the level of AKT phosphorylation and GAP-43 expression, increased active caspase-3 expression and thus significantly weakened IL-10-mediated protective effect in the OGD-induced injury model. IL-10NA, the IL-10 neutralizing antibody, reduced the level of p-PI3K phosphorylation and increased the expression of active caspase-3. These findings suggest that IL-10 provides neuroprotective effects by protecting neurites through PI3K/AKT signaling pathway in oxygen-glucose-deprived primary cortical neurons.

  5. Anti-inflammatory effects of essential oils from Chamaecyparis obtusa via the cyclooxygenase-2 pathway in rats.

    PubMed

    An, Beum-Soo; Kang, Ji-Houn; Yang, Hyun; Jung, Eui-Man; Kang, Hong-Seok; Choi, In-Gyu; Park, Mi-Jin; Jeung, Eui-Bae

    2013-07-01

    Essential oils are concentrated hydrophobic liquids containing volatile aromatic compounds from plants. In the present study, the essential oil of Chamaecyparis obtusa (C. obtusa), which is commercially used in soap, toothpaste and cosmetics, was extracted. Essential oil extracted from C. obtusa contains several types of terpenes, which have been shown to have anti-oxidative and anti-inflammatory effects. In the present study, we examined the anti-inflammatory effects of C. obtusa essential oil in vivo and in vitro following the induction of inflammation by lipopolysaccharides (LPS) in rats. While LPS induced an inflammatory response through the production of prostaglandin E2 (PGE2) in the blood and peripheral blood mononuclear cells (PMNCs), these levels were reduced when essential oil was pre-administered. Additionally, the mechanism of action underlying the anti-inflammatory effects of C. obtusa essential oil was investigated by measuring the mRNA expression of inflammation‑associated genes. LPS treatment significantly induced the expression of transforming growth factor α (TNFα) and cyclooxygenase-2 (COX-2) in rats, while C. obtusa essential oil inhibited this effect. Taken together, our results demonstrate that C. obtusa essential oil exerts anti‑inflammatory effects by regulating the production of PGE2 and TNFα gene expression through the COX-2 pathway. These findings suggest that C. obtusa essential oil may constitute a novel source of anti-inflammatory drugs.

  6. Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-κB, p38 and JNK.

    PubMed

    Daniele, Simona; Da Pozzo, Eleonora; Zappelli, Elisa; Martini, Claudia

    2015-08-01

    Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of major depression and that inflammatory processes may influence the antidepressant treatment response. Depressed patients exhibit increased levels of inflammatory markers in both the periphery and brain, and high co-morbidity exists between depression and diseases associated with inflammatory alterations. Trazodone (TDZ) is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors. Although the trophic and protective properties of classic antidepressants have extensively been exploited, the effects of TDZ remain to be fully elucidated. In this study, the pharmacological activities of TDZ on human neuronal-like cells were investigated under both physiological and inflammatory conditions. An in vitro inflammatory model was established using lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α), which efficiently mimic the stress-related changes in neurotrophic and pro-inflammatory genes. Our results showed that TDZ significantly increased the mRNA expression of both brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) and decreased the cellular release of the pro-inflammatory cytokine interferon gamma (IFN-γ) in neuronal-like cells. In contrast, neuronal cell treatment with LPS and TNF-α decreased the expression of CREB and BDNF and increased the expression of nuclear factor kappa B (NF-κB), a primary transcription factor that functions in inflammatory response initiation. Moreover, the two agents induced the release of pro-inflammatory cytokines (i.e., interleukin-6 and IFN-γ) and decreased the production of the anti-inflammatory cytokine interleukin-10. TDZ pre-treatment completely reversed the decrease in cell viability and counteracted the decrease in BDNF and CREB expression mediated by LPS-TNF-α. In addition, the production of inflammatory mediators was

  7. The aldosterone-mineralocorticoid receptor pathway exerts anti-inflammatory effects in endotoxin-induced uveitis.

    PubMed

    Bousquet, Elodie; Zhao, Min; Ly, André; Leroux Les Jardins, Guillaume; Goldenberg, Brigitte; Naud, Marie-Christine; Jonet, Laurent; Besson-Lescure, Bernadette; Jaisser, Frederic; Farman, Nicolette; De Kozak, Yvonne; Behar-Cohen, Francine

    2012-01-01

    We have previously shown that the eye is a mineralocorticoid-sensitive organ and we now question the role of mineralocorticoid receptor (MR) in ocular inflammation. The endotoxin-induced uveitis (EIU), a rat model of human intraocular inflammation, was induced by systemic administration of lipopolysaccharide (LPS). Evaluations were made 6 and 24 hours after intraocular injection of aldosterone (simultaneous to LPS injection). Three hours after onset of EIU, the MR and the glucocorticoid metabolizing enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression were down-regulated in iris/ciliary body and the corticosterone concentration was increased in aqueous humor, altering the normal MR/glucocorticoid receptor (GR) balance. At 24 hours, the GR expression was also decreased. In EIU, aldosterone reduced the intensity of clinical inflammation in a dose-dependent manner. The clinical benefit of aldosterone was abrogated in the presence of the MR antagonist (RU26752) and only partially with the GR antagonist (RU38486). Aldosterone reduced the release of inflammatory mediators (6 and 24 hours: TNF-α, IFN-γ, MIP-1α) in aqueous humor and the number of activated microglia/macrophages. Aldosterone partly prevented the uveitis-induced MR down-regulation. These results suggest that MR expression and activation in iris/ciliary body could protect the ocular structures against damages induced by EIU.

  8. Sophocarpine Protects Mice from ConA-Induced Hepatitis via Inhibition of the IFN-Gamma/STAT1 Pathway

    PubMed Central

    Sang, Xiu-Xiu; Wang, Rui-Lin; Zhang, Cong-En; Liu, Shi-Jing; Shen, Hong-Hui; Guo, Yu-Ming; Zhang, Ya-Ming; Niu, Ming; Wang, Jia-Bo; Bai, Zhao-Fang; Xiao, Xiao-He

    2017-01-01

    Sophocarpine is the major pharmacologically active compound of the traditional Chinese herbal medicine Radix Sophorae Subprostratae which has been used in treating hepatitis for years in China. It has been demonstrated that Sophocarpine exerts an activity in immune modulation and significantly decreases the production of inflammatory cytokines. However, the protective effects of Sophocarpine in T cell-dependent immune hepatitis remained unknown. The aim of this study was to determine the protective effects and pharmacological mechanisms of Sophocarpine on Concanavalin A (ConA)-induced hepatitis, an experimental model of T cell-mediated liver injury. BALB/C mice were pretreated with Sophocarpine or Bicyclol for five consecutive days. Thirty minutes after the final administration, the mice were injected with 15 mg⋅kg-1 of ConA intravenously. The results indicated that pretreatment with Sophocarpine significantly ameliorated liver inflammation and injury as evidenced by both biochemical and histopathological observations. Moreover, in Sophocarpine-pretreated mice, liver messenger RNA expression levels of chemokines and adhesion molecules, such as macrophage inflammatory protein-1α, CXC chemokine ligand 10, and Intercellular adhesion molecule-1, were markedly reduced. Further studies revealed that Sophocarpine significantly downregulated the expression of T-bet via inhibition of signal transducers and activators of transcription1 (STAT1) activation and overexpression of suppressor of cytokine signaling1, inhibiting the activation of Th1 cells and the expression of Interferon-γ (IFN-γ). Altogether, these results suggest new opportunities to use Sophocarpine in the treatment of T cell-mediated liver disease. In summary, Sophocarpine could attenuate ConA-induced liver injury, and the protective effect of Sophocarpine was associated with its inhibition effect of pro-inflammatory cytokines, chemokines, and the IFN-γ/STAT1 signaling pathway. PMID:28377718

  9. AGI-1067, a novel antioxidant and anti-inflammatory agent, enhances insulin release and protects mouse islets

    PubMed Central

    Crim, William S.; Wu, Runpei; Carter, Jeffrey D.; Cole, Banumathi K.; Trace, Anthony P.; Mirmira, Raghavendra G.; Kunsch, Charles; Nadler, Jerry L.; Nunemaker, Craig S.

    2010-01-01

    The antioxidant and anti-inflammatory compound AGI-1067 (succinobucol) has potential as an oral anti-diabetic agent. AGI-1067 reduces HbA1c, improves fasting plasma glucose, and reduces new-onset diabetes. We investigated AGI-1067 for possible effects on mouse pancreatic islets in vitro. Pretreatment with 10uM AGI-1067 increased glucose-stimulated insulin secretion (11mM) without affecting secretion in basal (3mM) glucose. AGI-1067 enhanced the intracellular calcium response to glucose stimulation in 7mM and 11mM glucose, but had no effect in 28mM or basal glucose. AGI-1067-pretreated islets also showed enhanced calcium responses to methyl pyruvate and alpha-ketoisocaproate at low doses, but not high doses. The AGI-1067-mediated effects on glucose-stimulated calcium were maintained during continuous diazoxide exposure, suggesting effects on the KATP-channel-independent pathway. AGI-1067 also reduced cytokine-induced islet cell death and expression of iNOS, a key component in cytokine signaling. This is the first report of direct stimulatory and protective effects of a first-in-class potential anti-diabetic agent on pancreatic islets. PMID:20211684

  10. Mycobacterium tuberculosis heat shock proteins use diverse Toll-like receptor pathways to activate pro-inflammatory signals.

    PubMed

    Bulut, Yonca; Michelsen, Kathrin S; Hayrapetian, Linda; Naiki, Yoshikazu; Spallek, Ralf; Singh, Mahavir; Arditi, Moshe

    2005-06-03

    Although the Toll-like receptors used by Mycobacterium tuberculosis membrane and secreted factors are known, the pathways activated by M. tuberculosis heat shock proteins are not. An efficient immune response against the intracellular pathogen M. tuberculosis is critically dependent on rapid detection of the invading pathogen by the innate immune system and coordinated activation of the adaptive immune response. Macrophage phagocytosis of M. tuberculosis is accompanied by activation of the transcription factor NF-kappaB and secretion of inflammatory mediators that play an important role in granuloma formation and immune protection during M. tuberculosis infection. The interaction between M. tuberculosis and the various Toll-like receptors is complex, and it appears that distinct mycobacterial components may interact with different members of the Toll-like receptor family. Here we show that recombinant, purified, mycobacterial heat shock proteins 65 and 70 induce NF-kappaB activity in a dose-dependent manner in human endothelial cells. Furthermore, we show that whereas mycobacterial heat shock protein 65 signals exclusively through Toll-like receptor 4, heat shock protein 70 also signals through Toll-like receptor 2. Mycobacterial heat shock protein 65-induced NF-kappaB activation was MyD88-, TIRAP-, TRIF-, and TRAM-dependent and required the presence of MD-2. A better understanding of the recognition of mycobacterial heat shock proteins and their role in the host immune response to the pathogen may open the way to a better understanding of the immunological processes induced by this important human pathogen and the host-pathogen interactions and may help in the rational design of more effective vaccines or vaccine adjuvants.

  11. IFN-τ Displays Anti-Inflammatory Effects on Staphylococcus aureus Endometritis via Inhibiting the Activation of the NF-κB and MAPK Pathways in Mice

    PubMed Central

    Zhang, Zhenbiao; Guo, Yingfang; Liu, Yuzhu; Li, Chengye

    2017-01-01

    The aim of the present study was to determine the anti-inflammatory effect of IFN-τ on endometritis using a mouse model of S. aureus-induced endometritis and to elucidate the mechanism of action underlying these effects. In the present study, the effect of IFN-τ on S. aureus growth was monitored by turbidimeter at 600 nm. IFN-τ did not affect S. aureus growth. The histopathological changes indicated that IFN-τ had a protective effect on uterus tissues with S. aureus infection. The ELISA and qPCR results showed the production of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 was decreased with IFN-τ treatment. In contrast, the level of the anti-inflammatory cytokine IL-10 was increased. We further studied the signaling pathway associated with these observations, and the qPCR results showed that the expression of TLR2 was repressed by IFN-τ. Furthermore, the western blotting results showed the phosphorylation of IκB, NF-κB p65, and MAPKs (p38, JNK, and ERK) was inhibited by IFN-τ treatment. The results suggested that IFN-τ may be a potential drug for the treatment of uterine infection due to S. aureus or other infectious inflammatory diseases. PMID:28331850

  12. Curcumin attenuates inflammatory responses by suppressing TLR4-mediated NF-κB signaling pathway in lipopolysaccharide-induced mastitis in mice.

    PubMed

    Fu, Yunhe; Gao, Ruifeng; Cao, Yongguo; Guo, Mengyao; Wei, Zhengkai; Zhou, Ershun; Li, Yimeng; Yao, Minjun; Yang, Zhengtao; Zhang, Naisheng

    2014-05-01

    Curcumin, the main constituent of the spice turmeric, has been reported to have potent anti-inflammatory properties. However, the effect of curcumin on lipopolysaccharide (LPS)-induced mice mastitis has not been investigated. The aim of this study was to investigate whether curcumin could ameliorate the inflammation response in LPS-induced mice mastitis and to clarify the possible mechanism. The mouse model of mastitis was induced by injection of LPS through the duct of the mammary gland. Curcumin was applied 1h before and 12h after LPS treatment. The results showed that curcumin attenuated the infiltration of inflammatory cells, the activity of myeloperoxidase (MPO), and the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in a dose-dependent manner. Additionally, Western blotting results showed that curcumin inhibited the phosphorylation of IκB-α and NF-κB p65 and the expression of TLR4. These results indicated that curcumin has protective effect on mice mastitis and the anti-inflammatory mechanism of curcumin on LPS-induced mastitis in mice may be due to its ability to inhibit TLR4-mediated NF-κB signaling pathways. Curcumin may be a potential therapeutic agent against mastitis.

  13. Alpinetin attenuates inflammatory responses by interfering toll-like receptor 4/nuclear factor kappa B signaling pathway in lipopolysaccharide-induced mastitis in mice.

    PubMed

    Chen, Haijin; Mo, Xiaodong; Yu, Jinlong; Huang, Zonghai

    2013-09-01

    Alpinetin, a novel plant flavonoid derived from Alpinia katsumadai Hayata, has been reported to exhibit anti-inflammatory properties. However, the effect of alpinetin on mastitis has not been investigated. The aim of this study was to investigate the protective effect of alpinetin against lipopolysaccharide (LPS)-induced mastitis and to clarify the possible mechanism. In the present study, primary mouse mammary epithelial cells and an LPS-induced mouse mastitis model were used to investigate the effect of alpinetin on mastitis and the possible mechanism. In vivo, we observed that alpinetin significantly attenuated the infiltration of neutrophilic granulocytes, and the activation of myeloperoxidase; down-regulated the level of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6; inhibited the phosphorylation of IκB-α, NF-κB p65 and the expression of TLR4, caused by LPS. In vitro, we also observed that alpinetin inhibited the expression of TLR4 and the production of TNF-α, IL-1β and IL-6 in LPS-stimulated primary mouse mammary epithelial cells. However, alpinetin could not inhibit the production of IL-1β and IL-6 in TNF-α-stimulated primary mouse mammary epithelial cells. In conclusion, our results suggest that the anti-inflammatory effects of alpinetin against LPS-induced mastitis may be due to its ability to inhibit TLR4-mediated NF-κB signaling pathways. Alpinetin may be a promising potential therapeutic reagent for mastitis treatment.

  14. Tauroursodeoxycholic acid protects bile acid homeostasis under inflammatory conditions and dampens Crohn's disease-like ileitis.

    PubMed

    Van den Bossche, Lien; Borsboom, Daniel; Devriese, Sarah; Van Welden, Sophie; Holvoet, Tom; Devisscher, Lindsey; Hindryckx, Pieter; De Vos, Martine; Laukens, Debby

    2017-02-06

    Bile acids regulate the expression of intestinal bile acid transporters and are natural ligands for nuclear receptors controlling inflammation. Accumulating evidence suggests that signaling through these receptors is impaired in inflammatory bowel disease. We investigated whether tauroursodeoxycholic acid (TUDCA), a secondary bile acid with cytoprotective properties, regulates ileal nuclear receptor and bile acid transporter expression and assessed its therapeutic potential in an experimental model of Crohn's disease (CD). Gene expression of the nuclear receptors farnesoid X receptor, pregnane X receptor and vitamin D receptor and the bile acid transporters apical sodium-dependent bile acid transporter and organic solute transporter α and β was analyzed in Caco-2 cell monolayers exposed to tumor necrosis factor (TNF)α, in ileal tissue of TNF(ΔARE/WT) mice and in inflamed ileal biopsies from CD patients by quantitative real-time polymerase chain reaction. TNF(ΔARE/WT) mice and wild-type littermates were treated with TUDCA or placebo for 11 weeks and ileal histopathology and expression of the aforementioned genes were determined. Exposing Caco-2 cell monolayers to TNFα impaired the mRNA expression of nuclear receptors and bile acid transporters, whereas co-incubation with TUDCA antagonized their downregulation. TNF(ΔARE/WT) mice displayed altered ileal bile acid homeostasis that mimicked the situation in human CD ileitis. Administration of TUDCA attenuated ileitis and alleviated the downregulation of nuclear receptors and bile acid transporters in these mice. These results show that TUDCA protects bile acid homeostasis under inflammatory conditions and suppresses CD-like ileitis. Together with previous observations showing similar efficacy in experimental colitis, we conclude that TUDCA could be a promising therapeutic agent for inflammatory bowel disease, warranting a clinical trial.Laboratory Investigation advance online publication, 6 February 2017; doi:10

  15. Bergenin Plays an Anti-Inflammatory Role via the Modulation of MAPK and NF-κB Signaling Pathways in a Mouse Model of LPS-Induced Mastitis.

    PubMed

    Gao, Xue-jiao; Guo, Meng-yao; Zhang, Ze-cai; Wang, Tian-cheng; Cao, Yong-guo; Zhang, Nai-sheng

    2015-01-01

    Mastitis is a major disease in humans and other animals and is characterized by mammary gland inflammation. It is a major disease of the dairy industry. Bergenin is an active constituent of the plants of genus Bergenia. Research indicates that bergenin has multiple biological activities, including anti-inflammatory and immunomodulatory properties. The objective of this study was to evaluate the protective effects and mechanism of bergenin on the mammary glands during lipopolysaccharide (LPS)-induced mastitis. In this study, mice were treated with LPS to induce mammary gland mastitis as a model for the disease. Bergenin treatment was initiated after LPS stimulation for 24 h. The results indicated that bergenin attenuated inflammatory cell infiltration and decreased the concentration of NO, TNF-α, IL-1β, and IL-6, which were increased in LPS-induced mouse mastitis. Furthermore, bergenin downregulated the phosphorylation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathway proteins in mammary glands with mastitis. In conclusion, bergenin reduced the expression of NO, TNF-α, IL-1β, and IL-6 proinflammatory cytokines by inhibiting the activation of the NF-κB and MAPKs signaling pathways, and it may represent a novel treatment strategy for mastitis.

  16. PM2.5 collected in China causes inflammatory and oxidative stress responses in macrophages through the multiple pathways.

    PubMed

    Bekki, Kanae; Ito, Tomohiro; Yoshida, Yasuhiro; He, Cuiying; Arashidani, Keiichi; He, Miao; Sun, Guifan; Zeng, Yang; Sone, Hideko; Kunugita, Naoki; Ichinose, Takamichi

    2016-07-01

    Air pollution continues to increase in East Asia, particularly in China, and is considered to cause serious health problems. In this study, we investigated the toxicological properties of particulate matter ≤2.5mm (PM2.5) collected in an urban area in China (Shenyang), focusing on inflammation and oxidative stress tightly linked to respiratory diseases. Exposure to PM2.5 significantly increased the expression levels of inflammatory (interleukin-1β and cyclooxygenase-2) and oxidative stress (heme oxygenase1) genes in the mouse macrophages. PM2.5-caused inflammatory response was strongly suppressed by endotoxin neutralizer (polymyxin B) and knock-out of toll-like receptor 4, while oxidative stress was not. On the other hand, an antioxidant (N-acetylcystein) suppressed oxidative stress, but not inflammatory response. These results suggest that PM2.5 in the atmospheric environment of China causes inflammation and oxidative stress in macrophages via separate pathways.

  17. Chloroquine Inhibits HMGB1 Inflammatory Signaling and Protects Mice from Lethal Sepsis

    PubMed Central

    Yang, Minghua; Cao, Lizhi; Xie, Min; Yu, Yan; Kang, Rui; Yang, Liangchun; Zhao, Mingyi; Tang, Daolin

    2013-01-01

    Sepsis is caused by an overwhelming immune response to bacterial infection. The discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal sepsis has prompted investigation into the development of new therapeutics which specifically target this protein. Here, we show that chloroquine, an anti-malarial drug, prevents lethality in mice with established endotoxemia or sepsis. This effect is still observed even if administration of chloroquine is delayed. The protective effects of chloroquine were mediated through inhibition of HMGB1 release in macrophages, monocytes, and endothelial cells, thereby preventing its cytokine-like activities. As an inhibitor of autophagy, chloroquine specifically inhibited HMGB1-induced Iκ-B degradation and NF-κB activation. These findings define a novel mechanism for the anti-inflammatory effects of chloroquine and also suggest a new potential clinical use for this drug in the setting of sepsis. PMID:23707973

  18. The RhoA/ROCK Pathway Ameliorates Adhesion and Inflammatory Infiltration Induced by AGEs in Glomerular Endothelial Cells.

    PubMed

    Rao, Jialing; Ye, Zengchun; Tang, Hua; Wang, Cheng; Peng, Hui; Lai, Weiyan; Li, Yin; Huang, Wanbing; Lou, Tanqi

    2017-01-05

    A recent study demonstrated that advanced glycation end products (AGEs) play a role in monocyte infiltration in mesangial areas in diabetic nephropathy. The Ras homolog gene family, member A Rho kinase (RhoA/ROCK) pathway plays a role in regulating cell migration. We hypothesized that the RhoA/ROCK pathway affects adhesion and inflammation in endothelial cells induced by AGEs. Rat glomerular endothelial cells (rGECs) were cultured with AGEs (80 μg/ml) in vitro. The ROCK inhibitor Y27632 (10 nmol/l) and ROCK1-siRNA were used to inhibit ROCK. We investigated levels of the intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein1 (MCP-1) in rGECs. Db/db mice were used as a diabetes model and received Fasudil (10 mg/kg/d, n = 6) via intraperitoneal injection for 12 weeks. We found that AGEs increased the expression of ICAM-1 and MCP-1 in rGECs, and the RhoA/ROCK pathway inhibitor Y27632 depressed the release of adhesion molecules. Moreover, blocking the RhoA/ROCK pathway ameliorated macrophage transfer to the endothelium. Reduced expression of adhesion molecules and amelioration of inflammatory cell infiltration in the glomerulus were observed in db/db mice treated with Fasudil. The RhoA/ROCK pathway plays a role in adhesion molecule expression and inflammatory cell infiltration in glomerular endothelial cells induced by AGEs.

  19. The RhoA/ROCK Pathway Ameliorates Adhesion and Inflammatory Infiltration Induced by AGEs in Glomerular Endothelial Cells

    PubMed Central

    Rao, Jialing; Ye, Zengchun; Tang, Hua; Wang, Cheng; Peng, Hui; Lai, Weiyan; Li, Yin; Huang, Wanbing; Lou, Tanqi

    2017-01-01

    A recent study demonstrated that advanced glycation end products (AGEs) play a role in monocyte infiltration in mesangial areas in diabetic nephropathy. The Ras homolog gene family, member A Rho kinase (RhoA/ROCK) pathway plays a role in regulating cell migration. We hypothesized that the RhoA/ROCK pathway affects adhesion and inflammation in endothelial cells induced by AGEs. Rat glomerular endothelial cells (rGECs) were cultured with AGEs (80 μg/ml) in vitro. The ROCK inhibitor Y27632 (10 nmol/l) and ROCK1-siRNA were used to inhibit ROCK. We investigated levels of the intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein1 (MCP-1) in rGECs. Db/db mice were used as a diabetes model and received Fasudil (10 mg/kg/d, n = 6) via intraperitoneal injection for 12 weeks. We found that AGEs increased the expression of ICAM-1 and MCP-1 in rGECs, and the RhoA/ROCK pathway inhibitor Y27632 depressed the release of adhesion molecules. Moreover, blocking the RhoA/ROCK pathway ameliorated macrophage transfer to the endothelium. Reduced expression of adhesion molecules and amelioration of inflammatory cell infiltration in the glomerulus were observed in db/db mice treated with Fasudil. The RhoA/ROCK pathway plays a role in adhesion molecule expression and inflammatory cell infiltration in glomerular endothelial cells induced by AGEs. PMID:28054559

  20. Is the Wnt/β-catenin pathway involved in the anti-inflammatory activity of glucocorticoids in spinal cord injury?

    PubMed

    Libro, Rosaliana; Giacoppo, Sabrina; Bramanti, Placido; Mazzon, Emanuela

    2016-09-28

    The Wnt canonical or the Wnt/β-catenin pathway has been implicated in the regulation of several physiopathological pathways such as inflammation. Glucocorticoids (GCs) are administered widely to treat inflammation in several diseases, including spinal cord injury (SCI). The aim of this study was to evaluate whether the Wnt canonical pathway is involved in experimental SCI and whether it is implicated in the anti-inflammatory activity of two different GCs: the methylprednisolone sodium succinate (MPSS), considered the standard treatment for acute SCI, and mometasone furoate (MF), mainly administered for the treatment of airway and skin diseases. Experimental SCI was induced in mice by surgical spinal cord compression at the T6-T7 level. Then, mice were treated with MPSS (6 mg/kg) or MF (0.1 mg/kg) for 7 days until they were killed. Both GCs were found to modulate the Wnt canonical pathway, but in particular, the MF treatment was shown to restore completely the downregulated pathway in SCI. The MF treatment also significantly increased peroxisome proliferator-activated receptor-γ, a Wnt target gene with anti-inflammatory properties, compared with MPSS, and it also inhibited the levels of the proinflammatory cytokines interleukin 1β and tumor necrosis factor-α. Here, we suggest that MF has more efficacy than MPSS in inhibiting inflammation in an SCI experimental model and we propose the β-catenin/peroxisome proliferator-activated receptor-γ axis as the mechanism by which MF exerts these beneficial effects.

  1. Fungal Morphogenetic Pathways Are Required for the Hallmark Inflammatory Response during Candida albicans Vaginitis

    PubMed Central

    Palmer, Glen E.; Nash, Andrea K.; Lilly, Elizabeth A.; Fidel, Paul L.; Noverr, Mairi C.

    2014-01-01

    Vulvovaginal candidiasis, caused primarily by Candida albicans, presents significant health issues for women of childbearing age. As a polymorphic fungus, the ability of C. albicans to switch between yeast and hyphal morphologies is considered its central virulence attribute. Armed with new criteria for defining vaginitis immunopathology, the purpose of this study was to determine whether the yeast-to-hypha transition is required for the hallmark inflammatory responses previously characterized during murine vaginitis. Kinetic analyses of vaginal infection with C. albicans in C57BL/6 mice demonstrated that fungal burdens remained constant throughout the observation period, while polymorphonuclear leukocyte (PMN), S100A8, and interleukin-1β levels obtained from vaginal lavage fluid increased by day 3 onward. Lactate dehydrogenase activity was also positively correlated with increased effectors of innate immunity. Additionally, immunodepletion of neutrophils in infected mice confirmed a nonprotective role for PMNs during vaginitis. Determination of the importance of fungal morphogenesis during vaginitis was addressed with a two-pronged approach. Intravaginal inoculation of mice with C. albicans strains deleted for key transcriptional regulators (bcr1Δ/Δ, efg1Δ/Δ, cph1Δ/Δ, and efg1Δ/Δ cph1Δ/Δ) controlling the yeast-to-hypha switch revealed a crucial role for morphogenetic signaling through the Efg1 and, to a lesser extent, the Bcr1 pathways in contributing to vaginitis immunopathology. Furthermore, overexpression of transcription factors NRG1 and UME6, to maintain yeast and hyphal morphologies, respectively, confirmed the importance of morphogenesis in generating innate immune responses in vivo. These results highlight the yeast-to-hypha switch and the associated morphogenetic response as important virulence components for the immunopathogenesis of Candida vaginitis, with implications for transition from benign colonization to symptomatic infection. PMID

  2. Protective links between vitamin D, inflammatory bowel disease and colon cancer.

    PubMed

    Meeker, Stacey; Seamons, Audrey; Maggio-Price, Lillian; Paik, Jisun

    2016-01-21

    Vitamin D deficiency has been associated with a wide range of diseases and multiple forms of cancer including breast, colon, and prostate cancers. Relatively recent work has demonstrated vitamin D to be critical in immune function and therefore important in inflammatory diseases such as inflammatory bowel disease (IBD). Because vitamin D deficiency or insufficiency is increasingly prevalent around the world, with an estimated 30%-50% of children and adults at risk for vitamin D deficiency worldwide, it could have a significant impact on IBD. Epidemiologic studies suggest that low serum vitamin D levels are a risk factor for IBD and colon cancer, and vitamin D supplementation is associated with decreased colitis disease activity and/or alleviated symptoms. Patients diagnosed with IBD have a higher incidence of colorectal cancer than the general population, which supports the notion that inflammation plays a key role in cancer development and underscores the importance of understanding how vitamin D influences inflammation and its cancer-promoting effects. In addition to human epidemiological data, studies utilizing mouse models of colitis have shown that vitamin D is beneficial in preventing or ameliorating inflammation and clinical disease. The precise role of vitamin D on colitis is unknown; however, vitamin D regulates immune cell trafficking and differentiation, gut barrier function and antimicrobial peptide synthesis, all of which may be protective from IBD and colon cancer. Here we focus on effects of vitamin D on inflammation and inflammation-associated colon cancer and discuss the potential use of vitamin D for protection and treatment of IBD and colon cancer.

  3. Suppression of TAK1 pathway by shear stress counteracts the inflammatory endothelial cell phenotype induced by oxidative stress and TGF-β1

    PubMed Central

    Lee, Ee Soo; Boldo, Llorenç Solé; Fernandez, Bernadette O.; Feelisch, Martin; Harmsen, Martin C.

    2017-01-01

    Endothelial dysfunction is characterised by aberrant redox signalling and an inflammatory phenotype. Shear stress antagonises endothelial dysfunction by increasing nitric oxide formation, activating anti-inflammatory pathways and suppressing inflammatory pathways. The TAK1 (MAP3K7) is a key mediator of inflammation and non-canonical TGF-β signalling. While the individual roles of TAK1, ERK5 (MAPK7) and TGF-β pathways in endothelial cell regulation are well characterised, an integrative understanding of the orchestration of these pathways and their crosstalk with the redox system under shear stress is lacking. We hypothesised that shear stress counteracts the inflammatory effects of oxidative stress and TGF-β1 on endothelial cells by restoring redox balance and repressing the TAK1 pathway. Using human umbilical vein endothelial cells, we here show that TGF-β1 aggravates oxidative stress-mediated inflammatory activation and that shear stress activates ERK5 signalling while attenuating TGF-β signalling. ERK5 activation restores redox balance, but fails to repress the inflammatory effect of TGF-β1 which is suppressed upon TAK1 inhibition. In conclusion, shear stress counteracts endothelial dysfunction by suppressing the pro-inflammatory non-canonical TGF-β pathway and by activating the ERK5 pathway which restores redox signalling. We propose that a pharmacological compound that abates TGF-β signalling and enhances ERK5 signalling may be useful to counteract endothelial dysfunction. PMID:28209993

  4. Anti-Inflammatory Effect of Streptochlorin via TRIF-Dependent Signaling Pathways in Cellular and Mouse Models

    PubMed Central

    Shim, Do-Wan; Shin, Hee Jae; Han, Ji-Won; Shin, Woo-Young; Sun, Xiao; Shim, Eun-Jeong; Kim, Tack-Joong; Kang, Tae-Bong; Lee, Kwang-Ho

    2015-01-01

    Streptochlorin, a small compound derived from marine actinomycete, has been shown to have anti-angiogenic, anti-tumor, and anti-allergic activities. However, the anti-inflammatory effects and underlying mechanisms have not yet been reported. In the present study, we investigated the effect of streptochlorin on lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. Streptochlorin attenuated the production of proinflammatory mediators such as nitric oxide, cyclooxygenase-2, pro-interleukin (IL)-1β, and IL-6 in LPS-stimulated RAW264.7 cells through inhibition of the Toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF)-dependent signaling pathway. Furthermore, streptochlorin suppressed the infiltration of immune cells such as neutrophils into the lung and proinflammatory cytokine production such as IL-6 and TNF-α in broncho-alveolar lavage fluid (BALF) in the LPS-induced acute lung injury (ALI) mouse model. Streptochlorin has potent anti-inflammatory effects through regulating TRIF-dependent signaling pathways, suggesting that streptochlorin may provide a valuable therapeutic strategy in treating various inflammatory diseases. PMID:25822875

  5. Protective Effects of Celastrol on Diabetic Liver Injury via TLR4/MyD88/NF-κB Signaling Pathway in Type 2 Diabetic Rats

    PubMed Central

    Han, Li-ping; Li, Chun-jun; Sun, Bei; Xie, Yun; Guan, Yue; Ma, Ze-jun; Chen, Li-ming

    2016-01-01

    Immune and inflammatory pathways play a central role in the pathogenesis of diabetic liver injury. Celastrol is a potent immunosuppressive and anti-inflammatory agent. So far, there is no evidence regarding the mechanism of innate immune alterations of celastrol on diabetic liver injury in type 2 diabetic animal models. The present study was aimed at investigating protective effects of celastrol on the liver injury in diabetic rats and at elucidating the possible involved mechanisms. We analyzed the liver histopathological and biochemical changes and the expressions of TLR4 mediated signaling pathway. Compared to the normal control group, diabetic rats were found to have obvious steatohepatitis and proinflammatory cytokine activities were significantly upregulated. Celastrol-treated diabetic rats show reduced hepatic inflammation and macrophages infiltration. The expressions of TLR4, MyD88, NF-κB, and downstream inflammatory factors IL-1β and TNFα in the hepatic tissue of treated rats were downregulated in a dose-dependent manner. We firstly found that celastrol treatment could delay the progression of diabetic liver disease in type 2 diabetic rats via inhibition of TLR4/MyD88/NF-κB signaling cascade pathways and its downstream inflammatory effectors. PMID:27057550

  6. The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

    PubMed Central

    Liu, Xin; Wang, Ning; Fan, Shijun; Zheng, Xinchuan; Yang, Yongjun; Zhu, Yuanfeng; Lu, Yongling; Chen, Qian; Zhou, Hong; Zheng, Jiang

    2016-01-01

    Excessive activation of the TLR4 signalling pathway is critical for inflammation-associated disorders, while negative regulators play key roles in restraining TLR4 from over-activation. Naringenin is a citrus flavonoid with remarkable anti-inflammatory activity, but the mechanisms underlying its inhibition of LPS/TLR4 signalling are less clear. This study investigated the molecular targets and therapeutic effects of naringenin in vitro and in vivo. In LPS-stimulated murine macrophages, naringenin suppressed the expression of TNF-α, IL-6, TLR4, inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2) and NADPH oxidase-2 (NOX2). Naringenin also inhibited NF-κB and mitogen-activated protein kinase (MAPK) activation. However, it did not affect the IRF3 signalling pathway or interferon production, which upregulate activating transcription factor 3 (ATF3), an inducible negative regulator of TLR4 signalling. Naringenin was demonstrated to directly increase ATF3 expression. Inhibition of AMPK and its upstream calcium-dependent signalling reduced ATF3 expression and dampened the anti-inflammatory activity of naringenin. In murine endotoxaemia models, naringenin ameliorated pro-inflammatory reactions and improved survival. Furthermore, it induced AMPK activation in lung tissues, which was required for ATF3 upregulation and the enhanced anti-inflammatory activity. Overall, this study reveals a novel mechanism of naringenin through AMPK-ATF3-dependent negative regulation of the LPS/TLR4 signalling pathway, which thereby confers protection against murine endotoxaemia. PMID:28004841

  7. Luteolin protects mice from severe acute pancreatitis by exerting HO-1-mediated anti-inflammatory and antioxidant effects

    PubMed Central

    Xiong, Jie; Wang, Kezhou; Yuan, Chunxiao; Xing, Rong; Ni, Jianbo; Hu, Guoyong; Chen, Fengling; Wang, Xingpeng

    2017-01-01

    from the mice in the Lut + ZnPP group was significantly increased following the suppression of HO-1 activity. On the whole, our findings demonstrate that luteolin protects mice from SAP by inducing HO-1-mediated anti-inflammatory and antioxidant activities, in association with the suppression of the activation of the NF-κB pathway. PMID:27878246

  8. Pro-inflammatory cytokines enhance ERAD and ATF6α pathway activity in salivary glands of Sjögren's syndrome patients.

    PubMed

    Barrera, María-José; Aguilera, Sergio; Castro, Isabel; Cortés, Juan; Bahamondes, Verónica; Quest, Andrew F G; Molina, Claudio; González, Sergio; Hermoso, Marcela; Urzúa, Ulises; Leyton, Cecilia; González, María-Julieta

    2016-12-01

    Salivary gland (SG) acinar-cells are susceptible to endoplasmic reticulum (ER) stress related to their secretory activity and the complexity of synthesized secretory products. SGs of Sjögren's syndrome patients (SS)-patients show signs of inflammation and altered proteostasis, associated with low IRE1α/XBP-1 pathway activity without avert increases in apoptosis. Acinar-cells may avoid apoptosis by activation of the ATF6α pathway and ER-associated protein degradation (ERAD). The aim of this study was to evaluate the role of pro-inflammatory cytokines in ATF6α pathway/ERAD activation and cell viability in labial salivary glands (LSG) of SS-patients. In biopsies from SS-patients increased ATF6α signaling pathway activity, as evidenced by generation of the ATF6f cleavage fragment, and increased expression of ERAD machinery components, such as EDEM1, p97, SEL1L, gp78, UBE2J1, UBE2G2, HERP and DERLIN1, were observed compared to controls. Alternatively, for pro- (active-caspase-3) and anti-apoptotic (cIAP2) markers no significant difference between the two experimental groups was detected. Increased presence of ATF6f and ERAD molecules correlated significantly with increased expression of pro-inflammatory cytokines. These observations were corroborated in vitro in 3D-acini treated with TNF-α and/or IFN-γ, where an increase in the expression and activation of the ATF6α sensor and ERAD machinery components was detected under ER stress conditions, while changes in cell viability and caspase-3 activation were not observed. Cytokine stimulation protected cells from death when co-incubated with an ERAD machinery inhibitor. Alternatively, when cytokines were eliminated from the medium prior to ERAD inhibition, cell death increased, suggesting that the presence of pro-inflammatory cytokines in the medium is essential to maintain cell viability. In conclusion, the ATF6α pathway and the ERAD machinery are active in LSG of SS-patients. Both were also activated by TNF

  9. Chronic vagus nerve stimulation attenuates vascular endothelial impairments and reduces the inflammatory profile via inhibition of the NF-κB signaling pathway in ovariectomized rats.

    PubMed

    Li, Ping; Liu, Huaipu; Sun, Peng; Wang, Xiaoyu; Wang, Chen; Wang, Ling; Wang, Tinghuai

    2016-02-01

    Vagus nerve stimulation (VNS), a method for activating cholinergic anti-inflammatory pathways, could suppress endothelial activation and minimize tissue injury during inflammation. The aim of this study was to investigate the effects of chronic VNS on endothelial impairments and the inflammatory profile in ovariectomized (OVX) rats. Sprague-Dawley rats (7-8 months old) were randomly assigned to the following four groups: sham-OVX, OVX, OVX+sham-VNS, and OVX+VNS. Throughout the experimental period, the OVX+VNS group received VNS for 3h (20.0 Hz, 1.0 mA, and 10.00 ms pulse width) at the same time every other day. After 12 weeks of VNS, blood samples and thoracic aortas were collected for further analyses. Light microscopy and electron microscopy analyses showed that chronic VNS prevented endothelial swelling, desquamation and even necrosis in the OVX rats. In addition, it obviously improved endothelial function in the OVX rats by restoring the endothelial nitric oxide synthase (e-NOS) and serum endothelin-1 level. Increased expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) in the thoracic aortas and increases in the levels of circulating cytokines (TNF-α, IL-6, MCP-1, and CINC/KC) were also observed in the OVX rats. Chronic VNS significantly restored these detrimental changes partly by increasing the ACh concentrations in vascular walls and blocking NF-κB pathway activity. The results of this in vivo study have shown that the administration of chronic VNS during, in the early stage of estrogen deficiency, protects OVX rats from endothelial impairments and the inflammatory profile. These findings indicate that activation of the vagus nerve could be a promising supplemental therapy for reducing the risks of suffering from further CVDs in postmenopausal women.

  10. Gastrointestinal HCO3- transport and epithelial protection in the gut: new techniques, transport pathways and regulatory pathways.

    PubMed

    Seidler, Ursula E

    2013-12-01

    The concept of a protective alkaline gastric and duodenal mucus layer is a century old, yet it is amazing how much new information on HCO3(-) transport pathways has emerged recently, made possible by the extensive utilization of gene-deleted and transgenic mice and novel techniques to study HCO3(-) transport. This review highlights recent findings regarding the importance of HCO3(-) for mucosal protection of duodenum and other gastrointestinal epithelia against luminal acid and other damaging factors. Recently, methods have been developed to visualize HCO3(-) transport in vivo by assessing the surface pH in the mucus layer, as well as the epithelial pH. New information about HCO3(-) transport pathways, and emerging concepts about the intricate regulatory network that governs duodenal HCO3(-) secretion are described, and new perspectives for drug therapy discussed.

  11. ERK Signaling Pathway Plays a Key Role in Baicalin Protection Against Acetaminophen-Induced Liver Injury.

    PubMed

    Liao, Chia-Chih; Day, Yuan-Ji; Lee, Hung-Chen; Liou, Jiin-Tarng; Chou, An-Hsun; Liu, Fu-Chao

    2017-01-01

    Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15-60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent.

  12. Protective effect of higenamine ameliorates collagen-induced arthritis through heme oxygenase-1 and PI3K/Akt/Nrf-2 signaling pathways

    PubMed Central

    Duan, Wenjiang; Chen, Jianmin; Wu, Yu; Zhang, Yong; Xu, Yuansheng

    2016-01-01

    Existing in Ranunculaceae Aconitum and tomato, with the chemical name 1-phydroxybenzyl-1,2,3,4-tetrahy-droisoquinoline, higenamine is widely distributed in China. Higenamine's anti-inflammatory, antioxidant and anti-apoptotic effects have been identified in previous studies. The present study attempted to determine the protective effect of higenamine against collagen-induced arthritis through heme oxygenase-1 (HO-1) and PI3K/Akt/Nrf-2 signaling pathways. A type II collagen (CII)-induced arthritis (CIA) model was established and clinical arthritis scores were used to appraise the curative effect of higenamine. Inflammatory reactions, oxidative damage and caspase-3/9 activation were detected using specific ELISA kits. In addition, western blotting was used to evaluate the expression of HO-1, Akt and Nrf-2 protein in CII-induced CIA mice. In CII-induced CIA mice, the clinical arthritis scores, inflammatory reactions, oxidation damage and caspase-3/9 activation were increased and activated. The results demonstrated that treatment with higenamine significantly reduced the elevation of clinical arthritis scores (P<0.01), and suppressed the promotion of inflammatory reactions, oxidation damage and caspase-3/9 activation. Furthermore, higenamine significantly increased HO-1 protein expression (P<0.01) and upregulated the PI3K/Akt/Nrf-2 signal pathway in CII-induced CIA mice. Collectively, it is concluded that higenamine protects against CII-induced CIA through the induction of HO-1 and the upregulation of the PI3K/Akt/Nrf-2 signaling pathway. In conclusion, higenamine may be a beneficial drug for protecting against CIA. PMID:27882125

  13. Investigation of Pharmacological Activity of Caralluma penicillata: Anti-Inflammatory Properties and Gastritis Protection against Indomethacin in Adult Guinea Pigs

    PubMed Central

    Albaser, Nabil; Ghanem, Najeeb; Shehab, Mohanad; Al-Adhal, Adnan

    2014-01-01

    Caralluma is a plant that possessing a great therapeutic potential in folk medicine in Yemen, namely, Caralluma penicillata (C. penicillata) as antiulcer. The study aims to evaluate the anti-inflammatory properties and gastritis protection activity of C. penicillata against indomethacin in adult guinea pigs. The study was divided into four parts: firstly, the optimum dose of extract as anti-inflammatory effect was determined. Secondly, the acute anti-inflammatory effect of extract were estimated. Thirdly, the repeated doses of extract against chronic inflammation was estimated. The anti-inflammatory activity of extract was compared with indomethacin as a prototype of drug against inflammation. Fourthly, the gastritis protection properties of extract with/without indomethacin were performed. The results showed that a 400 mg/kg of 10% ethanol extract produced the maximum of anti-inflammatory effect. Also, the single dose of extract was equipotent for indomethacin (10 mg/kg), but shorter in duration with regard to acute anti-inflammatory effect. In addition, the repeated doses of extract against chronic inflammation were less potent than indomethacin with regard to ulcerogenic effect. On the other hand, extract-indomethacin combination reduced the gastritis effect of indomethacin based on ulcer index and histological study. PMID:27433522

  14. Investigation of Pharmacological Activity of Caralluma penicillata: Anti-Inflammatory Properties and Gastritis Protection against Indomethacin in Adult Guinea Pigs.

    PubMed

    Albaser, Nabil; Ghanem, Najeeb; Shehab, Mohanad; Al-Adhal, Adnan; Amood Al-Kamarany, Mohammed

    2014-01-01

    Caralluma is a plant that possessing a great therapeutic potential in folk medicine in Yemen, namely, Caralluma penicillata (C. penicillata) as antiulcer. The study aims to evaluate the anti-inflammatory properties and gastritis protection activity of C. penicillata against indomethacin in adult guinea pigs. The study was divided into four parts: firstly, the optimum dose of extract as anti-inflammatory effect was determined. Secondly, the acute anti-inflammatory effect of extract were estimated. Thirdly, the repeated doses of extract against chronic inflammation was estimated. The anti-inflammatory activity of extract was compared with indomethacin as a prototype of drug against inflammation. Fourthly, the gastritis protection properties of extract with/without indomethacin were performed. The results showed that a 400 mg/kg of 10% ethanol extract produced the maximum of anti-inflammatory effect. Also, the single dose of extract was equipotent for indomethacin (10 mg/kg), but shorter in duration with regard to acute anti-inflammatory effect. In addition, the repeated doses of extract against chronic inflammation were less potent than indomethacin with regard to ulcerogenic effect. On the other hand, extract-indomethacin combination reduced the gastritis effect of indomethacin based on ulcer index and histological study.

  15. Chlamydial Lipoproteins Stimulate Toll-Like Receptors 1/2 Mediated Inflammatory Responses through MyD88-Dependent Pathway

    PubMed Central

    Wang, Yong; Liu, Qiong; Chen, Ding; Guan, Jie; Ma, Linghui; Zhong, Guangming; Shu, Hengping; Wu, Xiang

    2017-01-01

    Chlamydiae are very important pathogens which could cause several types of diseases in human, but little is known about its pathogenic mechanism. In order to elucidate host inflammatory response and the signal pathway induced by Chlamydial lipoproteins, the predicted lipoproteins of Chlamydia trachomatis were tested for their ability to induce the release of proinflammatory cytokines by mouse macrophages or human TLR (Toll-Like Receptor) expressing cell lines. The results showed that recombinant proteins of C. trachomatis D381, D541, D067, and D775 displayed a strong ability to induce the release of IL-8 in TLR expressing cell line. The signal pathways involved TLR1/2 and TLR2/CD14 but not TLR4. Moreover, except D067, the proinflammatory cytokine induction by D381, D541, and D775 required the thioacylation site (cysteine) for lipid modification and the induction was through MyD88-mediated pathway. Our data supported that lipoproteins played a vital role in pathogenesis of C. trachomatis-induced inflammatory responses via TLR pathway. It was the first study to characterize other chlamydial lipoproteins after identifying the role of MIP (D541) on pathogenesis of Chlamydial diseases. PMID:28184217

  16. Hydrogen sulfide (H2S) attenuates uranium-induced acute nephrotoxicity through oxidative stress and inflammatory response via Nrf2-NF-κB pathways.

    PubMed

    Zheng, Jifang; Zhao, Tingting; Yuan, Yan; Hu, Nan; Tang, Xiaoqing

    2015-12-05

    As an endogenous gaseous mediator, H2S exerts anti-oxidative, anti-inflammatory and cytoprotective effects in kidneys. This study was designed to investigate the protective effect of H2S against uranium-induced nephrotoxicity in adult SD male rats after in vivo effect of uranium on endogenous H2S formation was explored in kidneys. The levels of endogenous H2S and H2S-producing enzymes (CBS and CSE) were measured in renal homogenates from rats intoxicated by an intraperitoneally (i.p.) injection of uranyl acetate at a single dose of 2.5, 5 or 10 mg/kg. In rats injected i.p. with uranyl acetate (5 mg/kg) or NaHS (an H2S donor, 28 or 56 μmol/kg) alone or in combination, we determined biochemical parameters and histopathological alteration to assess kidney function, examined oxidative stress markers, and investigated Nrf2 and NF-κB pathways in kidney homogenates. The results suggest that uranium intoxication in rats decreased endogenous H2S generation as well as CBS and CSE protein expression. NaHS administration in uranium-intoxicated rats ameliorated the renal biochemical indices and histopathological effects, lowered MDA accumulation, and restored GSH level and anti-oxidative enzymes activities like SOD, CAT, GPx and GST. NaHS treatment in uranium-intoxicated rats activated uranium-inhibited protein expression and nuclear translocation of transcription factor Nrf2, which increased protein expression of downstream target-Nrf2 genes HO-1, NQO-1, GCLC, and TXNRD-1. NaHS administration in uranium-intoxicated rats inhibited uranium-induced nuclear translocation and phosphorylation of transcription factor κB/p65, which decreased protein expression of target-p65 inflammatory genes TNF-α, iNOS, and COX-2. Taken together, these data implicate that H2S can afford protection to rat kidneys against uranium-induced adverse effects through induction of antioxidant defense by activating Nrf2 pathway and reduction of inflammatory response by suppressing NF-κB pathway.

  17. Naringin inhibits TNF-α induced oxidative stress and inflammatory response in HUVECs via Nox4/NF-κ B and PI3K/Akt pathways.

    PubMed

    Li, Wenshuang; Wang, Changyuan; Peng, Jinyong; Liang, Jing; Jin, Yue; Liu, Qi; Meng, Qiang; Liu, Kexin; Sun, Huijun

    2014-01-01

    In the development of atherosclerosis, naringin has exhibited potential protective effects. However, the specific mechanisms are not clearly understood. The aim of this trial was to determine the anti-oxidative and anti-inflammatory effects of naringin and uncover the mechanisms in Tumor Necrosis Factor-alpha (TNF-α) induced Human Umbilical Vein Endothelial Cells (HUVECs). Reactive Oxygen Species (ROS) were measured by flow cytometry assay. The levels of NADPH oxidase 4 (Nox4), p22(phox), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) over-expressions were measured by qRT-PCR and Western blotting analyses. Activation of Phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Nuclear Factor-κB (NF-κB) was evaluated by Western blotting. Naringin inhibited ROS production as well as over-expression levels of Nox4, p22(phox) induced by TNF-α. Naringin inhibited TNF-α induced mRNA and protein over-expressions of ICAM-1 and VCAM-1. Naringin also suppressed activation of NF-κB and PI3K/Akt signaling pathways. These results indicated the preventive effects of naringin on HUVECs injury caused by oxidative stress and inflammation response and the effects might be obtained via inhibition of Nox4 and NF-κB pathways as well as activation of PI3K/Akt pathway. Naringin may be useful in preventing endothelial dysfunction, therefore to ameliorate the development of atherosclerosis.

  18. Protective effect of polyphenols in an inflammatory process associated with experimental pulmonary fibrosis in mice.

    PubMed

    Impellizzeri, Daniela; Talero, Elena; Siracusa, Rosalba; Alcaide, Antonio; Cordaro, Marika; Maria Zubelia, Jose; Bruschetta, Giuseppe; Crupi, Rosalia; Esposito, Emanuela; Cuzzocrea, Salvatore; Motilva, Virginia

    2015-09-28

    Polyphenols have been described to have a wide range of biological activities, and many reports, published during recent years, have highlighted the beneficial effects of phenolic compounds, illustrating their promising role as therapeutic tools in several acute and chronic disorders. The purpose of study was to evaluate, in an already-assessed model of lung injury caused by bleomycin (BLM) administration, the role of resveratrol and quercetin, as well as to explore the potential beneficial properties of a mango leaf extract, rich in mangiferin, and a grape leaf extract, rich in dihydroquercetin (DHQ), on the same model. Mice were subjected to intra-tracheal administration of BLM, and polyphenols were administered by oral route immediately after BLM instillation and daily for 7 d. Treatment with resveratrol, mangiferin, quercetin and DHQ inhibited oedema formation and body weight loss, as well as ameliorated polymorphonuclear infiltration into the lung tissue and reduced the number of inflammatory cells in bronchoalveolar lavage fluid. Moreover, polyphenols suppressed inducible nitric oxide synthase expression, and prevented oxidative and nitroxidative lung injury, as shown by the reduced nitrotyrosine and poly (ADP-ribose) polymerase levels. The degree of apoptosis, as evaluated by Bid and Bcl-2 balance, was also suppressed after polyphenol treatment. Finally, these natural products down-regulated cyclo-oxygenase-2, extracellular signal-regulated kinase phosphorylated expression and reduced NF-κBp65 translocation. Our findings confirmed the anti-inflammatory effects of resveratrol and quercetin in BLM-induced lung damage, and highlight, for the first time, the protective properties of exogenous administration of mangiferin and DHQ on experimental pulmonary fibrosis.

  19. Lymphatic system: an active pathway for immune protection.

    PubMed

    Liao, Shan; von der Weid, P Y

    2015-02-01

    Lymphatic vessels are well known to participate in the immune response by providing the structural and functional support for the delivery of antigens and antigen presenting cells to draining lymph nodes. Recent advances have improved our understanding of how the lymphatic system works and how it participates to the development of immune responses. New findings suggest that the lymphatic system may control the ultimate immune response through a number of ways which may include guiding antigen/dendritic cells (DC) entry into initial lymphatics at the periphery; promoting antigen/DC trafficking through afferent lymphatic vessels by actively facilitating lymph and cell movement; enabling antigen presentation in lymph nodes via a network of lymphatic endothelial cells and lymph node stroma cell and finally by direct lymphocytes exit from lymph nodes. The same mechanisms are likely also important to maintain peripheral tolerance. In this review we will discuss how the morphology and gene expression profile of the lymphatic endothelial cells in lymphatic vessels and lymph nodes provides a highly efficient pathway to initiate immune responses. The fundamental understanding of how lymphatic system participates in immune regulation will guide the research on lymphatic function in various diseases.

  20. Anti-inflammatory action of insulin via induction of Gadd45-β transcription by the mTOR signaling pathway

    PubMed Central

    Bortoff, Katherine D; Keeton, Adam B; Franklin, J Lee; Messina, Joseph L

    2010-01-01

    Insulin regulates a large number of genes in a tissue-specific manner. We have previously identified genes modulated by insulin in the liver and in liver-derived cells that have not yet been characterized as insulin regulated, and results of these previous studies indicated that numerous genes are induced by insulin via the MEK-ERK pathway. We now describe new studies indicating that Gadd45-β can be induced by acute insulin treatment. Although other regulators of Gadd45-β expression may utilize the MEK-ERK pathway, the data indicate that insulin utilizes signaling pathways separate from either MEK-ERK, PI3-K, or p38 signaling pathways in the regulation of Gadd45-β transcription. Our findings show that activation of a downstream effector of multiple signaling pathways, mTOR, was required for insulin-induction of Gadd45-β gene transcription. Increased expression of Gadd45-β can inhibit c-Jun N-terminal kinase (JNK) activity. Since TNFα is increased during inflammation, and acts, at least in part, via the JNK signaling pathway, insulin induction of Gadd45-β suggests a mechanism for the anti-inflammatory actions of insulin. PMID:21286247

  1. Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats

    PubMed Central

    2013-01-01

    Background Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. Results EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat’s paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. Conclusions The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats. PMID:23517865

  2. Individuals with increased inflammatory response to ozone demonstrate muted signaling of immune cell trafficking pathways

    EPA Science Inventory

    Background Exposure to ozone activates innate immune function and causes neutrophilic (PMN) airway inflammation that in some individuals is robustly elevated. The interplay between immunoinflammatory function and genomic signaling in those with heightened inflammatory responsive...

  3. Taxonomic applicability of inflammatory cytokines in adverse outcome pathway (AOP) development

    EPA Science Inventory

    Cytokines, low-molecular-weight messenger proteins that act as intercellular immunomodulatory signals, have become a mainstream preclinical marker for assessing the systemic inflammatory response to external stressors. The challenge is to quantitate from healthy subjects cytokine...

  4. Esculin exhibited anti-inflammatory activities in vivo and regulated TNF-α and IL-6 production in LPS-stimulated mouse peritoneal macrophages in vitro through MAPK pathway.

    PubMed

    Niu, Xiaofeng; Wang, Yu; Li, Weifeng; Zhang, Hailin; Wang, Xiumei; Mu, Qingli; He, Zehong; Yao, Huan

    2015-12-01

    Esculin, a coumarinic derivative found in Aesculus hippocastanum L. (Horse-chestnut), has been reported to have potent anti-inflammatory properties. The present study is designed to investigate the protective effects of esculin on various inflammation models in vivo and in vitro and to clarify the possible mechanism. Induced-animal models of inflammation and lipopolysaccharide (LPS)-challenged mouse peritoneal macrophages were used to examine the anti-inflammatory activity of esculin. In present study, xylene-induced mouse ear edema, carrageenan-induced rat paw edema, and carrageenan-induced mouse pleurisy were attenuated by esculin. In vitro, the pro-inflammatory cytokine levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in supernatant were reduced by esculin. Meanwhile, we found that esculin significantly inhibited LPS-induced activation of mitogen-activated protein kinase (MAPK) pathway in peritoneal macrophages. These results suggest that esculin has potent anti-inflammatory activities in vivo and in vitro, which may involve the inhibition of the MAPK pathway. Esculin may be a promising preventive agent for inflammatory diseases in human.

  5. Can the TLR-4-Mediated Signaling Pathway Be “A Key Inflammatory Promoter for Sporadic TAA”?

    PubMed Central

    Ruvolo, Giovanni; Pisano, Calogera; Candore, Giuseppina; Lio, Domenico; Palmeri, Cesira; Maresi, Emiliano; Balistreri, Carmela R.

    2014-01-01

    Thoracic aorta shows with advancing age various changes and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur as pathological entities responsible principally for the sporadic TAA onset. Little is known about their genetic, molecular, and cellular mechanisms. Recent evidence is proposing the strong role of a chronic immune/inflammatory process in their evocation and progression. Thus, we evaluated the potential role of Toll like receptor- (TLR-) 4-mediated signaling pathway and its polymorphisms in sporadic TAA. Genetic, immunohistochemical, and biochemical analyses were assessed. Interestingly, the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA (OR = 14.4, P = 0.0008) and it represents, together with rs1799752 ACE, rs3918242 MMP-9, and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA. Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing. Thus, TLR4 pathway should seem to have a key role in sporadic TAA. It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments. PMID:25120286

  6. Gastrodia elata attenuates inflammatory response by inhibiting the NF-κB pathway in rheumatoid arthritis fibroblast-like synoviocytes.

    PubMed

    Li, Yu; Wang, Li-Min; Xu, Jian-Zhong; Tian, Ke; Gu, Chen-Xi; Li, Zhi-Fu

    2017-01-01

    Gastrodia elata (GE), which belongs to the Orchidaceae family, was found to possess anti-inflammatory activity. However, the effect of GE on inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) remains largely unknown. Thus, the aim of this study was to investigate the effects of GE on tumor necrosis factor-α (TNF-α)-induced inflammatory response in RA-FLS and the underlying molecular mechanism was also explored. Our results demonstrated that GE significantly attenuated TNF-α-induced IL-6 and IL-8 production in RA-FLS. GE also inhibited TNF-α-induced MMP-3 and MMP-13 expression in RA-FLS. Furthermore, pretreatment with GE significantly attenuated TNF-α-induced the expression of p-p65 and IκBα degradation in RA-FLS. In conclusion, this study demonstrated for the first time that GE attenuated inflammatory response by inhibiting the NF-κB pathway signaling in RA-FLS. Thus, GE might have a therapeutic potential towards the treatment of RA.

  7. Binding model for eriodictyol to Jun-N terminal kinase and its anti-inflammatory signaling pathway

    PubMed Central

    Lee, Eunjung; Jeong, Ki-Woong; Shin, Areum; Jin, Bonghwan; Jnawali, Hum Nath; Jun, Bong-Hyun; Lee, Jee-Young; Heo, Yong-Seok; Kim, Yangmee

    2013-01-01

    The anti-inflammatory activity of eriodictyol and its mode of action were investigated. Eriodictyol suppressed tumor necrosis factor (mTNF)-α, inducible nitric oxide synthase (miNOS), interleukin (mIL)-6, macrophage inflammatory protein (mMIP)-1, and mMIP-2 cytokine release in LPS-stimulated macrophages. We found that the anti-inflammatory cascade of eriodictyol is mediated through the Toll-like Receptor (TLR)4/CD14, p38 mitogen-activated protein kinases (MAPK), extracellular-signalregulated kinase (ERK), Jun-N terminal kinase (JNK), and cyclooxygenase (COX)-2 pathway. Fluorescence quenching and saturation-transfer difference (STD) NMR experiments showed that eriodictyol exhibits good binding affinity to JNK, 8.79 × 105 M-1. Based on a docking study, we propose a model of eriodictyol and JNK binding, in which eriodictyol forms 3 hydrogen bonds with the side chains of Lys55, Met111, and Asp169 in JNK, and in which the hydroxyl groups of the B ring play key roles in binding interactions with JNK. Therefore, eriodictyol may be a potent anti-inflammatory inhibitor of JNK. [BMB Reports 2013; 46(12): 594-599] PMID:24195792

  8. Low-intensity pulsed ultrasound (LIPUS) prevents periprosthetic inflammatory loosening through FBXL2-TRAF6 ubiquitination pathway.

    PubMed

    Zhao, Xiang; Zhao, Gangsheng; Shi, Zhongli; Zhou, Chenhe; Chen, Yunlin; Hu, Bin; Yan, Shigui

    2017-04-05

    Previous studies have shown that Low intensity pulsed ultrasound(LIPUS) prevents polyethylene-debris-induced periprosthetic loosening in vivo, but the details of the mechanism by which it does so remain unclear. In this article, we used polyethylene debris induced RAW 264.7 cells as the in vitro model, and tested the effect of LIPUS on this model. Changes in the level of inflammatory cytokines, cell proliferation, and apoptosis were assessed. Gene overexpression and siRNA technique were applied, and the levels of expression of FBXL2, TRAF6, ERK, and related inflammatory cytokines were also measured. Results indicated that FBXL2-mediated TRAF6 ubiquitination and degradation also plays an important role in aseptic periprosthetic loosening process, and LIPUS prevents such loosening by strengthening this pathway.

  9. Low-intensity pulsed ultrasound (LIPUS) prevents periprosthetic inflammatory loosening through FBXL2-TRAF6 ubiquitination pathway

    PubMed Central

    Zhao, Xiang; Zhao, Gangsheng; Shi, Zhongli; Zhou, Chenhe; Chen, Yunlin; Hu, Bin; Yan, Shigui

    2017-01-01

    Previous studies have shown that Low intensity pulsed ultrasound(LIPUS) prevents polyethylene-debris-induced periprosthetic loosening in vivo, but the details of the mechanism by which it does so remain unclear. In this article, we used polyethylene debris induced RAW 264.7 cells as the in vitro model, and tested the effect of LIPUS on this model. Changes in the level of inflammatory cytokines, cell proliferation, and apoptosis were assessed. Gene overexpression and siRNA technique were applied, and the levels of expression of FBXL2, TRAF6, ERK, and related inflammatory cytokines were also measured. Results indicated that FBXL2-mediated TRAF6 ubiquitination and degradation also plays an important role in aseptic periprosthetic loosening process, and LIPUS prevents such loosening by strengthening this pathway. PMID:28378753

  10. Protective Effect of Zingiber officinale Against Dalton's Lymphoma Ascites Tumour by Regulating Inflammatory Mediator and Cytokines.

    PubMed

    Rubila, Sundararaj; Ranganathan, Thottiam Vasudevan; Sakthivel, Kunnathur Murugesan

    2016-12-01

    The aim of the present investigation was to evaluate Zingiber officinale paste against Dalton's lymphoma ascites (DLA)-induced tumours in Swiss albino mice. Experimental animals received Z. officinale paste (low dose 100 mg/kg bw and high dose 500 mg/kg bw) orally for eight alternative days. Treatment with Z. officinale paste showed significant increase in haemoglobin level and decrease in aspartate amino transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma glutamyl transferase (γ-GT) level. Z. officinale paste reduced the inflammatory mediators and cytokine levels, such as inducible nitric oxide (iNOS), tumour necrosis factor level (TNF-α) and interleukin-1β (IL-1β). Treatment with Z. officinale paste also significantly increased the antioxidant enzyme level, such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione transferase (GST), and decreased the lipid peroxidation. Treatment also increased the vitamin C and E levels in treated animals compared with the DLA-bearing host. Histopathological studies also confirmed the protective influence of Z. officinale paste against DLA. The present study suggested that Z. officinale paste could be used as natural spice and a potent antitumour agent.

  11. MMP9 is protective against lethal inflammatory mass lesions in the mouse colon

    PubMed Central

    Hald, Andreas; Rønø, Birgitte; Melander, Maria C.; Ding, Ming; Holck, Susanne; Lund, Leif R.

    2011-01-01

    SUMMARY The family of matrix metalloproteinases (MMPs) is responsible for extracellular matrix degradation during physiological and pathophysiological tissue remodeling processes such as embryogenesis, tissue repair and cancer progression. Despite these important roles of MMPs, inhibition or ablation of individual members of the MMP family in animal models have been shown to have little effect. It has been speculated that this results from a functional overlap between individual MMPs and (as-yet-unclassified) functional overlaps between MMPs and other protease systems. We here present genetic data showing that concomitant ablation of MMP9 (gelatinase B) and the serine protease plasmin results in lethal inflammatory mass lesions in the colon. These lesions possessed several histological attributes that are characteristic of mucosal prolapse seen in humans, and they were found to be associated with splenomegaly, enlarged mesenteric lymph nodes, decreased thymus size and altered populations of circulating immune cells. A time-course study provided evidence that the massive lymphoid hyperplasia and reactive changes were secondary to discrete fibrinous lesions also observed in mice only deficient for plasminogen (Plg), the zymogen for plasmin. These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg. PMID:21123624

  12. Protective effect of aqueous extract of Spinacia oleracea leaves in experimental paradigms of inflammatory bowel disease.

    PubMed

    Otari, Kishor Vasant; Gaikwad, Priyanka Subhash; Shete, Rajkumar Virbhadrappa; Upasani, Chandrashekhar Devidas

    2012-10-01

    The present study was aimed to assess the protective effect of aqueous extract of Spinacia oleracea leaves (AESO 250, 500, and 1,000 mg/kg, p.o.) in inflammatory bowel disease using acetic acid- and ethanol-induced colitis in mice and indomethacin-induced enterocolitis in rats. The preliminary phytochemical analysis and further high performance thin layer chromatographic (HPTLC) analysis and phytochemical tests of HPTLC bands confirmed the presence of flavonoids and tannins in AESO. In acute oral toxicity study, administration of AESO (5,000 mg/kg, p.o.) did not show any sign of toxicity and mortality. The treatment with AESO significantly increased body weight, decreased diarrhea with bloody stools, increased blood hemoglobin and plasma total protein, and decreased serum and ileum or colon malondialdehyde content and attenuated the extent of lesions and ameliorated the histological injury of mucosa in all paradigms. The most prominent effects were evident for AESO 1,000 mg/kg. The results of the present study revealed that AESO was effective in attenuating almost all the symptoms of IBD in experimental paradigms. The effect might be due to the antioxidant activity of the flavonoids present in the AESO.

  13. Protective Effect of Amygdalin on LPS-Induced Acute Lung Injury by Inhibiting NF-κB and NLRP3 Signaling Pathways.

    PubMed

    Zhang, Ao; Pan, Weiyun; Lv, Juan; Wu, Hui

    2017-03-16

    The acute lung injury (ALI) is a leading cause of morbidity and mortality in critically ill patients. Amygdalin is derived from the bitter apricot kernel, an efficacious Chinese herbal medicine. Although amygdalin is used by many cancer patients as an antitumor agent, there is no report about the effect of amygdalin on acute lung injury. Here we explored the protective effect of amygdalin on ALI using lipopolysaccharide (LPS)-induced murine model by detecting the lung wet/dry ratio, the myeloperoxidase (MPO) in lung tissues, inflammatory cells in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines production, as well as NLRP3 and NF-κB signaling pathways. The results showed that amygdalin significantly reduced LPS-induced infiltration of inflammatory cells and the production of TNF-α, IL-1β, and IL-6 in the BALF. The activity of MPO and lung wet/dry ratio were also attenuated by amygdalin. Furthermore, the western blotting analysis showed that amygdalin remarkably inhibited LPS-induced NF-κB and NLRP3 activation. These findings indicate that amygdalin has a protective effect on LPS-induced ALI in mice. The mechanism may be related to the inhibition of NF-κB and NLRP3 signaling pathways.

  14. Study of plasma protein C and inflammatory pathways: biomarkers for dimethylnitrosamine-induced liver fibrosis in rats.

    PubMed

    Saha, Joy K; Xia, Jinqi; Sandusky, George E; Chen, Yun-Fei; Gerlitz, Bruce; Grinnell, Brian; Jakubowski, Joseph A

    2007-12-01

    The present investigation was designed to identify potential biomarker(s) and assess the involvement of inflammatory pathway in dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Following DMN-treatment (10 mg/ml/kg, i.p., given three consecutive days each week for 4 weeks) body and liver weights were significantly decreased concurrent with increasing severity of liver damage assessed by bridging fibrosis, a histopathologic assessment and characteristic of human liver disease. Protein C along with albumin, C-reactive-protein (CRP), haptoglobin and total protein were significantly reduced and correlated with changes in liver histopathology. Biochemical markers of liver functions were significantly increased and correlated with changes in liver histopathology and plasma levels of protein C. Soluble intracellular-adhesion-molecule-1 (sICAM-1) levels were increased significantly but were poorly correlated with histopathology and protein C levels. Inflammatory chemokines and other analytes, monocyte-chemoattractant-protein-1 and 3 (MCP-1 and MCP-3), macrophage-colony-stimulating-factor (M-CSF) were significantly increased during the disease progression, whereas macrophage-derived-chemokine (MDC) and CRP were significantly suppressed. Circulating neutrophils and monocytes were also increased along with disease progression. The differential changes in sICAM-1, hyaluronic acid, gamma-glutamyltranspeptidase (GGT), neutrophil and other inflammatory chemokines suggest the involvement of inflammatory pathways in DMN-induced liver fibrosis. In conclusion, the progressive changes in protein C along with other noninvasive biochemical parameters whose levels were significantly correlated with disease progression may serve as biomarkers for pharmacological assessment of targeted therapy for liver fibrosis.

  15. Folic Acid Is Able to Polarize the Inflammatory Response in LPS Activated Microglia by Regulating Multiple Signaling Pathways

    PubMed Central

    Salvatore, Rosaria; Porro, Chiara; Trotta, Teresa

    2016-01-01

    We investigated the ability of folic acid to modulate the inflammatory responses of LPS activated BV-2 microglia cells and the signal transduction pathways involved. To this aim, the BV-2 cell line was exposed to LPS as a proinflammatory response inducer, in presence or absence of various concentrations of folic acid. The production of nitric oxide (NO) was determined by the Griess test. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-10 were determined by ELISA. Inducible NO synthase (iNOS), nuclear transcription factor-kappa B (NF-κB) p65, MAPKs protein, and suppressors of cytokine signaling (SOCS)1 and SOCS3 were analyzed by western blotting. TNF-α and IL-1β, as well as iNOS dependent NO production, resulted significantly inhibited by folic acid pretreatment in LPS-activated BV-2 cells. We also observed that folic acid dose-dependently upregulated both SOCS1 and SOCS3 expression in BV-2 cells, leading to an increased expression of the anti-inflammatory cytokine IL-10. Finally, p-IκBα, which indirectly reflects NF-κB complex activation, and JNK phosphorylation resulted dose-dependently downregulated by folic acid pretreatment of LPS-activated cells, whereas p38 MAPK phosphorylation resulted significantly upregulated by folic acid treatment. Overall, these results demonstrated that folic acid was able to modulate the inflammatory response in microglia cells, shifting proinflammatory versus anti-inflammatory responses through regulating multiple signaling pathways. PMID:27738387

  16. Reflex control of inflammation by the splanchnic anti-inflammatory pathway is sustained and independent of anesthesia.

    PubMed

    Martelli, Davide; Yao, Song T; Mancera, Julian; McKinley, Michael J; McAllen, Robin M

    2014-11-01

    Following an immune challenge, there is two-way communication between the nervous and immune systems. It is proposed that a neural reflex--the inflammatory reflex--regulates the plasma levels of the key proinflammatory cytokine TNF-α, and that its efferent pathway is in the splanchnic sympathetic nerves. The evidence for this reflex is based on experiments on anesthetized animals, but anesthesia itself suppresses inflammation, confounding interpretation. Here, we show that previous section of the splanchnic nerves strongly enhances the levels of plasma TNF-α in conscious rats 90 min after they received intravenous LPS (60 μg/kg). The same reflex mechanism, therefore, applies in conscious as in anesthetized animals. In anesthetized rats, we then determined the longer-term effects of splanchnic nerve section on responses to LPS (60 μg/kg iv). We confirmed that prior splanchnic nerve section enhanced the early (90 min) peak in plasma TNF-α and found that it reduced the 90-min peak of the anti-inflammatory cytokine IL-10; both subsequently fell to low levels in all animals. Splanchnic nerve section also enhanced the delayed rise in two key proinflammatory cytokines IL-6 and interferon γ. That enhancement was undiminished after 6 h, when other measured cytokines had subsided. Finally, LPS treatment caused hypotensive shock in rats with cut splanchnic nerves but not in sham-operated animals. These findings demonstrate that reflex activation of the splanchnic anti-inflammatory pathway has a powerful and sustained restraining influence on inflammatory processes.

  17. Protein kinase CK2α catalytic subunit ameliorates diabetic renal inflammatory fibrosis via NF-κB signaling pathway.

    PubMed

    Huang, Junying; Chen, Zhiquan; Li, Jie; Chen, Qiuhong; Li, Jingyan; Gong, Wenyan; Huang, Jiani; Liu, Peiqing; Huang, Heqing

    2017-02-23

    Activation of casein kinase 2 (CK2) is closely linked to the body disturbance of carbohydrate metabolism and inflammatory reaction. The renal chronic inflammatory reaction in the setting of diabetes is one of the important hallmarks of diabetic renal fibrosis. However, it remains unknown whether CK2 influences the process of diabetic renal fibrosis. The current study is aimed to investigate if CK2α ameliorates renal inflammatory fibrosis in diabetes via NF-κB pathway. To explore potential regulatory mechanism of CK2α, the expression and activity of CK2α, which were studied by plasmid transfection, selective inhibitor, small-interfering RNA (siRNA) and adenovirus infection in vitro or in vivo, were analyzed by means of western blotting (WB), dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The following findings were observed: (1) Expression of CK2α was upregulated in kidneys of db/db and KKAy diabetic mice; (2) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression suppressed high glucose-induced expressions of FN and ICAM-1 in glomerular mesangial cells (GMCs); (3) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression not only restrained IκB degradation, but also suppressed HG-induced nuclear accumulation, transcriptional activity and DNA binding activity of NF-κB in GMCs; (4) Treatment of TBB or CK2α RNAi adenovirus infection ameliorated renal fibrosis in diabetic animals; (5) Treatment of TBB or CK2α RNAi adenovirus infection suppressed IκB degradation and NF-κB nuclear accumulation in glomeruli of diabetic animals. This study indicates the essential role of CK2α in regulating the diabetic renal pathological process of inflammatory fibrosis via NF-κB pathway, and inhibition of CK2α may serve as a promising therapeutic strategy for diabetic nephropathy.

  18. Mitochondrial DNA-Induced Inflammatory Responses and Lung Injury in Thermal Injury Rat Model: Protective Effect of Epigallocatechin Gallate.

    PubMed

    Liu, Ruiqi; Xu, Fei; Si, Si; Zhao, Xueshan; Bi, Siwei; Cen, Ying

    2017-02-06

    Lungs are easily damaged by the inflammatory responses induced after extensive burns. The aim here was to investigate the protective role of epigallocatechin gallate (EGCG) in mitochondrial DNA (mtDNA)-mediated inflammatory responses and acute respiratory distress syndrome (ARDS) in a rat model of thermal injury. Male Sprague-Dawley rats were randomly assigned to five groups. In the first experiment, a full-thickness thermal injury or control procedure, covering 30% of the TBSA, was inflicted on three groups designated as the thermal injury, EGCG, and sham control groups. In the second experiment, another two groups were established by transfusion with either mtDNA (mtDNA group) or phosphate-buffered saline (phosphate-buffered saline group). Blood samples and lung tissue from all five groups were collected and the plasma concentrations of mtDNA and inflammatory mediators were measured. Bronchoalveolar lavage fluid was collected and histological analysis of the lung tissue was performed to evaluate the severity of ARDS. Significant increases in mtDNA and inflammatory mediator plasma concentrations were seen in the thermal injury and EGCG groups when compared with controls (P < .05). The plasma concentrations of mtDNA and inflammatory mediators were significantly decreased after the administration of EGCG (P < .05). EGCG also significantly reduced the severity of acute lung injury (P < .05). Intravenous administration of mtDNA significantly increased concentrations of inflammatory mediators and caused severe ARDS (P < .05). Our results suggest that mtDNA is important for thermal injury-induced inflammation and associated ARDS. EGCG possesses anti-inflammatory and lung-protective properties, and might act by limiting mtDNA release after thermal injury.

  19. Orientin Ameliorates LPS-Induced Inflammatory Responses through the Inhibitory of the NF-κB Pathway and NLRP3 Inflammasome

    PubMed Central

    Xiao, Qingfei; Zhao, Ying; Yang, Liming

    2017-01-01

    Inflammation is a complex response to diverse pathological conditions, resulting in negative rather than protective effects when uncontrolled. Orientin (Ori), a flavonoid component isolated from natural plants, possesses abundant properties. Thus, we aimed to discover the potential therapeutic effects of orientin on lipopolysaccharide- (LPS-) induced inflammation in RAW 264.7 cells and the underlying mechanisms. In our studies, we evaluated the effects of Ori on proinflammatory mediator production stimulated by LPS, including tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-18, and IL-1β, along with prostaglandin E2 (PGE2) and NO. Our data indicated that orientin dramatically inhibited the levels of these mediators. Consistent with these results, the expression levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were also reduced. Further study demonstrated that such inhibitory effects of Ori were due to suppression of the nuclear factor-kappa B (NF-κB) pathway and nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3) inflammasome activation, which may contribute to its anti-inflammatory effects. Together, these findings show that Ori may be an effective candidate for ameliorating LPS-induced inflammatory responses. PMID:28197210

  20. Carbocisteine attenuates hydrogen peroxide-induced inflammatory injury in A549 cells via NF-κB and ERK1/2 MAPK pathways.

    PubMed

    Wang, Wei; Zheng, Jin-Ping; Zhu, Shao-Xuan; Guan, Wei-Jie; Chen, Mao; Zhong, Nan-Shan

    2015-02-01

    Carbocisteine is a mucolytic drug with anti-oxidative effect, we had previously proved that carbocisteine remarkably reduced the rate of acute exacerbations and improved the quality of life in patients with chronic obstructive pulmonary disease (COPD), however, very little is known about its mechanisms. In this study, we aimed to investigate the anti-inflammatory effects of carbocisteine against hydrogen peroxide (H2O2). A549 cells were cultured in vitro and treated with H2O2 as damaged cell models, carbocisteine was administered 24h prior to or after H2O2 exposure, and the protective effects of carbocisteine were determined by MTT, qRT-PCR, ELISA, western blot and immunofluorescence assays. The results showed that carbocisteine could increase cell viability and decrease LDH, IL-6 and IL-8 levels in the supernatant. Additionally, carbocisteine decreased IL-6, IL-8, TNF-α, IP-10 and MIP-1β mRNA in a dose-dependent manner. Moreover, carbocisteine could attenuate phosphorylation of NF-κB p65 and ERK1/2 and inhibit the nuclear translocation of pNF-κB p65 induced by H2O2. In conclusion, carbocisteine inhibited H2O2-induced inflammatory injury in A549 cells, NF-κB and ERK1/2 MAPK were the target pathways.

  1. The mitochondrial alternative oxidase pathway protects the photosynthetic apparatus against photodamage in Rumex K-1 leaves

    PubMed Central

    2012-01-01

    Background It is known that excess reducing equivalents in the form of NADPH in chloroplasts can be transported via shuttle machineries, such as the malate-oxaloacetate (OAA) shuttle, into the mitochondria, where they are efficiently oxidised by the mitochondrial alternative oxidase (AOX) respiratory pathway. Therefore, it has been speculated that the AOX pathway may protect plants from photoinhibition, but the mechanism by which this protection occurs remains to be elucidated. Results The observation that the malate-OAA shuttle activity and the AOX pathway capacity increased markedly after intense light treatment in Rumex K-1 leaves indicates that excess NADPH was transported from the chloroplasts and oxidised by the AOX pathway. The inhibition of the AOX pathway by salicylhydroxamic acid (SHAM) caused the over-reduction of the photosystem I (PSI) acceptor side, as indicated by the increases in the extent of reduction of P700+. Furthermore, the photosynthetic linear electron flow was restricted, which was indicated by the decreases in the PSII electron transport rate (ETR) and the photosynthetic O2 evolution rate. The restriction of the photosynthetic linear electron flow, which generates the thylakoid ΔpH, inevitably decreased the de-epoxidation of the xanthophyll cycle (ΔPRI). Therefore, the induction of non-photochemical quenching (NPQ) was suppressed when the AOX pathway was inhibited. The effect of the inhibition of the AOX pathway on NPQ induction was less at 20 mM NaHCO3 than at 1 mM NaHCO3. The suppression of NPQ induction by the inhibition of the AOX pathway was also observed during the induction phase of photosynthesis. In addition, the inhibition of the AOX pathway increased the accumulation of hydrogen peroxide (H2O2), suggesting that the AOX pathway functions as an antioxidant mechanism. Conclusions The inhibition of the AOX pathway resulted in the rapid accumulation of NADPH in the chloroplasts, which caused the over-reduction of the PSI acceptor

  2. WNT/β-catenin pathway modulates the TNF-α-induced inflammatory response in bronchial epithelial cells.

    PubMed

    Jang, Jaewoong; Jung, Yoonju; Chae, Seyeon; Chung, Sang-In; Kim, Seok-Min; Yoon, Yoosik

    2017-03-04

    In this study, TNF-α was found to activate the WNT/β-catenin pathway in BEAS-2B human bronchial epithelial cells. Levels of phospho-LRP6, Dvl-2, and phospho-GSK-3β were elevated, while that of Axin was reduced by TNF-α treatment. Nuclear translocation of β-catenin and the reporter activity of a β-catenin-responsive promoter were increased by TNF-α treatment. Under the same experimental conditions, TNF-α activated the NF-κB signaling, which includes the phosphorylation and degradation of IκB and nuclear translocation and target DNA binding of NF-κB, and it was found that an inhibitor of NF-κB activation, JSH-23, inhibited TNF-α-induced Wnt signaling as well as NF-κB signaling. It was also found that recombinant Wnt proteins induced NF-κB nuclear translocations and its target DNA binding, suggesting that Wnt signaling and NF-κB signaling were inter-connected. TNF-α-induced modulations of IκB and NF-κB as well as pro-inflammatory cytokine expression were significantly suppressed by the transfection of β-catenin siRNA compared to that of control siRNA. Transfection of a β-catenin expression plasmid augmented the TNF-α-induced modulations of IκB and NF-κB as well as pro-inflammatory cytokine expression. These results clearly demonstrated that the WNT/β-catenin pathway modulates the inflammatory response induced by TNF-α, suggesting that this pathway may be a useful target for the effective treatment of bronchial inflammation.

  3. Hsp65-Producing Lactococcus lactis Prevents Inflammatory Intestinal Disease in Mice by IL-10- and TLR2-Dependent Pathways.

    PubMed

    Gomes-Santos, Ana Cristina; de Oliveira, Rafael Pires; Moreira, Thaís Garcias; Castro-Junior, Archimedes Barbosa; Horta, Bernardo Coelho; Lemos, Luísa; de Almeida, Leonardo Augusto; Rezende, Rafael Machado; Cara, Denise Carmona; Oliveira, Sérgio Costa; Azevedo, Vasco Ariston Carvalho; Miyoshi, Anderson; Faria, Ana Maria Caetano

    2017-01-01

    Heat shock proteins (Hsps) are highly expressed at all sites of inflammation. As they are ubiquitous and immunodominant antigens, these molecules represent good candidates for the therapeutic use of oral tolerance in autoimmune and chronic inflammatory diseases. Evidences from human and animal studies indicate that inflammatory bowel disease (IBD) results from uncontrolled inflammatory responses to intestinal microbiota. Hsps are immunodominant proteins expressed by several immune cells and by commensal bacteria. Using an IBD mouse model, we showed that oral pretreatment with genetically modified Lactococcus lactis that produces and releases Mycobacterium Hsp65, completely prevented DSS-induced colitis in C57BL/6 mice. Protection was associated with reduced pro-inflammatory cytokines, such as IFN-γ, IL-6, and TNF-α; increased IL-10 production in colonic tissue; and expansion of CD4(+)Foxp3(+) and CD4(+)LAP(+) regulatory T cells in spleen and mesenteric lymph nodes. This effect was dependent on IL-10 and toll-like receptor 2. Thus, this approach may open alternative options for long-term management of IBD.

  4. Hsp65-Producing Lactococcus lactis Prevents Inflammatory Intestinal Disease in Mice by IL-10- and TLR2-Dependent Pathways

    PubMed Central

    Gomes-Santos, Ana Cristina; de Oliveira, Rafael Pires; Moreira, Thaís Garcias; Castro-Junior, Archimedes Barbosa; Horta, Bernardo Coelho; Lemos, Luísa; de Almeida, Leonardo Augusto; Rezende, Rafael Machado; Cara, Denise Carmona; Oliveira, Sérgio Costa; Azevedo, Vasco Ariston Carvalho; Miyoshi, Anderson; Faria, Ana Maria Caetano

    2017-01-01

    Heat shock proteins (Hsps) are highly expressed at all sites of inflammation. As they are ubiquitous and immunodominant antigens, these molecules represent good candidates for the therapeutic use of oral tolerance in autoimmune and chronic inflammatory diseases. Evidences from human and animal studies indicate that inflammatory bowel disease (IBD) results from uncontrolled inflammatory responses to intestinal microbiota. Hsps are immunodominant proteins expressed by several immune cells and by commensal bacteria. Using an IBD mouse model, we showed that oral pretreatment with genetically modified Lactococcus lactis that produces and releases Mycobacterium Hsp65, completely prevented DSS-induced colitis in C57BL/6 mice. Protection was associated with reduced pro-inflammatory cytokines, such as IFN-γ, IL-6, and TNF-α; increased IL-10 production in colonic tissue; and expansion of CD4+Foxp3+ and CD4+LAP+ regulatory T cells in spleen and mesenteric lymph nodes. This effect was dependent on IL-10 and toll-like receptor 2. Thus, this approach may open alternative options for long-term management of IBD. PMID:28194152

  5. Protective Effects of Platycodin D on Lipopolysaccharide-Induced Acute Lung Injury by Activating LXRα–ABCA1 Signaling Pathway

    PubMed Central

    Hu, Xiaoyu; Fu, Yunhe; Lu, Xiaojie; Zhang, Zecai; Zhang, Wenlong; Cao, Yongguo; Zhang, Naisheng

    2017-01-01

    The purpose of this study was to investigate the protective effects of platycodin D (PLD) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and clarify the possible mechanism. An LPS-induced ALI model was used to confirm the anti-inflammatory activity of PLD in vivo. The A549 lung epithelial cells were used to investigate the molecular mechanism and targets of PLD in vitro. In vivo, the results showed that PLD significantly attenuated lung histopathologic changes, myeloperoxidase activity, and pro-inflammatory cytokines levels, including TNF-α, IL-1β, and IL-6. In vitro, PLD inhibited LPS-induced IL-6 and IL-8 production in LPS-stimulated A549 lung epithelial cells. Western blot analysis showed that PLD suppressed LPS-induced NF-κB and IRF3 activation. Moreover, PLD did not act though affecting the expression of TLR4. We also showed that PLD disrupted the formation of lipid rafts by depleting cholesterol and prevented LPS-induced TLR4 trafficking to lipid rafts, thereby blocking LPS-induced inflammatory response. Finally, PLD activated LXRα–ABCA1-dependent cholesterol efflux. Knockdown of LXRα abrogated the anti-inflammatory effects of PLD. The anti-inflammatory effects of PLD was associated with upregulation of the LXRα–ABCA1 pathway, which resulted in disrupting lipid rafts by depleting cholesterol and reducing translocation of TLR4 to lipid rafts. PMID:28096801

  6. Perceived Barriers and Protective Factors of Juvenile Offenders on Their Developmental Pathway to Adulthood

    ERIC Educational Resources Information Center

    Unruh, Deanne; Povenmire-Kirk, Tiana; Yamamoto, Scott

    2009-01-01

    Adolescents involved in the juvenile justice system face multiple challenges on their pathway to adulthood. These adolescents not only have an increased risk of committing future crimes and are further at risk of not becoming healthy, productive adults. The purpose of this study was to examine the risk and protective factors and associations…

  7. Anti-inflammatory properties of lipoxin A4 protect against diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury

    PubMed Central

    Han, Jiang-quan; Liu, Cheng-ling; Wang, Zheng-yuan; Liu, Ling; Cheng, Ling; Fan, Ya-dan

    2016-01-01

    Lipoxin A4 can alleviate cerebral ischemia/reperfusion injury by reducing the inflammatory reaction, but it is currently unclear whether it has a protective effect on diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury. In this study, we established rat models of diabetes mellitus using an intraperitoneal injection of streptozotocin. We then induced focal cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. After administration of lipoxin A4 via the lateral ventricle, infarction volume was reduced, the expression levels of pro-inflammatory factors tumor necrosis factor alpha and nuclear factor-kappa B in the cerebral cortex were decreased, and neurological functioning was improved. These findings suggest that lipoxin A4 has strong neuroprotective effects in diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury and that the underlying mechanism is related to the anti-inflammatory action of lipoxin A4. PMID:27212926

  8. Allicin protects traumatic spinal cord injury through regulating the HSP70/Akt/iNOS pathway in mice

    PubMed Central

    Wang, Shunyi; Ren, Dongliang

    2016-01-01

    Allicin is a major component of garlic, extracted as an oily liquid. The present study was designed to investigate the beneficial effects of allicin on traumatic spinal cord injury (TSCI) in mice, and whether the effects are mediated via regulation of the heat shock protein 70 (HSP70), v-akt murine thymoma viral oncogene homolog 1 (Akt) and inducible nitric oxide synthase (iNOS) pathways. Adult BALB/c mice (30–40 g) received a laminectomy at the T9 vertebral level as a model of TSCI. In the present study, treatment of the TSCI mice with allicin significantly increased their Basso, Beattie and Bresnahan (BBB) scores (P<0.01) and reduced the spinal cord water content (P<0.01). This protective effect was associated with the inhibition of oxidative stress and inflammatory responses in TSCI mice. Western blot analysis demonstrated that allicin increased the protein levels of HSP70, increased the phosphorylation of Akt and reduced the iNOS protein expression levels in TSCI mice. Additionally, treatment with allicin significantly reduced the levels of ROS and enhanced the NADH levels in TSCI mice. Collectively, these data demonstrate that the effects of allicin on TSCI are mediated via regulation of the HSP70, Akt and iNOS pathways in mice. PMID:27573340

  9. Intravenous immunoglobulin protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways.

    PubMed

    Widiapradja, Alexander; Vegh, Viktor; Lok, Ker Zhing; Manzanero, Silvia; Thundyil, John; Gelderblom, Mathias; Cheng, Yi-Lin; Pavlovski, Dale; Tang, Sung-Chun; Jo, Dong-Gyu; Magnus, Tim; Chan, Sic L; Sobey, Christopher G; Reutens, David; Basta, Milan; Mattson, Mark P; Arumugam, Thiruma V

    2012-07-01

    Intravenous immunoglobulin (IVIg) preparations obtained by fractionating blood plasma, are increasingly being used increasingly as an effective therapeutic agent in treatment of several inflammatory diseases. Its use as a potential therapeutic agent for treatment of stroke and Alzheimer's disease has been proposed, but little is known about the neuroprotective mechanisms of IVIg. In this study, we investigated the effect of IVIg on downstream signaling pathways that are involved in neuronal cell death in experimental models of stroke and Alzheimer's disease. Treatment of cultured neurons with IVIg reduced simulated ischemia- and amyloid βpeptide (Aβ)-induced caspase 3 cleavage, and phosphorylation of the cell death-associated kinases p38MAPK, c-Jun NH2 -terminal kinase and p65, in vitro. Additionally, Aβ-induced accumulation of the lipid peroxidation product 4-hydroxynonenal was attenuated in neurons treated with IVIg. IVIg treatment also up-regulated the anti-apoptotic protein, Bcl2 in cortical neurons under ischemia-like conditions and exposure to Aβ. Treatment of mice with IVIg reduced neuronal cell loss, apoptosis and infarct size, and improved functional outcome in a model of focal ischemic stroke. Together, these results indicate that IVIg acts directly on neurons to protect them against ischemic stroke and Aβ-induced neuronal apoptosis by inhibiting cell death pathways and by elevating levels of the anti-apoptotic protein Bcl2.

  10. The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(αi) signalling.

    PubMed

    Kim, Sung Hye; MacIntyre, David A; Hanyaloglu, Aylin C; Blanks, Andrew M; Thornton, Steven; Bennett, Phillip R; Terzidou, Vasso

    2016-01-15

    Oxytocin (OT) plays an important role in the onset of human labour by stimulating uterine contractions and promoting prostaglandin/inflammatory cytokine synthesis in amnion via oxytocin receptor (OTR) coupling. The OTR-antagonist, Atosiban, is widely used as a tocolytic for the management of acute preterm labour. We found that in primary human amniocytes, Atosiban (10 μM) signals via PTX-sensitive Gαi to activate transcription factor NF-κB p65, ERK1/2, and p38 which subsequently drives upregulation of the prostaglandin synthesis enzymes, COX-2 and phospho-cPLA2 and excretion of prostaglandins (PGE2) (n = 6; p < 0.05, ANOVA). Moreover, Atosiban treatment increased expression and excretion of the inflammatory cytokines, IL-6 and CCL5. We also showed that OT-simulated activation of NF-κB, ERK1/2, and p38 and subsequent prostaglandin and inflammatory cytokine synthesis is via Gαi-2 and Gαi-3 but not Gαq, and is not inhibited by Atosiban. Activation or exacerbation of inflammation is not a desirable effect of tocolytics. Therefore therapeutic modulation of the OT/OTR system for clinical management of term/preterm labour should consider the effects of differential G-protein coupling of the OTR and the role of OT or selective OTR agonists/antagonists in activating proinflammatory pathways.

  11. Taurine protects cisplatin induced cardiotoxicity by modulating inflammatory and endoplasmic reticulum stress responses.

    PubMed

    Chowdhury, Sayantani; Sinha, Krishnendu; Banerjee, Sharmistha; Sil, Parames C

    2016-11-12

    Oxidative stress, ER stress, inflammation, and apoptosis results in the pathogenesis of cisplatin-induced cardiotoxicity. The present study was designed to investigate the signaling mechanisms involved in the ameliorating effect of taurine, a conditionally essential amino acid, against cisplatin-mediated cardiac ER stress dependent apoptotic death and inflammation. Mice were simultaneously treated with taurine (150 mg kg(-1) body wt, i.p.) and cisplatin (10 mg kg(-1) body wt, i.p.) for a week. Cisplatin exposure significantly altered serum creatine kinase and troponin T levels. In addition, histological studies revealed disintegration in the normal radiation pattern of cardiac muscle fibers. However, taurine administration could abate such adverse effects of cisplatin. Taurine administration significantly mitigated the reactive oxygen species production, alleviated the overexpression of nuclear factor-κB (NF-κB), and inhibited the elevation of proinflammatoy cytokines, adhesion molecules, and chemokines. Cisplatin exposure resulted in the unfolded protein response (UPR)-regulated CCAAT/enhancer binding protein (CHOP) up-regulation, induction of GRP78: a marker of ER stress and eIF2α signaling. Increase in calpain-1 expression level, activation of caspase-12 and caspase-3, cleavage of the PARP protein as well as the inhibition of antiapoptotic protein Bcl-2 were reflected on cisplatin-triggered apoptosis. Taurine could, however, combat against such cisplatin induced cardiac-abnormalities. The above mentioned findings suggest that taurine plays a beneficial role in providing protection against cisplatin-induced cardiac damage by modulating inflammatory responses and ER stress. © 2016 BioFactors, 42(6):647-664, 2016.

  12. Bioactive Fraction of Geopropolis from Melipona scutellaris Decreases Neutrophils Migration in the Inflammatory Process: Involvement of Nitric Oxide Pathway

    PubMed Central

    Franchin, Marcelo; da Cunha, Marcos Guilherme; Denny, Carina; Napimoga, Marcelo Henrique; Cunha, Thiago Mattar; Bueno-Silva, Bruno; Matias de Alencar, Severino; Ikegaki, Masaharu; Luiz Rosalen, Pedro

    2013-01-01

    The aim of this study was to evaluate the activity of the ethanolic extract of geopropolis (EEGP) from Melipona scutellaris and its fractions on the modulation of neutrophil migration in the inflammatory process, and the participation of nitric oxide (NO) pathway, as well as to check the chemical profile of the bioactive fraction. EEGP and its aqueous fraction decreased neutrophil migration in the peritoneal cavity and also the interaction of leukocytes (rolling and adhesion) with endothelial cells. The levels of chemokines CXCL1/KC and CXCL2/MIP-2 were not altered after treatment with EEGP and the aqueous fraction. It was found that the injection of NO pathway antagonists abolished the EEGP and the aqueous fraction inhibitory activity on the neutrophil migration. The expression of intercellular adhesion molecule type 1 (ICAM-1) was reduced, and nitrite levels increased after treatment with EEGP and aqueous fraction. In the carrageenan-induced paw edema model, EEGP and the aqueous fraction showed antiedema activity. No pattern of flavonoid and phenolic acid commonly found in propolis samples of Apis mellifera could be detected in the aqueous fraction samples. These data indicate that the aqueous fraction found has promising bioactive substances with anti-inflammatory activity. PMID:23737853

  13. Redeeming an old foe: protective as well as pathophysiological roles for tumor necrosis factor in inflammatory bowel disease

    PubMed Central

    Dubé, Philip E.; Punit, Shivesh

    2014-01-01

    Tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2 are major therapeutic targets for inflammatory bowel disease. Research advances have demonstrated that TNF produces pleiotropic responses in the gastrointestinal (GI) tract. Although in excess TNF can contribute to GI pathology, TNF is also a critical protective factor to promote GI homeostasis following injury and inflammation. Genetic studies using candidate and genome-wide association study approaches have identified variants in TNF or its receptors that are associated with Crohn's disease or ulcerative colitis in multiple populations, although the basis for these associations remains unclear. This review considers the efficacy and mechanism of anti-TNF therapies for inflammatory bowel disease to reconcile the many disparate aspects of TNF research and to consider the potential protective effects of TNF signaling in GI health. PMID:25477373

  14. Sesamin protects against renal ischemia reperfusion injury by promoting CD39-adenosine-A2AR signal pathway in mice.

    PubMed

    Li, Ke; Gong, Xia; Kuang, Ge; Jiang, Rong; Wan, Jingyuan; Wang, Bin

    2016-01-01

    Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury with high morbidity and mortality due to limited therapy. Here, we examine whether sesamin attenuates renal IRI in an animal model and explore the underlying mechanisms. Male mice were subjected to right renal ischemia for 30 min followed by reperfusion for 24 h with sesamin (100 mg/kg) during which the left kidney was removed. Renal damage and function were assessed subsequently. The results showed that sesamin reduced kidney ischemia reperfusion injury, as assessed by decreased serum creatinine (Scr) and Blood urea nitrogen (BUN), alleviated tubular damage and apoptosis. In addition, sesamin inhibited neutrophils infiltration and pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β production in IR-preformed kidney. Notably, sesamin promoted the expression of CD39, A2A adenosine receptor (A2AAR), and A2BAR mRNA and protein as well as adenosine production. Furthermore, CD39 inhibitor or A2AR antagonist abolished partly the protection of sesamin in kidney IRI. In conclusion, sesamin could effectively protect kidney from IRI by inhibiting inflammatory responses, which might be associated with promoting the adenosine-CD39-A2AR signaling pathway.

  15. Sesamin protects against renal ischemia reperfusion injury by promoting CD39-adenosine-A2AR signal pathway in mice

    PubMed Central

    Li, Ke; Gong, Xia; Kuang, Ge; Jiang, Rong; Wan, Jingyuan; Wang, Bin

    2016-01-01

    Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury with high morbidity and mortality due to limited therapy. Here, we examine whether sesamin attenuates renal IRI in an animal model and explore the underlying mechanisms. Male mice were subjected to right renal ischemia for 30 min followed by reperfusion for 24 h with sesamin (100 mg/kg) during which the left kidney was removed. Renal damage and function were assessed subsequently. The results showed that sesamin reduced kidney ischemia reperfusion injury, as assessed by decreased serum creatinine (Scr) and Blood urea nitrogen (BUN), alleviated tubular damage and apoptosis. In addition, sesamin inhibited neutrophils infiltration and pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β production in IR-preformed kidney. Notably, sesamin promoted the expression of CD39, A2A adenosine receptor (A2AAR), and A2BAR mRNA and protein as well as adenosine production. Furthermore, CD39 inhibitor or A2AR antagonist abolished partly the protection of sesamin in kidney IRI. In conclusion, sesamin could effectively protect kidney from IRI by inhibiting inflammatory responses, which might be associated with promoting the adenosine-CD39-A2AR signaling pathway. PMID:27347331

  16. Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways.

    PubMed

    Inoue, Takayuki; Tanaka, Masashi; Masuda, Shinya; Ohue-Kitano, Ryuji; Yamakage, Hajime; Muranaka, Kazuya; Wada, Hiromichi; Kusakabe, Toru; Shimatsu, Akira; Hasegawa, Koji; Satoh-Asahara, Noriko

    2017-02-22

    Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA+DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA+DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD(+) level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA+DHA also inhibited phosphorylation of the stress-associated transcription factor NF-κB subunit p65 at Ser536, which is known to enhance NF-κB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA+DHA increased the LC3-II/LC3-I ratio, an indicator of autophagy. Suppression of TNF-α and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-α suppression but not IL-6 suppression. Accordingly, these ω-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-κB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and -unrelated pathways.

  17. Progranulin protects against endotoxin-induced acute kidney injury by downregulating renal cell death and inflammatory responses in mice.

    PubMed

    Xu, Xiaoying; Gou, Linfeng; Zhou, Meng; Yang, Fusheng; Zhao, Yihan; Feng, Tingting; Shi, Peikun; Ghavamian, Armin; Zhao, Weiming; Yu, Yuan; Lu, Yi; Yi, Fan; Liu, Guangyi; Tang, Wei

    2016-09-01

    Progranulin (PGRN), a pluripotent secreted growth factor, is involved in various physiologic and disease processes. However, the role of PGRN in endotoxin-induced septic acute kidney injury (AKI) remains unknown. The objective of this study is to investigate the protective effects of PGRN on an endotoxin-induced AKI mouse model by using PGRN-deficient mice and recombinant PGRN (rPGRN) pretreatment. PGRN levels were increased in kidneys of wild-type (WT) mice at 6 and 24h after lipopolysaccharide (LPS) injection. Renal function detection, hematoxylin and eosin staining, immunohistochemical staining, ELISA and in situ terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling were used to reveal tissue injury, inflammatory cell infiltration, production of inflammatory mediators and cell death in mouse kidneys after LPS injection. PGRN deficiency resulted in severe kidney injury and increased apoptotic death, inflammatory cell infiltration, production of pro-inflammatory mediators and the expression and nucleus-to-cytoplasmic translocation of HMGB1 in the kidney. In addition, rPGRN administration before LPS treatment ameliorated the endotoxin-induced AKI in WT mice. PGRN may be a novel biologic agent with therapeutic potential for endotoxin-induced septic AKI possibly by inhibiting LPS-induced renal cell death and inflammatory responses in mice.

  18. Interactions between Nitric Oxide and Hypoxia-Inducible Factor Signaling Pathways in Inflammatory Disease

    PubMed Central

    Olson, Nels; van der Vliet, Albert

    2011-01-01

    Induction and activation of nitric oxide (NO) synthases (NOS) and excessive production of NO are common features of almost all diseases associated with infection and acute or chronic inflammation, although the contribution of NO to the pathophysiology of these diseases is highly multifactorial and often still a matter of controversy. Because of its direct impact on tissue oxygenation and cellular oxygen (O2) consumption and redistribution, the ability of NO to regulate various aspects of hypoxia-induced signaling has received widespread attention. Conditions of tissue hypoxia and the activation of hypoxia-inducible factors (HIF) have been implicated in hypoxia or in cancer biology, but are also being increasingly recognized as important features of acute and chronic inflammation. Thus, the activation of HIF transcription factors has been increasingly implicated in inflammatory diseases, and recent studies have indicated its critical importance in regulating phagocyte function, inflammatory mediator production, and regulation of epithelial integrity and repair processes. Finally, HIF also appears to contribute to important features of tissue fibrosis and epithelial-to-mesenchymal transition, processes that are associated with tissue remodeling in various non-malignant chronic inflammatory disorders. In this review, we briefly summarize the current state of knowledge with respect to the general mechanisms involved in HIF regulation and the impact of NO on HIF activation. Secondly, we will summarize the major recent findings demonstrating a role for HIF signaling in infection, inflammation, and tissue repair and remodeling, and will address the involvement of NO. The growing interest in hypoxia-induced signaling and its relation with NO biology is expected to lead to further insights into the complex roles of NO in acute or chronic inflammatory diseases and may point to the importance of HIF signaling as key feature of NO-mediated events during these disorders. PMID

  19. Ozone Inhalation Provokes Glucocorticoid-Dependent and -Independent Effects on Inflammatory and Metabolic Pathways.

    PubMed

    Thomson, Errol M; Pal, Shinjini; Guénette, Josée; Wade, Michael G; Atlas, Ella; Holloway, Alison C; Williams, Andrew; Vincent, Renaud

    2016-07-01

    Growing evidence implicates air pollutants in adverse health effects beyond respiratory and cardiovascular disease, including metabolic impacts (diabetes, metabolic syndrome, obesity) and neurological/neurobehavioral outcomes (neurodegenerative disease, cognitive decline, perceived stress, depression, suicide). We have shown that inhalation of particulate matter or ozone activates the hypothalamic-pituitary-adrenal axis in rats and increases plasma levels of the glucocorticoid corticosterone. To investigate the role of corticosterone in mediating inflammatory and metabolic effects of pollutant exposure, in this study male Fischer-344 rats were administered the 11β-hydroxylase inhibitor metyrapone (0, 50, 150 mg/kg body weight) and exposed by nose-only inhalation for 4 h to air or 0.8 ppm ozone. Ozone inhalation provoked a 2-fold increase in plasma corticosterone, an effect blocked by metyrapone, but did not alter epinephrine levels. Inhibition of corticosterone production was associated with increased inflammatory signaling in the lungs and plasma in response to ozone, consistent with a role for glucocorticoids in limiting local and systemic inflammatory responses. Effects of ozone on insulin and glucagon, but not ghrelin or plasminogen activator inhibitor-1, were modified by metyrapone, revealing glucocorticoid-dependent and -independent effects on circulating metabolic and hemostatic factors. Several immunosuppressive and metabolic impacts of ozone in the lungs, heart, liver, kidney, and spleen were blocked by metyrapone and reproduced through exogenous administration of corticosterone (10 mg/kg body weight), demonstrating glucocorticoid-dependent effects in target tissues. Our results support involvement of endogenous glucocorticoids in ozone-induced inflammatory and metabolic effects, providing insight into potential biological mechanisms underlying health impacts and susceptibility.

  20. A Novel Biological Role of α-Mangostin in Modulating Inflammatory Response Through the Activation of SIRT-1 Signaling Pathway.

    PubMed

    Franceschelli, Sara; Pesce, Mirko; Ferrone, Alessio; Patruno, Antonia; Pasqualone, Livia; Carlucci, Giuseppe; Ferrone, Vincenzo; Carlucci, Maura; de Lutiis, Maria Anna; Grilli, Alfredo; Felaco, Mario; Speranza, Lorenza

    2016-11-01

    Several studies have shown that xanthones obtained from Garcinia Mangostana (GM) have remarkable biological activities. α-mangostin (α-MG) is the main constituent of the fruit hull of the GM. Several findings have suggested that SIRT-1, a nuclear histone deacetylase, could influence cellular function by the inhibition of NF-kB signaling. ROS can inhibit SIRT-1 activity by initiating oxidative modifications on its cysteine residues, and suppression of SIRT-1 enhances the NF-κB signaling resulting in inflammatory responses. The goals of the present study were to evaluate the quantity of α-MG in the methanolic extract of GM (Vithagroup Spa) and to investigate the activity of this xanthone in U937 cell line and in human monocytes from responsive to inflammatory insult analyzing the possible changes on the activation of SIRT-1 protein via NF-Kb. Cells were treated with the methanolic extract of GM and/or LPS. The chromatographic separation of α-MG was performed by an HPLC analysis. EX 527, a specific SIRT-1 inhibitor, was used to determine if SIRT-1/NfkB signaling pathway might be involved in α-MG action on cells. Our results show that α-MG inhibits p65 acetylation and down-regulates the pro-inflammatory gene products as COX-2, iNOS via SIRT-1 activation. Cells treated with EX 527 showed an up-regulation of NFkB acetylation and an over expression of inducible enzymes and their product of catalysis (NO and PGE2). These results suggest that α-MG may be useful for the development of alternative pharmacological strategies aimed at reducing the inflammatory process. J. Cell. Physiol. 231: 2439-2451, 2016. © 2016 Wiley Periodicals, Inc.

  1. Imipramine protects retinal ganglion cells from oxidative stress through the tyrosine kinase receptor B signaling pathway

    PubMed Central

    Han, Ming-lei; Liu, Guo-hua; Guo, Jin; Yu, Shu-juan; Huang, Jing

    2016-01-01

    Retinal ganglion cell (RGC) degeneration is irreversible in glaucoma and tyrosine kinase receptor B (TrkB)-associated signaling pathways have been implicated in the process. In this study, we attempted to examine whether imipramine, a tricyclic antidepressant, may protect hydrogen peroxide (H2O2)-induced RGC degeneration through the activation of the TrkB pathway in RGC-5 cell lines. RGC-5 cell lines were pre-treated with imipramine 30 minutes before exposure to H2O2. Western blot assay showed that in H2O2 -damaged RGC-5 cells, imipramine activated TrkB pathways through extracellular signal-regulated protein kinase/TrkB phosphorylation. TUNEL staining assay also demonstrated that imipramine ameliorated H2O2 -induced apoptosis in RGC-5 cells. Finally, TrkB-IgG intervention was able to reverse the protective effect of imipramine on H2O2 -induced RGC-5 apoptosis. Imipramine therefore protects RGCs from oxidative stress-induced apoptosis through the TrkB signaling pathway. PMID:27127489

  2. Flavonoid myricetin inhibits TNF-α-stimulated production of inflammatory mediators by suppressing the Akt, mTOR and NF-κB pathways in human keratinocytes.

    PubMed

    Lee, Da Hee; Lee, Chung Soo

    2016-08-05

    Flavonoid myricetin has been shown to exhibit anti-inflammatory and anti-oxidant effects. Nevertheless, the effect of myricetin on the TNF-α-stimulated production of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we examined the effect of myricetin on the TNF-α-stimulated production of inflammatory mediators in relation to the Akt, mTOR and NF-κB pathways, which regulate the transcription genes involved in immune and inflammatory responses. TNF-α stimulated production of the inflammatory mediators and reactive oxygen species in keratinocytes, and activation of the Akt, mTOR and NF-κB pathways in HaCaT cells and primary keratinocytes. Myricetin, Akt inhibitor, Bay 11-7085 (an inhibitor of NF-κB activation), rapamycin (mTOR inhibitor) and N-acetylcysteine attenuated TNF-α-induced activation of Akt, mTOR and NF-κB. Myricetin and N-acetylcysteine attenuated the TNF-α-stimulated production of cytokines and chemokines, and production of reactive oxygen species in keratinocytes. The results show that myricetin may reduce TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of the Akt, mTOR and NF-κB pathways. The effect of myricetin appears to be associated with inhibition of the production of reactive oxygen species. Further, myricetin appears to attenuate the proinflammatory mediator-induced inflammatory skin diseases.

  3. Putative transcriptomic biomarkers in the inflammatory cytokine pathway differentiate major depressive disorder patients from control subjects and bipolar disorder patients.

    PubMed

    Powell, Timothy R; McGuffin, Peter; D'Souza, Ursula M; Cohen-Woods, Sarah; Hosang, Georgina M; Martin, Charlotte; Matthews, Keith; Day, Richard K; Farmer, Anne E; Tansey, Katherine E; Schalkwyk, Leonard C

    2014-01-01

    Mood disorders consist of two etiologically related, but distinctly treated illnesses, major depressive disorder (MDD) and bipolar disorder (BPD). These disorders share similarities in their clinical presentation, and thus show high rates of misdiagnosis. Recent research has revealed significant transcriptional differences within the inflammatory cytokine pathway between MDD patients and controls, and between BPD patients and controls, suggesting this pathway may possess important biomarker properties. This exploratory study attempts to identify disorder-specific transcriptional biomarkers within the inflammatory cytokine pathway, which can distinguish between control subjects, MDD patients and BPD patients. This is achieved using RNA extracted from subject blood and applying synthesized complementary DNA to quantitative PCR arrays containing primers for 87 inflammation-related genes. Initially, we use ANOVA to test for transcriptional differences in a 'discovery cohort' (total n = 90) and then we use t-tests to assess the reliability of any identified transcriptional differences in a 'validation cohort' (total n = 35). The two most robust and reliable biomarkers identified across both the discovery and validation cohort were Chemokine (C-C motif) ligand 24 (CCL24) which was consistently transcribed higher amongst MDD patients relative to controls and BPD patients, and C-C chemokine receptor type 6 (CCR6) which was consistently more lowly transcribed amongst MDD patients relative to controls. Results detailed here provide preliminary evidence that transcriptional measures within inflammation-related genes might be useful in aiding clinical diagnostic decision-making processes. Future research should aim to replicate findings detailed in this exploratory study in a larger medication-free sample and examine whether identified biomarkers could be used prospectively to aid clinical diagnosis.

  4. Tricin, flavonoid from Njavara reduces inflammatory responses in hPBMCs by modulating the p38MAPK and PI3K/Akt pathways and prevents inflammation associated endothelial dysfunction in HUVECs.

    PubMed

    Shalini, V; Pushpan, Chithra K; G, Sindhu; A, Jayalekshmy; A, Helen

    2016-02-01

    Previous studies revealed the potent anti-inflammatory activity of tricin, the active component of Njavara rice bran. Here, we report the involvement of specific signaling pathways in the protective effect of tricin against LPS induced inflammation in hPBMCs and the role of tricin in modulating endothelial dysfunction in LPS induced HUVECs. Pretreatment with tricin (15μM) significantly inhibited the release of TNF-α and was comparable to the specific pathway blockers like ERK inhibitor (PD98059), JNK inhibitor (SP600125) and p38 inhibitor (SB203580), whereas an increased release of TNF-α was observed in PI3K/Akt inhibitor (LY294002) treated cells. Tricin alone and combination treatment of tricin and SB203580 showed more significant inhibition of activation of COX-2 and TNF-α than that of SB203580 alone treated group. Combination treatment of tricin and LY294002 showed increased activation of COX-2 and TNF-α, proved that PI3K activation is essential for the anti-inflammatory effect of tricin. Studies conducted on HUVECs revealed the protective effect of tricin against endothelial dysfunction associated with LPS induced inflammation by inhibiting the activation of proinflammatory mediators like TNF-α, IFN-γ, MCP 1 by modulating NF-κB and MAPK signaling pathways. ELISA and flow cytometric analysis again confirmed the protection of tricin against endothelial damage, especially from the decreased activation of cell adhesion molecules like ICAM-1, VCAM-1 and E-Selectin upon tricin treatment. This work establishes the mechanism behind the potent anti-inflammatory activity of the flavonoid tricin.

  5. Dynamic Shear Stress Regulation of Inflammatory and Thrombotic Pathways in Baboon Endothelial Outgrowth Cells

    PubMed Central

    Hinds, Monica T.; Nerem, Robert M.

    2013-01-01

    Endothelial outgrowth cells (EOCs) have garnered much attention as a potential autologous endothelial source for vascular implants or in tissue engineering applications due to their ease of isolation and proliferative ability; however, how these cells respond to different hemodynamic cues is ill-defined. This study investigates the inflammatory and thrombotic response of baboon EOCs (BaEOCs) to four hemodynamic conditions using the cone and plate shear apparatus: steady, laminar shear stress (SS); pulsatile, nonreversing laminar shear stress (PS); oscillatory, laminar shear stress (OS); and net positive, pulsatile, reversing laminar shear stress (RS). In summary, endothelial nitric oxide synthase (eNOS) mRNA was significantly upregulated by SS compared to OS. No differences were found in the mRNA levels of the inflammatory markers intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1 (VCAM-1) between the shear conditions; however, OS significantly increased the number of monocytes bound when compared to SS. Next, SS increased the anti-thrombogenic mRNA levels of CD39, thrombomodulin, and endothelial protein-C receptor (EPCR) compared to OS. SS also significantly increased CD39 and EPCR mRNA levels compared to RS. Finally, no significant differences were detected when comparing pro-thrombotic tissue factor mRNA or its activity levels. These results indicate that shear stress can have beneficial (SS) or adverse (OS, RS) effects on the inflammatory or thrombotic potential of EOCs. Further, these results suggest SS hemodynamic preconditioning may be optimal in increasing the efficacy of a vascular implant or in tissue-engineered applications that have incorporated EOCs. PMID:23406430

  6. Activation of the interleukin-34 inflammatory pathway in response to influenza A virus infection.

    PubMed

    Yu, Guozheng; Bing, Yuntao; Zhu, Siying; Li, Wei; Xia, Lin; Li, Yong; Liu, Zhisu

    2015-02-01

    Interleukin 34 (IL-34) is a newly recognized cytokine that functions similarly to macrophage colony-stimulating factor. This study investigated the mechanism by which IL-34 is produced in response to exogenous pathogen infections in humans. The results showed that the IL-34 levels were higher in the serum and peripheral blood mononuclear cells (PBMCs) from 155 influenza A virus (IAV)-infected patients than in those from 145 healthy individuals. The expression level of IL-34 in IAV-infected PBMCs was blocked by IL-22-specific siRNA. This result indicated that IL-34 was induced by IL-22 in the inflammatory cascade. The mRNA and protein expression levels of IL-22 activated by IAV infection were significantly inhibited by IL-34 overexpression but induced by IL-34-specific siRNA. Thus, a feedback system most likely exists between IL-34 and IL-22. The IL-22 expression in T helper type 17 (Th17) cells of PBMCs was higher than IL-34 expression in Th17 cells of PBMCs, and there was IL-34 expression in IL-22+ Th17 cells. This result showed that the production of IL-22 and IL-34 is both from the same and different subset of cells, which indicated that the regulatory mechanism of IL-22/IL-34 is through the autocrine or paracrine systems. In conclusion, IL-34 is induced by IL-22 in the inflammatory cascade in response to IAV infection. Therefore, IL-34 is a promising target for the screening of anti-inflammatory medicines.

  7. Alteration in inflammatory/apoptotic pathway and histone modifications by nordihydroguaiaretic acid prevents acute pancreatitis in swiss albino mice.

    PubMed

    Mahajan, Ujwal Mukund; Gupta, Chanchal; Wagh, Preshit Ravindra; Karpe, Pinakin Arun; Tikoo, Kulbhushan

    2011-11-01

    Reactive oxygen radicals, pro-inflammatory mediators and cytokines have been implicated in caerulein induced acute pancreatitis. Nordihydroguaiaretic acid (NDGA), a plant lignin, has marked anti-inflammatory properties. The present study aimed to investigate the possible protective effect of NDGA against caerulein induced pancreatitis. Acute pancreatitis was induced by intraperitoneal administration of eight doses of caerulein in male swiss albino mice. NDGA was administered after 9 h of acute pancreatitis induction. Pancreatic damage and the protective effect of NDGA were assessed by oxidative stress parameters and histopathology of pancreas. The mRNA expression of heat shock proteins (DNAJ C15 and HSPD1) was examined by real-time RT-PCR analysis. Expression of HSP 27, NF-κB, TNF-α, p-p38, Bcl-2, p-PP2A, procaspase-3, caspase-3 and histone modifications were examined by western blotting. NDGA attenuated the oxidative stress, led to increased plasma α-amylase and decreased IGF-1 in AP mice. It modulated the mRNA and protein levels of heat shock proteins and reduced the expression of NF-κB, TNF-α and p-p38. It increased the number of TUNEL positive apoptotic cells in the pancreas of AP mice. In addition, NDGA prevented the changes in modifications of histone H3 in acute pancreatitis. To best of our knowledge, this is the first report which suggests that NDGA prevents the progression of acute pancreatitis by involving alteration of histone H3 modifications and modulating the expression of genes involved in inflammatory/apoptotic cascade, which may be responsible for decreased necrosis and increased apoptosis in this model of acute pancreatitis.

  8. Dietary Fish Oil Inhibits Pro-Inflammatory and ER Stress Signalling Pathways in the Liver of Sows during Lactation

    PubMed Central

    Gessner, Denise K.; Gröne, Birthe; Couturier, Aline; Rosenbaum, Susann; Hillen, Sonja; Becker, Sabrina; Erhardt, Georg; Reiner, Gerald; Ringseis, Robert; Eder, Klaus

    2015-01-01

    Lactating sows have been shown to develop typical signs of an inflammatory condition in the liver during the transition from pregnancy to lactation. Hepatic inflammation is considered critical due to the induction of an acute phase response and the activation of stress signaling pathways like the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), both of which impair animal´s health and performance. Whether ER stress-induced UPR is also activated in the liver of lactating sows and whether dietary fish oil as a source of anti-inflammatory effects n-3 PUFA is able to attenuate hepatic inflammation and ER stress-induced UPR in the liver of sows is currently unknown. Based on this, two experiments with lactating sows were performed. The first experiment revealed that ER stress-induced UPR occurs also in the liver of sows during lactation. This was evident from the up-regulation of a set of genes regulated by the UPR and numerically increased phosphorylation of the ER stress-transducer PERK and PERK-mediated phosphorylation of eIF2α and IκB. The second experiment showed that fish oil inhibits ER stress-induced UPR in the liver of lactating sows. This was demonstrated by decreased mRNA levels of a number of UPR-regulated genes and reduced phosphorylation of PERK and PERK-mediated phosphorylation of eIF2α and IκB in the liver of the fish oil group. The mRNA levels of various nuclear factor-κB-regulated genes encoding inflammatory mediators and acute phase proteins in the liver of lactating sows were also reduced in the fish oil group. In line with this, the plasma levels of acute phase proteins were reduced in the fish oil group, although differences to the control group were not significant. In conclusion, ER stress-induced UPR is present in the liver of lactating sows and fish oil is able to inhibit inflammatory signaling pathways and ER stress-induced UPR in the liver. PMID:26351857

  9. Early Activation of Th2/Th22 Inflammatory and Pruritogenic Pathways in Acute Canine Atopic Dermatitis Skin Lesions.

    PubMed

    Olivry, Thierry; Mayhew, David; Paps, Judy S; Linder, Keith E; Peredo, Carlos; Rajpal, Deepak; Hofland, Hans; Cote-Sierra, Javier

    2016-10-01

    Determining inflammation and itch pathway activation in patients with atopic dermatitis (AD) is fraught with the inability to precisely assess the age of skin lesions, thus affecting the analysis of time-dependent mediators. To characterize inflammatory events occurring during early experimental acute AD lesions, biopsy samples were collected 6, 24, and 48 hours after epicutaneous application of Dermatophagoides farinae house dust mites to sensitized atopic dogs. The skin transcriptome was assessed using a dog-specific microarray and quantitative PCR. Acute canine AD skin lesions had a significant up-regulation of genes encoding T helper (Th) 2 (e.g., IL4, IL5, IL13, IL31, and IL33), Th9 (IL9), and Th22 (IL22) cytokines as well as Th2-promoting chemokines such as CCL5 and CCL17. Proinflammatory (e.g., IL6, LTB, and IL18) cytokines were also up-regulated. Other known pruritogenic pathways were also activated: there was significant up-regulation of genes encoding proteases cathepsin S (CTSS), mast cell chymase (CMA1), tryptase (TPS1) and mastin, neuromedin-B (NMB), nerve growth factor (NGF), and leukotriene-synthesis enzymes (ALOX5, ALOX5AP, and LTA4H). Experimental acute canine house dust mite-induced AD lesions exhibit an activation of innate and adaptive immune responses and pruritogenic pathways similar to those seen in humans with acute AD, thereby validating this model to test innovative therapeutics modalities for this disease.

  10. Molecular determinants of P2Y2 nucleotide receptor function: implications for proliferative and inflammatory pathways in astrocytes.

    PubMed

    Weisman, Gary A; Wang, M; Kong, Q; Chorna, N E; Neary, J T; Sun, Grace Y; González, Fernando A; Seye, C I; Erb, L

    2005-01-01

    In the mammalian nervous system, P2 nucleotide receptors mediate neurotransmission, release of proinflammatory cytokines, and reactive astrogliosis. Extracellular nucleotides activate multiple P2 receptors in neurons and glial cells, including G protein-coupled P2Y receptors and P2X receptors, which are ligand-gated ion channels. In glial cells, the P2Y2 receptor subtype, distinguished by its ability to be equipotently activated by ATP and UTP, is coupled to pro-inflammatory signaling pathways. In situ hybridization studies with rodent brain slices indicate that P2Y2 receptors are expressed primarily in the hippocampus and cerebellum. Astrocytes express several P2 receptor subtypes, including P2Y2 receptors whose activation stimulates cell proliferation and migration. P2Y2 receptors, via an RGD (Arg-Gly-Asp) motif in their first extracellular loop, bind to alphavbeta3/beta5 integrins, whereupon P2Y2 receptor activation stimulates integrin signaling pathways that regulate cytoskeletal reorganization and cell motility. The C-terminus of the P2Y2 receptor contains two Src-homology-3 (SH3)-binding domains that upon receptor activation, promote association with Src and transactivation of growth factor receptors. Together, our results indicate that P2Y2 receptors complex with both integrins and growth factor receptors to activate multiple signaling pathways. Thus, P2Y2 receptors present novel targets to control reactive astrogliosis in neurodegenerative diseases.

  11. MiR-150 impairs inflammatory cytokine production by targeting ARRB-2 after blocking CD28/B7 costimulatory pathway

    PubMed Central

    Sang, Wei; Wang, Ying; Zhang, Cong; Zhang, Dianzheng; Sun, Cai; Niu, Mingshan; Zhang, Zhe; Wei, Xiangyu; Pan, Bin; Chen, Wei; Yan, Dongmei; Zeng, Lingyu; Loughran, Thomas P.; Xu, Kailin

    2016-01-01

    MiR-150, a major modulator negatively regulating the development and differentiation of various immune cells, is widely involved in orchestrating inflammation. In transplantation immunity, miR-150 can effectively induce immune tolerance, although the underlying mechanisms have not been fully elucidated. In the current study, we found that miR-150 is elevated after blocking CD28/B7 co-stimulatory signaling pathway and impaired IL-2 production by targeting ARRB2. Further investigation suggested that miR-150 not only repressed the level of ARRB2/PDE4 directly but also prevented AKT/ARRB2/PDE4 trimer recruitment into the lipid raft by inhibiting the activities of PI3K and AKT through the cAMP-PKA-Csk signaling pathway. This leads to the interruption of cAMP degradation and subsequently results in inhibition of the NF-kB pathway and reduced production of both IL-2 and TNF. In conclusion, our study demonstrated that miR-150 can effectively prevent CD28/B7 co-stimulatory signaling transduction, decrease production of inflammatory cytokines, such as IL-2 and TNF, and elicit the induction of immune tolerance. Therefore, miR-150 could become a novel potential therapeutic target in transplantation immunology. PMID:26549736

  12. Molecular approaches toward targeted cancer prevention with some food plants and their products: inflammatory and other signal pathways.

    PubMed

    Khuda-Bukhsh, Anisur Rahman; Das, Sreemanti; Saha, Santu Kumar

    2014-01-01

    In recent years, there has been growing interest in cancer prevention by food plants and their products. Although several plant parts have potentials for chemoprevention and other therapeutic use, their molecular mechanisms of action are not always well understood. Extensive research has identified several molecular targets that can potentially be used for the prevention and/or treatment of cancer. In this review, we accumulate evidences of modulating abilities of some dietary plants and their products on several signaling pathways, including the inflammatory and apoptotic ones, which may be targeted for cancer therapy. We have mainly focused on several phytochemicals like resveratrol (red grapes and peanuts), allicin (garlic), lycopene (tomato), indole-3-carbinol (cruciferous vegetables), vitamin C (citrus fruits), [6]-gingerol (ginger), emodin (aloe), natural antioxidant mixture (spinach), beta carotenoids (carrots), sulphoraphane (mustard), ellagic acid (pomegranate), myrecitin (cranberry), carnosol (rosemary), vanillin (vanilla) and eugenol (cloves). They act through one or more signaling pathways like nuclear factor kappa B, cyclooxygenase-2, signal transducer and activator of transcription 3, Akt, mitogen activated protein kinase/extracellular regulated kinase, Bcl-2, caspases, poly (ADP-ribose) polymerase, matrix metalloproteinase 2/9, and cyclin D1. Critical knowledge on these compounds and their signaling pathways may help in formulation of effective anticancer drugs.

  13. Amelioration of nandrolone decanoate-induced testicular and sperm toxicity in rats by taurine: Effects on steroidogenesis, redox and inflammatory cascades, and intrinsic apoptotic pathway

    SciTech Connect

    Ahmed, Maha A.E.

    2015-02-01

    The wide abuse of the anabolic steroid nandrolone decanoate by athletes and adolescents for enhancement of sporting performance and physical appearance may be associated with testicular toxicity and infertility. On the other hand, taurine; a free β-amino acid with remarkable antioxidant activity, is used in taurine-enriched beverages to boost the muscular power of athletes. Therefore, the purpose of this study was to investigate the mechanisms of the possible protective effects of taurine on nandrolone decanoate-induced testicular and sperm toxicity in rats. To achieve this aim, male Wistar rats were randomly distributed into four groups and administered either vehicle, nandrolone decanoate (10 mg/kg/week, I.M.), taurine (100 mg/kg/day, p.o.) or combination of taurine and nandrolone decanoate, for 8 successive weeks. Results of the present study showed that taurine reversed nandrolone decanoate-induced perturbations in sperm characteristics, normalized serum testosterone level, and restored the activities of the key steroidogenic enzymes; 3β-HSD, and 17β-HSD. Moreover, taurine prevented nandrolone decanoate-induced testicular toxicity and DNA damage by virtue of its antioxidant, anti-inflammatory, and anti-apoptotic effects. This was evidenced by taurine-induced modulation of testicular LDH-x activity, redox markers (MDA, NO, GSH contents, and SOD activity), inflammatory indices (TNF-α, ICAM-1 levels, and MMP-9 gene expression), intrinsic apoptotic pathway (cytochrome c gene expression and caspase-3 content), and oxidative DNA damage markers (8-OHdG level and comet assay). In conclusion, at the biochemical and histological levels, taurine attenuated nandrolone decanoate-induced poor sperm quality and testicular toxicity in rats. - Highlights: • Nandrolone decanoate (ND) disrupts sperm profile and steroidogenesis in rats. • ND upregulates gene expression of inflammatory and apoptotic markers. • Taurine normalizes sperm profile and serum testosterone level

  14. Doxycycline Promotes Carcinogenesis & Metastasis via Chronic Inflammatory Pathway: An In Vivo Approach

    PubMed Central

    Nanda, Neha; Dhawan, Devinder K.; Bhatia, Alka; Mahmood, Akhtar; Mahmood, Safrun

    2016-01-01

    Background Doxycycline (DOX) exhibits anti-inflammatory, anti-tumor, and pro-apoptotic activity and is being tested in clinical trials as a chemotherapeutic agent for several cancers, including colon cancer. Materials & Methods In the current study, the chemotherapeutic activity of doxycycline was tested in a rat model of colon carcinogenesis, induced by colon specific cancer promoter, 1,2, dimethylhydrazine (DMH) as well as study the effect of DOX-alone on a separate group of rats. Results Doxycycline administration in DMH-treated rats (DMH-DOX) unexpectedly increased tumor multiplicity, stimulated progression of colonic tumor growth from adenomas to carcinomas and revealed metastasis in small intestine as determined by macroscopic and histopathological analysis. DOX-alone treatment showed markedly enhanced chronic inflammation and reactive hyperplasia, which was dependent upon the dose of doxycycline administered. Moreover, immunohistochemical analysis revealed evidence of inflammation and anti-apoptotic action of DOX by deregulation of various biomarkers. Conclusion These results suggest that doxycycline caused chronic inflammation in colon, small intestine injury, enhanced the efficacy of DMH in tumor progression and provided a mechanistic link between doxycycline-induced chronic inflammation and tumorigenesis. Ongoing studies thus may need to focus on the molecular mechanisms of doxycycline action, which lead to its inflammatory and tumorigenic effects. PMID:26998758

  15. Sulforaphane Protects Rodent Retinas against Ischemia-Reperfusion Injury through the Activation of the Nrf2/HO-1 Antioxidant Pathway

    PubMed Central

    Liu, Ruixing; Brecha, Nicholas C.; Yu, Albert Cheung Hoi; Pu, Mingliang

    2014-01-01

    Retinal ischemia-reperfusion (I/R) injury induces oxidative stress, leukocyte infiltration, and neuronal cell death. Sulforaphane (SF), which can be obtained in cruciferous vegetables such as broccoli, exerts protective effects in response to oxidative stress in various tissues. These effects can be initiated through nuclear factor E2-related factor 2 (Nrf2)-mediated induction of heme oxygenase-1 (HO-1). This investigation was designed to elucidate the neural protective mechanisms of SF in the retinal I/R rat model. Animals were intraperitoneally (i.p.) injected with SF (12.5 mg/kg) or vehicle (corn oil) once a day for 7 consecutive days. Then, retinal I/R was made by elevating the intraocular pressure (IOP) to 130 mmHg for 1 h. To determine if HO-1 was involved in the Nrf2 antioxidant pathway, rats were subjected to protoporphyrin IX zinc (II) (ZnPP, 30 mg/kg, i.p.) treatments at 24 h before retinal ischemia. The neuroprotective effects of SF were assessed by determining the morphology of the retina, counting the infiltrating inflammatory cells and the surviving retinal ganglion cells (RGCs) and amacrine cells, and measuring apoptosis in the retinal layers. The expression of Nrf2 and HO-1 was studied by immunofluorescence analysis and western blotting. I/R induced a marked increase of ROS generation, caused pronounced inflammation, increased the apoptosis of RGCs and amacrine cells and caused the thinning of the inner retinal layer (IRL), and these effects were diminished or abolished by SF pretreatment. Meanwhile, SF pretreatment significantly elevated the nuclear accumulation of Nrf2 and the level of HO-1 expression in the I/R retinas; however, ZnPP reversed the protective effects of SF on I/R retinas. Together, we offer direct evidence that SF had protective effects on I/R retinas, which could be attributed, at least in part, to the activation of the Nrf2/HO-1 antioxidant pathway. PMID:25470382

  16. Puerarin protects mouse liver against nickel-induced oxidative stress and inflammation associated with the TLR4/p38/CREB pathway.

    PubMed

    Liu, Chan-Min; Ma, Jie-Qiong; Liu, Si-Si; Feng, Zhao-Jun; Wang, Ai-Min

    2016-01-05

    Nickel (Ni), one of hazardous environmental chemicals, is known to cause liver injury. Accumulating evidence showed that puerarin (PU) possessed comprehensive biological effects. The purpose of the current study was to test the hypothesis that the puerarin protects against enhanced liver injury caused by Ni in mice. ICR mice received intraperitoneally nickel sulfate (20 mg/kg/body weight, daily) for 20 days, and puerarin (200 and 400 mg/kg/body weight) was applied before Ni exposure. The results indicated that puerarin markedly inhibited Ni-induced liver injury, which was characterized by decreased aminotransferase activities and inflammation. Puerarin also inhibited the oxidative stress and decreased the metallothionein (MT) levels. Puerarin decreased the level of pro-inflammatory cytokines TNF-α and IL-6 in livers. Puerarin significantly inhibited the TLR4 activation and p38 MAPK phosphorylation, which in turn inhibited NF-κB activity. Likewise, Ni-induced inflammatory responses were diminished by puerarin as observed by a remarkable reduction in the levels of phosphorylated CREB. Furthermore, puerarin also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) levels in livers. Data from this study suggested that the inhibition of Ni-induced oxidative stress and inflammatory responses by puerarin is due to its ability to modulate the TLR4/p38/CREB signaling pathway.

  17. Vanillin Protects Dopaminergic Neurons against Inflammation-Mediated Cell Death by Inhibiting ERK1/2, P38 and the NF-κB Signaling Pathway.

    PubMed

    Yan, Xuan; Liu, Dian-Feng; Zhang, Xiang-Yang; Liu, Dong; Xu, Shi-Yao; Chen, Guang-Xin; Huang, Bing-Xu; Ren, Wen-Zhi; Wang, Wei; Fu, Shou-Peng; Liu, Ju-Xiong

    2017-02-12

    Neuroinflammation plays a very important role in the pathogenesis of Parkinson's disease (PD). After activation, microglia produce pro-inflammatory mediators that damage surrounding neurons. Consequently, the inhibition of microglial activation might represent a new therapeutic approach of PD. Vanillin has been shown to protect dopaminergic neurons, but the mechanism is still unclear. Herein, we further study the underlying mechanisms in lipopolysaccharide (LPS)-induced PD models. In vivo, we firstly established rat models of PD by unilateral injection of LPS into substantia nigra (SN), and then examined the role of vanillin in motor dysfunction, microglial activation and degeneration of dopaminergic neurons. In vitro, murine microglial BV-2 cells were treated with vanillin prior to the incubation of LPS, and then the inflammatory responses and the related signaling pathways were analyzed. The in vivo results showed that vanillin markedly improved the motor dysfunction, suppressed degeneration of dopaminergic neurons and inhibited microglial over-activation induced by LPS intranigral injection. The in vitro studies demonstrated that vanillin reduces LPS-induced expression of inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), IL-1β, and IL-6 through regulating ERK1/2, p38 and NF-κB signaling. Collectively, these data indicated that vanillin has a role in protecting dopaminergic neurons via inhibiting inflammatory activation.

  18. Vanillin Protects Dopaminergic Neurons against Inflammation-Mediated Cell Death by Inhibiting ERK1/2, P38 and the NF-κB Signaling Pathway

    PubMed Central

    Yan, Xuan; Liu, Dian-Feng; Zhang, Xiang-Yang; Liu, Dong; Xu, Shi-Yao; Chen, Guang-Xin; Huang, Bing-Xu; Ren, Wen-Zhi; Wang, Wei; Fu, Shou-Peng; Liu, Ju-Xiong

    2017-01-01

    Neuroinflammation plays a very important role in the pathogenesis of Parkinson’s disease (PD). After activation, microglia produce pro-inflammatory mediators that damage surrounding neurons. Consequently, the inhibition of microglial activation might represent a new therapeutic approach of PD. Vanillin has been shown to protect dopaminergic neurons, but the mechanism is still unclear. Herein, we further study the underlying mechanisms in lipopolysaccharide (LPS)-induced PD models. In vivo, we firstly established rat models of PD by unilateral injection of LPS into substantia nigra (SN), and then examined the role of vanillin in motor dysfunction, microglial activation and degeneration of dopaminergic neurons. In vitro, murine microglial BV-2 cells were treated with vanillin prior to the incubation of LPS, and then the inflammatory responses and the related signaling pathways were analyzed. The in vivo results showed that vanillin markedly improved the motor dysfunction, suppressed degeneration of dopaminergic neurons and inhibited microglial over-activation induced by LPS intranigral injection. The in vitro studies demonstrated that vanillin reduces LPS-induced expression of inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), IL-1β, and IL-6 through regulating ERK1/2, p38 and NF-κB signaling. Collectively, these data indicated that vanillin has a role in protecting dopaminergic neurons via inhibiting inflammatory activation. PMID:28208679

  19. Identification of signaling pathways associated with cancer protection in Laron syndrome.

    PubMed

    Lapkina-Gendler, Lena; Rotem, Itai; Pasmanik-Chor, Metsada; Gurwitz, David; Sarfstein, Rive; Laron, Zvi; Werner, Haim

    2016-05-01

    The growth hormone (GH)-insulin-like growth factor-1 (IGF1) pathway emerged in recent years as a critical player in cancer biology. Enhanced expression or activation of specific components of the GH-IGF1 axis, including the IGF1 receptor (IGF1R), is consistently associated with a transformed phenotype. Recent epidemiological studies have shown that patients with Laron syndrome (LS), the best-characterized entity among the congenital IGF1 deficiencies, seem to be protected from cancer development. To identify IGF1-dependent genes and signaling pathways associated with cancer protection in LS, we conducted a genome-wide analysis using immortalized lymphoblastoid cells derived from LS patients and healthy controls of the same gender, age range, and ethnic origin. Our analyses identified a collection of genes that are either over- or under-represented in LS-derived lymphoblastoids. Gene differential expression occurs in several gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT signaling, and PI3K-AKT signaling. Major differences between LS and healthy controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. Our results highlight the key role of the GH-IGF1 axis in the initiation and progression of cancer. Furthermore, data are consistent with the concept that homozygous congenital IGF1 deficiency may confer protection against future tumor development.

  20. Aspirin-triggered resolvin D1 down-regulates inflammatory responses and protects against endotoxin-induced acute kidney injury

    SciTech Connect

    Chen, Jiao; Shetty, Sreerama; Zhang, Ping; Gao, Rong; Hu, Yuxin; Wang, Shuxia; Li, Zhenyu; Fu, Jian

    2014-06-01

    The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1 h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.

  1. Natural Compound Histone Deacetylase Inhibitors (HDACi): Synergy with Inflammatory Signaling Pathway Modulators and Clinical Applications in Cancer.

    PubMed

    Losson, Hélène; Schnekenburger, Michael; Dicato, Mario; Diederich, Marc

    2016-11-23

    The remarkable complexity of cancer involving multiple mechanisms of action and specific organs led researchers Hanahan and Weinberg to distinguish biological capabilities acquired by cancer cells during the multistep development of human tumors to simplify its understanding. These characteristic hallmarks include the abilities to sustain proliferative signaling, evade growth suppressors, resist cell death, enable replicative immortality, induce angiogenesis, activate invasion and metastasis, avoid immune destruction, and deregulate cellular energetics. Furthermore, two important characteristics of tumor cells that facilitate the acquisition of emerging hallmarks are tumor-promoting inflammation and genome instability. To treat a multifactorial disease such as cancer, a combination treatment strategy seems to be the best approach. Here we focus on natural histone deacetylase inhibitors (HDACi), their clinical uses as well as synergies with modulators of the pro-inflammatory transcription factor signaling pathways.

  2. Accumulation of Palmitoylcarnitine and Its Effect on Pro‐Inflammatory Pathways and Calcium Influx in Prostate Cancer

    PubMed Central

    Al‐Bakheit, Ala'a; Traka, Maria; Saha, Shikha; Mithen, Richard

    2016-01-01

    BACKGROUND Acylcarnitines are intermediates of fatty acid oxidation and accumulate as a consequence of the metabolic dysfunction resulting from the insufficient integration between β‐oxidation and the tricarboxylic acid (TCA) cycle. The aim of this study was to investigate whether acylcarnitines accumulate in prostate cancer tissue, and whether their biological actions could be similar to those of dihydrotestosterone (DHT), a structurally related compound associated with cancer development. METHODS Levels of palmitoylcarnitine (palcar), a C16:00 acylcarnitine, were measured in prostate tissue using LC‐MS/MS. The effect of palcar on inflammatory cytokines and calcium (Ca2+) influx was investigated in in vitro models of prostate cancer. RESULTS We observed a significantly higher level of palcar in prostate cancerous tissue compared to benign tissue. High levels of palcar have been associated with increased gene expression and secretion of the pro‐inflammatory cytokine IL‐6 in cancerous PC3 cells, compared to normal PNT1A cells. Furthermore, we found that high levels of palcar induced a rapid Ca2+ influx in PC3 cells, but not in DU145, BPH‐1, or PNT1A cells. This pattern of Ca2+ influx was also observed in response to DHT. Through the use of whole genome arrays we demonstrated that PNT1A cells exposed to palcar or DHT have a similar biological response. CONCLUSIONS This study suggests that palcar might act as a potential mediator for prostate cancer progression through its effect on (i) pro‐inflammatory pathways, (ii) Ca2+ influx, and (iii) DHT‐like effects. Further studies need to be undertaken to explore whether this class of compounds has different biological functions at physiological and pathological levels. Prostate 76:1326–1337, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc. PMID:27403764

  3. Micheliolide provides protection of mice against Staphylococcus aureus and MRSA infection by down-regulating inflammatory response

    PubMed Central

    Jiang, Xinru; Wang, Yuli; Qin, Yifei; He, Weigang; Benlahrech, Adel; Zhang, Qingwen; Jiang, Xin; Lu, Zhenhui; Ji, Guang; Zheng, Yuejuan

    2017-01-01

    A major obstacle to therapy in intensive care units is sepsis caused by severe infection. In recent years gram-positive (G+) bacteria, most commonly staphylococci, are thought to be the main pathogens. Micheliolide (MCL) was demonstrated to provide a therapeutic role in rheumatoid arthritis, inflammatory intestinal disease, colitis-associated cancer, and lipopolysaccharide (LPS, the main component of G− bacterial cell wall) induced septic shock. We proved here that MCL played an anti-inflammatory role in Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) induced peritonitis. It inhibited the expression of inflammatory cytokines and chemokines in macrophages and dendritic cells upon stimulation with peptidoglycan (PGN, the main cell wall composition of G+ bacteria). PI3K/Akt and NF-κB pathways account for the anti-inflammatory role of MCL after PGN stimulation. MCL reduced IL-6 secretion through down-regulating NF-κB activation and improved the survival status in mice challenged with a lethal dose of S. aureus. In MRSA infection mouse model, MCL down-regulated the expression of IL-6, TNF-α, MCP-1/CCL2 and IFN-γ in sera, and ameliorated the organ damage of liver and kidney. In conclusion, MCL can help maintain immune equilibrium and decrease PGN, S. aureus and MRSA-triggered inflammatory response. These provide the rationality for the potential usage of MCL in sepsis caused by G+ bacteria (e.g., S. aureus) and antibiotic-resistant bacteria (e.g., MRSA). PMID:28165033

  4. Anti-inflammatory effects of Perilla frutescens in activated human neutrophils through two independent pathways: Src family kinases and Calcium

    PubMed Central

    Chen, Chun-Yu; Leu, Yann-Lii; Fang, Yu; Lin, Chwan-Fwu; Kuo, Liang-Mou; Sung, Wei-Che; Tsai, Yung-Fong; Chung, Pei-Jen; Lee, Ming-Chung; Kuo, Yu-Ting; Yang, Hsuan-Wu; Hwang, Tsong-Long

    2015-01-01

    The leaves of Perilla frutescens (L.) Britt. have been traditionally used as an herbal medicine in East Asian countries to treat a variety diseases. In this present study, we investigated the inhibitory effects of P. frutescens extract (PFE) on N-formyl-Met-Leu-Phe (fMLF)-stimulated human neutrophils and the underlying mechanisms. PFE (1, 3, and 10 μg/ml) inhibited superoxide anion production, elastase release, reactive oxygen species formation, CD11b expression, and cell migration in fMLF-activated human neutrophils in dose-dependent manners. PFE inhibited fMLF-induced phosphorylation of the Src family kinases (SFKs), Src (Tyr416) and Lyn (Tyr396), and reduced their enzymatic activities. Both PFE and PP2 (a selective inhibitor of SFKs) reduced the phosphorylation of Burton’s tyrosine kinases (Tyr223) and Vav (Tyr174) in fMLF-activated human neutrophils. Additionally, PFE decreased intracellular Ca2+ levels ([Ca2+]i), whereas PP2 prolonged the time required for [Ca2+]i to return to its basal level. Our findings indicated that PFE effectively regulated the inflammatory activities of fMLF-activated human neutrophils. The anti-inflammatory effects of PFE on activated human neutrophils were mediated through two independent signaling pathways involving SFKs (Src and Lyn) and mobilization of intracellular Ca2+. PMID:26659126

  5. Anti-inflammatory effects of Perilla frutescens in activated human neutrophils through two independent pathways: Src family kinases and Calcium.

    PubMed

    Chen, Chun-Yu; Leu, Yann-Lii; Fang, Yu; Lin, Chwan-Fwu; Kuo, Liang-Mou; Sung, Wei-Che; Tsai, Yung-Fong; Chung, Pei-Jen; Lee, Ming-Chung; Kuo, Yu-Ting; Yang, Hsuan-Wu; Hwang, Tsong-Long

    2015-12-14

    The leaves of Perilla frutescens (L.) Britt. have been traditionally used as an herbal medicine in East Asian countries to treat a variety diseases. In this present study, we investigated the inhibitory effects of P. frutescens extract (PFE) on N-formyl-Met-Leu-Phe (fMLF)-stimulated human neutrophils and the underlying mechanisms. PFE (1, 3, and 10 μg/ml) inhibited superoxide anion production, elastase release, reactive oxygen species formation, CD11b expression, and cell migration in fMLF-activated human neutrophils in dose-dependent manners. PFE inhibited fMLF-induced phosphorylation of the Src family kinases (SFKs), Src (Tyr416) and Lyn (Tyr396), and reduced their enzymatic activities. Both PFE and PP2 (a selective inhibitor of SFKs) reduced the phosphorylation of Burton's tyrosine kinases (Tyr223) and Vav (Tyr174) in fMLF-activated human neutrophils. Additionally, PFE decreased intracellular Ca(2+) levels ([Ca(2+)]i), whereas PP2 prolonged the time required for [Ca(2+)]i to return to its basal level. Our findings indicated that PFE effectively regulated the inflammatory activities of fMLF-activated human neutrophils. The anti-inflammatory effects of PFE on activated human neutrophils were mediated through two independent signaling pathways involving SFKs (Src and Lyn) and mobilization of intracellular Ca(2+).

  6. Berberine relieves insulin resistance via the cholinergic anti-inflammatory pathway in HepG2 cells.

    PubMed

    Li, Fen; Zhao, Yun-bin; Wang, Ding-kun; Zou, Xin; Fang, Ke; Wang, Kai-fu

    2016-02-01

    Berberine (BBR) is an isoquinoline alkaloid extracted from Rhizoma coptidis and has been used for treating type 2 diabetes mellitus (T2DM) in China. The development of T2DM is often associated with insulin resistance and impaired glucose uptake in peripheral tissues. In this study, we examined whether BBR attenuated glucose uptake dysfunction through the cholinergic anti-inflammatory pathway in HepG2 cells. Cellular glucose uptake, quantified by the 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-2-deoxy-D-glucose (2-NBDG), was inhibited by 21% after HepG2 cells were incubated with insulin (10(-6) mol/L) for 36 h. Meanwhile, the expression of alpha7 nicotinic acetylcholine receptor (α7nAChR) protein was reduced without the change of acetylcholinesterase (AChE) activity. The level of interleukin-6 (IL-6) in the culture supernatant, the ratio of phosphorylated I-kappa-B kinase-β (IKκβ) Ser181/IKKβ and the expression of nuclear factor-kappa B (NF-κB) p65 protein were also increased. However, the treatment with BBR enhanced the glucose uptake, increased the expression of α7nAChR protein and inhibited AChE activity. These changes were also accompanied with the decrease of the ratio of pIKKβ Ser181/IKKβ, NF-κB p65 expression and IL-6 level. Taken together, these results suggest that BBR could enhance glucose uptake, and relieve insulin resistance and inflammation in HepG2 cells. The mechanism may be related to the cholinergic anti-inflammatory pathway and the inhibition of AChE activity.

  7. Paeonol suppresses lipopolysaccharide-induced inflammatory cytokines in macrophage cells and protects mice from lethal endotoxin shock.

    PubMed

    Chen, Na; Liu, Dianfeng; Soromou, Lanan Wassy; Sun, Jingjing; Zhong, Weiting; Guo, Weixiao; Huo, Meixia; Li, Hongyu; Guan, Shuang; Chen, Zhenwen; Feng, Haihua

    2014-06-01

    Paeonol (2'-hydroxy-4'-methoxyacetophenone) is the main phenolic compound of the radix of Paeonia suffruticosa which has been used as traditional Chinese medicine. In this study, we primarily investigated the anti-inflammatory effects and the underlying mechanisms of paeonol in RAW macrophage cells; and based on these effects, we assessed the protective effects of paeonol on lipopolysaccharide-induced endotoxemia in mice. The in vitro study showed that paeonol regulated the production of TNF-α, IL-1β, IL-6, and IL-10 via inactivation of IκBα, ERK1/2, JNK, and p38 MAPK. In mouse model of lipopolysaccharide-induced endotoxemia, pro- and anti-inflammatory cytokines are significantly regulated, and thus the survival rates of lipolysaccharide-challenged mice are improved by paeonol (150, 200, or 250 mg/kg). Therefore, paeonol has a beneficial activity against lipopolysaccharide-induced inflammation in RAW 264.7 cell and mouse models.

  8. Protection against Chlamydia trachomatis infection in vitro and modulation of inflammatory response in vivo by membrane-bound glycosaminoglycans.

    PubMed

    Darville, Toni; Yedgar, Saul; Krimsky, M; Andrews, C W; Jungas, Thomas; Ojcius, David M

    2004-04-01

    Glycosaminoglycans (GAG) efficiently inhibit adherence of several strains of Chlamydia trachomatis to cell lines in vitro, but none of the GAG have been able to inhibit infections in vivo. One possible cause for failure of GAG inhibition in vivo is the inability to deliver a sustained concentration of GAG at the mucosal surface. We tested the possibility of enhancing cell protection by increasing the cell-surface concentration of GAG using membrane-anchored GAG (MAG), composed of phosphatidylethanolamine (PE)-linked GAG. These lipid conjugates were originally designed as extracellular phospholipase A2 (PLA2) inhibitors and exhibit a dual effect: the lipid moiety incorporates into the cell membrane, interfering with the action of PLA2 on cell membranes, and the anchored GAG protects the cell membrane from exogenous inflammatory mediators. We tested the ability of MAG to block chlamydia infection in vitro and in vivo. The MAG blocked infection of epithelial cells in vitro when added to the cells at the same time or before infection, but not if added after the bacteria had already invaded the host cells. One of the MAG led to the production of aberrant Chlamydia vacuoles, suggesting it may inhibit intracellular PLA2 associated with development of the vacuole. Although the MAG did not inhibit vaginal infection of mice, they decreased significantly the level of secretion of the inflammatory cytokines TNF-alpha and IFN-gamma but had no effect on secretion of the neutrophil chemokine, macrophage inflammatory protein-2 (MIP-2). Acute and chronic inflammatory cell infiltrates were not altered by MAG treatment. These findings suggest that lipid conjugation of GAG could be used as a novel approach for increasing cell-surface concentrations of GAG. The inconclusive in vivo results might be due to the physical properties of the tested MAG or an insufficient application protocol, and their improvement might provide the desired inhibitory effects.

  9. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

    PubMed Central

    Mukhopadhyay, Partha; Rajesh, Mohanraj; Horváth, Béla; Bátkai, Sándor; Park, Ogyi; Tanashian, Galin; Gao, Rachel Y; Patel, Vivek; Wink, David A.; Liaudet, Lucas; Haskó, György; Mechoulam, Raphael; Pacher, Pál

    2011-01-01

    Ischemia-reperfusion (I/R) is a pivotal mechanism of liver damage following liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol(CBD), the non-psychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor alpha (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, inter-cellular adhesion molecule 1 mRNA levels, tissue neutrophil infiltration, nuclear factor kappa B (NF-KB) activation), stress signaling (p38MAPK and JNK) and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress and cell death, and also attenuated the bacterial endotoxin-triggered NF-KB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecules expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α, and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent from classical CB1/2 receptors. PMID:21362471

  10. Effect of silibinin in reducing inflammatory pathways in in vitro and in vivo models of infection-induced preterm birth.

    PubMed

    Lim, Ratana; Morwood, Carrington J; Barker, Gillian; Lappas, Martha

    2014-01-01

    Infection-induced preterm birth is the largest cause of infant death and of neurological disabilities in survivors. Silibinin, from milk thistle, exerts potent anti-inflammatory activities in non-gestational tissues. The aims of this study were to determine the effect of silibinin on pro-inflammatory mediators in (i) human fetal membranes and myometrium treated with bacterial endotoxin lipopolysaccharide (LPS) or the pro-inflammatory cytokine IL-1β, and (ii) in preterm fetal membranes with active infection. The effect of silibinin on infection induced inflammation and brain injury in pregnant mice was also assessed. Fetal membranes and myometrium (tissue explants and primary cells) were treated with 200 μM silibinin in the presence or absence of 10 μg/ml LPS or 1 ng/ml IL-1β. C57BL/6 mice were injected with 70 mg/kg silibinin with or without 50 μg LPS on embryonic day 16. Fetal brains were collected after 6 h. In human fetal membranes, silibinin significantly decreased LPS-stimulated expression of IL-6 and IL-8, COX-2, and prostaglandins PGE2 and PGF2α. In primary amnion and myometrial cells, silibinin also decreased IL-1β-induced MMP-9 expression. Preterm fetal membranes with active infection treated with silibinin showed a decrease in IL-6, IL-8 and MMP-9 expression. Fetal brains from mice treated with silibinin showed a significant decrease in LPS-induced IL-8 and ninjurin, a marker of brain injury. Our study demonstrates that silibinin can reduce infection and inflammation-induced pro-labour mediators in human fetal membranes and myometrium. Excitingly, the in vivo results indicate a protective effect of silibinin on infection-induced brain injury in a mouse model of preterm birth.

  11. Nonsteroidal anti-inflammatory drugs modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways

    PubMed Central

    Mozolewski, Paweł; Moskot, Marta; Jakóbkiewicz-Banecka, Joanna; Węgrzyn, Grzegorz; Bocheńska, Katarzyna; Banecki, Bogdan; Gabig-Cimińska, Magdalena

    2017-01-01

    In this report, selected non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin and nimesulide, and analgesics acetaminophen, alone, as well as in combination with isoflavone genistein as potential glycosaminoglycan (GAG) metabolism modulators were considered for the treatment of mucopolysaccharidoses (MPSs) with neurological symptoms due to the effective blood-brain barrier (BBB) penetration properties of these compounds. We found that indomethacin and nimesulide, but not acetaminophen, inhibited GAG synthesis in fibroblasts significantly, while the most pronounced impairment of glycosaminoglycan production was observed after exposure to the mixture of nimesulide and genistein. Phosphorylation of the EGF receptor (EGFR) was inhibited even more effective in the presence of indomethacin and nimesulide than in the presence of genistein. When examined the activity of phosphatidylinositol-3-kinase (PI3K) production, we observed its most significant decrease in the case of fibroblast exposition to nimesulide, and afterwards to indomethacin and genistein mix, rather than indomethacin used alone. Some effects on expression of individual GAG metabolism-related and lysosomal function genes, and significant activity modulation of a number of genes involved in intracellular signal transduction pathways and metabolism of DNA and proteins were detected. This study documents that NSAIDs, and their mixtures with genistein modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways. PMID:28240227

  12. Alpinetin attenuates inflammatory responses by suppressing TLR4 and NLRP3 signaling pathways in DSS-induced acute colitis

    PubMed Central

    He, Xuexiu; Wei, Zhengkai; Wang, Jingjing; Kou, Jinhua; Liu, Weijian; Fu, Yunhe; Yang, Zhengtao

    2016-01-01

    Alpinetin, a composition of Alpinia katsumadai Hayata, has been reported to have a number of biological properties, such as antibacterial, antitumor and other important therapeutic activities. However, the effect of alpinetin on inflammatory bowel disease (IBD) has not yet been reported. The purpose of this study was to investigate the anti-inflammatory effect and mechanism of alpinetin on dextran sulfate sodium (DSS)-induced colitis in mice. In vivo, DSS-induced mice colitis model was established by giving mice drinking water containing 5% (w/v) DSS for 7 days. Alpinetin (25, 50 and 100 mg/kg) were administered once a day by intraperitoneal injection 3 days before DSS treatment. In vitro, phorbol myristate acetate (PMA)-differentiated monocytic THP-1 macrophages were treated with alpinetin and stimulated by lipopolysaccharide (LPS). The results showed that alpinetin significantly attenuated diarrhea, colonic shortening, histological injury, myeloperoxidase (MPO) activity and the expressions of tumor necrosis factor (TNF-α) and interleukin (IL-1β) production in mice. In vitro, alpinetin markedly inhibited LPS-induced TNF-α and IL-1β production, as well as Toll-like receptor 4 (TLR4) mediated nuclear transcription factor-kappaB (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, this study demonstrated that alpinetin had protective effects on DSS-induced colitis and may be a promising therapeutic reagent for colitis treatment. PMID:27321991

  13. Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions.

    PubMed

    Dal-Cim, Tharine; Ludka, Fabiana K; Martins, Wagner C; Reginato, Charlise; Parada, Esther; Egea, Javier; López, Manuela G; Tasca, Carla I

    2013-08-01

    Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 μM) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti-inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A1 receptor, phosphatidylinositol-3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin-sensitive G-protein-coupled signaling, blockade of adenosine A2A receptors (A2A R), but not via A1 receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake.

  14. Protective effect of kaempferol on LPS plus ATP-induced inflammatory response in cardiac fibroblasts.

    PubMed

    Tang, Xi-Lan; Liu, Jian-Xun; Dong, Wei; Li, Peng; Li, Lei; Hou, Jin-Cai; Zheng, Yong-Qiu; Lin, Cheng-Ren; Ren, Jun-Guo

    2015-02-01

    Inflammatory response is an important mechanism in the pathogenesis of cardiovascular diseases. Cardiac fibroblasts play a crucial role in cardiac inflammation and might become a potential therapeutic target in cardiovascular diseases. Kaempferol, a flavonoid commonly existing in many edible fruits, vegetables, and Chinese herbs, is well known to possess anti-inflammatory property and thus has a therapeutic potential for the treatment of inflammatory diseases. To date, the effect of kaempferol on cardiac fibroblasts inflammation is unknown. In this study, we investigated the anti-inflammatory effect of kaempferol on lipopolysaccharide (LPS) plus ATP-induced cardiac fibroblasts and explored the underlying mechanisms. Our results showed that kaempferol at concentrations of 12.5 and 25 μg/mL significantly suppressed the release of TNF-α, IL-1β, IL-6, and IL-18 and inhibited activation of NF-κB and Akt in LPS plus ATP-induced cardiac fibroblasts. These findings suggest that kaempferol attenuates cardiac fibroblast inflammation through suppression of activation of NF-κB and Akt.

  15. Wedelolactone protects human bronchial epithelial cell injury against cigarette smoke extract-induced oxidant stress and inflammation responses through Nrf2 pathway.

    PubMed

    Ding, Shumin; Hou, Xuefeng; Yuan, Jiarui; Tan, Xiaobin; Chen, Juan; Yang, Nan; Luo, Yi; Jiang, Ziyu; Jin, Ping; Dong, Zibo; Feng, Liang; Jia, Xiaobin

    2015-12-01

    Cigarette smoke is the leading cause of the development of various lung diseases including lung cancer through triggering oxidant stress and inflammatory responses which contributed to the lesions of normal human bronchial epithelial (NHBE) cell. Wedelolactone (WEL), a natural compound from Eclipta prostrata L., has been found to possess the inhibitive effects on the proliferation and growth of cancers. In the present study, we investigated the effects of WEL on NHBE cell injury induced by cigarette smoke extract (CSE) in vitro. It showed that the pretreatment WEL (2.5-20μM) resulted in a significant protective effect on 10% CSE-induced cell death in NHBE cells. The pretreatment with WEL dose-dependently and significantly reversed the activities of SOD, CAT, GSH and the level of MDA to normal level. We also found that the protein expression levels of COX-2 and ICAM-1 which are related to inflammatory response were remarkably reduced by WEL compared with 10% CSE treatment. Additionally, WEL also reduced the expressions of antioxidases including NAD(P)H dehydrogenase:Quinone 1 (NQO1) and heme oxygenase-1 (HO-1). Moreover, Nrf2 inhibitor all-trans-retinoic acid (ATRA) decreased remarkably their expressions. These results suggest that WEL protects NHBE cell against CSE-induced injury through modulating Nrf2 pathway. Our study indicates that WEL may be a new potential protective agent against CSE-induced lung injury.

  16. Protective Effects of Green Tea Polyphenol Against Renal Injury Through ROS-Mediated JNK-MAPK Pathway in Lead Exposed Rats.

    PubMed

    Wang, Haidong; Li, Deyuan; Hu, Zhongze; Zhao, Siming; Zheng, Zhejun; Li, Wei

    2016-06-30

    To investigate the potential therapeutic effects of polyphenols in treating Pb induced renal dysfunction and intoxication and to explore the detailed underlying mechanisms. Wistar rats were divided into four groups: control groups (CT), Pb exposure groups (Pb), Pb plus Polyphenols groups (Pb+PP) and Polyphenols groups (PP). Animals were kept for 60 days and sacrificed for tests of urea, serum blood urea nitrogen (BUN) and creatinine. Histological evaluations were then performed. In vitro studies were performed using primary kidney mesangial cells to reveal detailed mechanisms. Cell counting kit-8 (CCK-8) was used to evaluate cell viability. Pb induced cell apoptosis was measured by flow cytometry. Reactive oxygen species (ROS) generation and scavenging were tested by DCFH-DA. Expression level of tumor necrosis factor-α (TNF-α), interleukin-1-β (IL-1-β) and IL-6 were assayed by ELISA. Western blot and qPCR were used to measure the expression of ERK1/2, JNK1/2 and p38. Polyphenols have obvious protective effects on Pb induced renal dysfunction and intoxication both in vivo and in vitro. Polyphenols reduced Pb concentration and accumulation in kidney. Polyphenols also protected kidney mesangial cells from Pb induced apoptosis. Polyphenols scavenged Pb induced ROS generation and suppressed ROS-mediated ERK/JNK/p38 pathway. Downstream pro-inflammatory cytokines were inhibited in consistency. Polyphenol is protective in Pb induced renal intoxication and inflammatory responses. The underlying mechanisms lie on the antioxidant activity and ROS scavenging activity of polyphenols.

  17. Involvement of Galectin-9/TIM-3 Pathway in the Systemic Inflammatory Response in Early-Onset Preeclampsia

    PubMed Central

    Miko, Eva; Meggyes, Matyas; Bogar, Barbara; Schmitz, Nora; Barakonyi, Aliz; Varnagy, Akos; Farkas, Balint; Tamas, Peter; Bodis, Jozsef; Szekeres-Bartho, Julia; Illes, Zsolt; Szereday, Laszlo

    2013-01-01

    Background Preeclampsia is a common obstetrical disease affecting 3-5% of pregnancies and representing one of the leading causes of both maternal and fetal mortality. Maternal symptoms occur as an excessive systemic inflammatory reaction in response to the placental factors released by the oxidatively stressed and functional impaired placenta. The T-cell immunoglobulin domain and mucin domain (TIM) family is a relatively newly described group of molecules with a conserved structure and important immunological functions. Identification of Galectin-9 as a ligand for TIM-3 has established the Galectin-9/TIM-3 pathway as an important regulator of Th1 immunity and tolerance induction. Methods The aim of our study was to investigate the expression and function of Galectin-9 and TIM-3 molecules by peripheral blood mononuclear cells and the possible role of Galectin-9/TIM-3 pathway in the immunoregulation of healthy pregnancy and early-onset preeclampsia. We determined TIM-3 and Gal-9 expression and cytotoxicicty of peripheral lymphocytes of early-onset preeclamptic women and healthy pregnant woman using flow cytometry. Results Investigating peripheral lymphocytes of women with early-onset preeclampsia, our results showed a decreased TIM-3 expression by T cells, cytotoxic T cells, NK cells and CD56dim NK cells compared to healthy pregnant women. Interestingly, we found a notably increased frequency of Galectin-9 positive cells in each investigated lymphocyte population in the case of early-onset preeclamptic patients. We further demonstrated increased cytotoxic activity by cytotoxic T and CD56dim NK cells in women with early-onset preeclampsia. Our findings showed that the strongest cellular cytotoxic response of lymphocytes occurred in the TIM-3 positive subpopulations of different lymphocytes subsets in early-onset preeclampsia. Conclusion These data suggest that Gal-9/TIM-3 pathway could play an important role in the immune regulation during pregnancy and the altered

  18. Inflammatory and Repair Pathways Induced in Human Bronchoalveolar Lavage Cells with Ozone Inhalation

    PubMed Central

    Wong, Hofer; Tenney, Rachel; Chen, Chun; Stiner, Rachel; Balmes, John R.; Paquet, Agnès C.; Arjomandi, Mehrdad

    2015-01-01

    Background Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury. Methods To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay]. Results Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an α9β1 integrin-dependent manner. Conclusions Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury. PMID:26035830

  19. The stress polarity pathway: AMPK ‘GIV’-es protection against metabolic insults

    PubMed Central

    Ghosh, Pradipta

    2017-01-01

    Loss of cell polarity impairs organ development and function; it can also serve as one of the first triggers for oncogenesis. In 2006-2007 two groups simultaneously reported the existence of a special pathway for maintaining epithelial polarity in the face of environmental stressors. In this pathway, AMPK, a key sensor of metabolic stress stabilizes tight junctions, preserves cell polarity, and thereby, maintains epithelial barrier functions. Accumulating evidence since has shown that pharmacologic activation of AMPK by Metformin protects the epithelial barrier against multiple environmental and pathological stressful states and suppresses tumorigenesis. How AMPK protects the epithelium remained unknown until recently Aznar et al. identified GIV/Girdin as a novel effector of AMPK at the cell-cell junctions; phosphorylation of GIV at a single site by AMPK appears to be both necessary and sufficient for strengthening tight junctions and preserving cell polarity and epithelial barrier function in the face of energetic stress. Here we review the fundamentals of this specialized signaling pathway that buttresses cell-cell junctions against stress-induced collapse and discuss its pathophysiologic relevance in the context of a variety of diseases, including cancers, diabetes, aging, and the growing list of beneficial effects of the AMPK-activator, Metformin. PMID:28209925

  20. The Fanconi Anemia Pathway Protects Genome Integrity from R-loops.

    PubMed

    García-Rubio, María L; Pérez-Calero, Carmen; Barroso, Sonia I; Tumini, Emanuela; Herrera-Moyano, Emilia; Rosado, Iván V; Aguilera, Andrés

    2015-11-01

    Co-transcriptional RNA-DNA hybrids (R loops) cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA) pathway, we investigated the FA role in R loop-dependent genome instability. Using human and murine cells defective in FANCD2 or FANCA and primary bone marrow cells from FANCD2 deficient mice, we show that the FA pathway removes R loops, and that many DNA breaks accumulated in FA cells are R loop-dependent. Importantly, FANCD2 foci in untreated and MMC-treated cells are largely R loop dependent, suggesting that the FA functions at R loop-containing sites. We conclude that co-transcriptional R loops and R loop-mediated DNA damage greatly contribute to genome instability and that one major function of the FA pathway is to protect cells from R loops.

  1. Insulin-like Growth Factor 1 Signaling Axis Meets p53 Genome Protection Pathways

    PubMed Central

    Werner, Haim; Sarfstein, Rive; LeRoith, Derek; Bruchim, Ilan

    2016-01-01

    Clinical, epidemiological, and experimental evidence indicate that the insulin-like growth factors (IGFs) are important mediators in the biochemical chain of events that lead from a phenotypically normal to a neoplastic cell. The IGF1 receptor (IGF1R), which mediates the biological actions of IGF1 and IGF2, exhibits potent pro-survival and antiapoptotic activities. The IGF1R is highly expressed in most types of cancer and is regarded as a promising therapeutic target in oncology. p53 is a transcription factor with tumor suppressor activity that is usually activated in response to DNA damage and other forms of cellular stress. On the basis of its protective activities, p53 is commonly regarded as the guardian of the genome. We provide evidence that the IGF signaling axis and p53 genome protection pathways are tightly interconnected. Wild-type, but not mutant, p53 suppresses IGF1R gene transcription, leading to abrogation of the IGF signaling network, with ensuing cell cycle arrest. Gain-of-function, or loss-of-function, mutations of p53 in tumor cells may disrupt its inhibitory activity, thus generating oncogenic molecules capable of transactivating the IGF1R gene. The interplay between the IGF1 and p53 pathways is also of major relevance in terms of metabolic regulation, including glucose transport and glycolysis. A better understanding of the complex physical and functional interactions between these important signaling pathways will have major basic and translational relevance. PMID:27446805

  2. The Fanconi Anemia Pathway Protects Genome Integrity from R-loops

    PubMed Central

    García-Rubio, María L.; Pérez-Calero, Carmen; Barroso, Sonia I.; Tumini, Emanuela; Herrera-Moyano, Emilia; Rosado, Iván V.; Aguilera, Andrés

    2015-01-01

    Co-transcriptional RNA-DNA hybrids (R loops) cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA) pathway, we investigated the FA role in R loop-dependent genome instability. Using human and murine cells defective in FANCD2 or FANCA and primary bone marrow cells from FANCD2 deficient mice, we show that the FA pathway removes R loops, and that many DNA breaks accumulated in FA cells are R loop-dependent. Importantly, FANCD2 foci in untreated and MMC-treated cells are largely R loop dependent, suggesting that the FA functions at R loop-containing sites. We conclude that co-transcriptional R loops and R loop-mediated DNA damage greatly contribute to genome instability and that one major function of the FA pathway is to protect cells from R loops. PMID:26584049

  3. Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway.

    PubMed

    Dou, Wei; Zhang, Jingjing; Li, Hao; Kortagere, Sandhya; Sun, Katherine; Ding, Lili; Ren, Gaiyan; Wang, Zhengtao; Mani, Sridhar

    2014-09-01

    Isorhamnetin is an O-methylated flavonol present in fruit and vegetables. We recently reported the identification of isorhamnetin as an activator of the human pregnane X receptor (PXR), a known target for abrogating inflammation in inflammatory bowel disease (IBD). The current study investigated the role of isorhamnetin as a putative mouse PXR activator in ameliorating chemically induced IBD. Using two different models (ulcerative colitis like and Crohn's disease like) of experimental IBD in mice, we demonstrated that isorhamnetin abrogated inflammation through inhibiting the activity of myeloperoxidase, the levels of TNF-α and IL-6, the mRNA expression of proinflammatory mediators (iNOS, ICAM-1, COX2, TNF-α, IL-2 and IL-6) and the phosphorylation of IκBα and NF-κB p65. PXR gene overexpression inhibited NF-κB luciferase activity, and the inhibition was potentiated by isorhamnetin treatment. PXR knockdown by siRNA demonstrated the necessity for PXR in isorhamnetin-mediated up-regulation of xenobiotic metabolism genes. Ligand pocket-filling mutants (S247W/C284W and S247W/C284W/S208W) of human PXR weakened the effect of isorhamnetin on PXR activation. Molecular docking studies and time-resolved fluorescence resonance energy transfer competitive binding assays confirmed the ligand (isorhamnetin)-binding affinity. These results clearly demonstrated the ameliorating effect of isorhamnetin on experimental IBD via PXR-mediated up-regulation of xenobiotic metabolism and down-regulation of NF-κB signaling. The novel findings may contribute to the effective utilization of isorhamnetin or its derivatives as a PXR ligand in the treatment of human IBD.

  4. Role of pro-inflammatory cytokine IL-17 in Leishmania pathogenesis and in protective immunity by Leishmania vaccines.

    PubMed

    Banerjee, Antara; Bhattacharya, Parna; Joshi, Amritanshu B; Ismail, Nevien; Dey, Ranadhir; Nakhasi, Hira L

    2016-11-01

    The clinical outcome of Leishmania pathogenesis ranges from active skin lesions to fatal visceral dissemination and severely impaired T cell immunity. It is well established that a strong Th1 immune response is protective against cutaneous forms of the disease, however a mixed Th1/Th2 response is most commonly observed against visceral infections as evident from previous studies. Aside from Th1/Th2 cytokines, the pro-inflammatory IL-17 cytokine family plays an important role in the clearance of intracellular pathogens. In Leishmania induced skin lesions, IL-17 produced by Th17 cells is shown to exacerbate the disease, suggesting a role in pathogenesis. However, a protective role for IL-17 is indicated by the expansion of IL-17 producing cells in vaccine-induced immunity. In human visceral leishmaniasis (VL) it has been demonstrated that IL-17 and IL-22 are associated with protection against re-exposure to Leishmania, which further suggests the involvement of IL-17 in vaccine induced protective immunity. Although there is no vaccine against any form of leishmaniasis, the development of genetically modified live attenuated parasites as vaccine candidates prove to be promising, as they successfully induce a robust protective immune response in various animal models. However, the role of IL-17 producing cells and Th17 cells in response to these vaccine candidates remains unexplored. In this article, we review the role of IL-17 in Leishmania pathogenesis and the potential impact on vaccine induced immunity, with a special focus on live attenuated Leishmania parasites.

  5. An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury.

    PubMed

    Takyar, Seyedtaghi; Zhang, Yi; Haslip, Maria; Jin, Lei; Shan, Peiying; Zhang, Xuchen; Lee, Patty J

    2016-03-01

    TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium-specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway.

  6. TRAM1 protects AR42J cells from caerulein-induced acute pancreatitis through ER stress-apoptosis pathway.

    PubMed

    Cai, Yongxia; Shen, Yanbo; Xu, Guangling; Tao, Ran; Yuan, Weiyan; Huang, Zhongwei; Zhang, Dongmei

    2016-05-01

    Chronic endoplasmic reticulum (ER) stress in pancreatic acinar cells has emerged as a major contributor to the recovery of acute pancreatitis (AP). However, the molecular mechanisms linking AP and ER stress remain not fully understood. In this study, we employed caerulein to induce AP-like inflammation in the AR42J rat pancreatic acinar cells to mimic the AP-like acinar cell injury. Caerulein can activate ER stress in AR42J cells, but the molecular link between AP and ER stress remains to be identified. We here reported that translocating chain-associated membrane protein 1 (TRAM1), an ER-resident multispanning membrane protein, was involved in the onset of AP-like injury on AR42J cells. TRAM1 was significantly elevated in caerulein-treated AR42J cells. Furthermore, we showed that knockdown of TRAM1 led to hyperactivation of 78 kDa glucose-regulated protein precursor (GRP78) and C/EBP homologous protein (CHOP) and the activation of downstream apoptosis pathway. Given the fact that the activation of ER stress played a protection role in AP, the pro-inflammatory mediators TNF-α and IL-6 and the marker of cell injury LDH were also analyzed. We found that depletion of TRAM1 markedly increased the secretion of TNF-α, IL-6, and LDH in the cells. Moreover, flow cytometry indicated that treatment with caerulein induced a significant decrease of apoptotic index and increase of necrosis index in TRAM1-siRNA cells, compared with control groups, as indicated by downregulated expression of cleaved caspase-3, caspase-8, and caspase-9 mRNA expression activity in TRAM1-siRNA cells. These data implicated that TRAM1 might protect AR42J cells against caerulein-induced AP in AR42J cells through alleviating ER stress.

  7. Sinomenine protects mice against ischemia reperfusion induced renal injury by attenuating inflammatory response and tubular cell apoptosis

    PubMed Central

    Zhao, Zhiqing; Guan, Rui; Song, Shaohua; Zhang, Mingjian; Liu, Fang; Guo, Meng; Guo, Wenyuan; Yu, Qilin; Zhang, Luding; Wang, Quanxing

    2013-01-01

    Sinomenine (SIN) is a purified alkaloid from the Chinese herb Sinomenium acutum. Previous studies demonstrated that SIN possesses anti-inflammatory and anti-apoptotic properties. We thus in the present report conducted studies to examine its impact on ischemia reperfusion (IR) induced renal injury. Precondition of mice with 200 mg/kg of SIN provided significant protection for mice against IR-induced renal injury as manifested by the attenuated serum creatinine (Cre) and blood urea nitrogen (BUN) along with less severity for histological changes and tubular cell apoptosis. In line with these results, treatment of mice with SIN suppressed IR-induced inflammatory infiltration and the expression of chemokine CXCL-10, adhesion molecule ICAM-1, and cytokines TNF-а/IL-6. Mechanistic studies revealed that SIN inhibits NF-κB transcriptional activity to suppress IR-induced inflammatory response in the kidney, while it attenuates MAP kinase signaling to prevent tubular cells undergoing apoptosis after IR insult. Altogether, our data support that SIN could be a useful therapeutic agent for prevention and treatment of IR-induced renal injury in the clinical settings. PMID:24040435

  8. Sinomenine protects mice against ischemia reperfusion induced renal injury by attenuating inflammatory response and tubular cell apoptosis.

    PubMed

    Zhao, Zhiqing; Guan, Rui; Song, Shaohua; Zhang, Mingjian; Liu, Fang; Guo, Meng; Guo, Wenyuan; Yu, Qilin; Zhang, Luding; Wang, Quanxing

    2013-01-01

    Sinomenine (SIN) is a purified alkaloid from the Chinese herb Sinomenium acutum. Previous studies demonstrated that SIN possesses anti-inflammatory and anti-apoptotic properties. We thus in the present report conducted studies to examine its impact on ischemia reperfusion (IR) induced renal injury. Precondition of mice with 200 mg/kg of SIN provided significant protection for mice against IR-induced renal injury as manifested by the attenuated serum creatinine (Cre) and blood urea nitrogen (BUN) along with less severity for histological changes and tubular cell apoptosis. In line with these results, treatment of mice with SIN suppressed IR-induced inflammatory infiltration and the expression of chemokine CXCL-10, adhesion molecule ICAM-1, and cytokines TNF-а/IL-6. Mechanistic studies revealed that SIN inhibits NF-κB transcriptional activity to suppress IR-induced inflammatory response in the kidney, while it attenuates MAP kinase signaling to prevent tubular cells undergoing apoptosis after IR insult. Altogether, our data support that SIN could be a useful therapeutic agent for prevention and treatment of IR-induced renal injury in the clinical settings.

  9. Induction of protective therapy for autoimmune diseases by targeted DNA vaccines encoding pro-inflammatory cytokines and chemokines.

    PubMed

    Karin, Nathan

    2004-02-01

    T-cell-mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or type 1 diabetes result from an aggressive attack of self-components by autoimmune T-cells. Pro-inflammatory mediators, particularly cytokines and chemokines, direct the homing and effectorfunction of these cells. It has recently been demonstrated that the immune system, which can attack self-components, also generates 'beneficial' autoimmunity against pro-inflammatory mediators. During the course of an autoimmune condition, and to a much lesser extent in response to microbial inflammation, the immune system produces auto-antibodies to pro-inflammatory mediators. This reduces the harm from these diseases. We also discovered that targeted DNA vaccines could effectively amplify these responses to provide protective immunity. The underlying mechanism is partially understood. At the site of immunization, the relevant gene product is produced and then presented by dendritic cells/macrophages, which undergo activation due to an interaction of plasmid CpG with toll-like receptor 9 on the dendritic cell. This then activates CD4+ T-cells, which help the production of T-cell-dependent antibodies against the gene product of the vaccines. These antibodies neutralize their target product and suppress inflammation. This review explores this interesting concept and its therapeutic implications.

  10. Chronic Trigeminal Nerve Stimulation Protects Against Seizures, Cognitive Impairments, Hippocampal Apoptosis, and Inflammatory Responses in Epileptic Rats.

    PubMed

    Wang, Qian-Qian; Zhu, Li-Jun; Wang, Xian-Hong; Zuo, Jian; He, Hui-Yan; Tian, Miao-Miao; Wang, Lei; Liang, Gui-Ling; Wang, Yu

    2016-05-01

    Trigeminal nerve stimulation (TNS) has recently been demonstrated effective in the treatment of epilepsy and mood disorders. Here, we aim to determine the effects of TNS on epileptogenesis, cognitive function, and the associated hippocampal apoptosis and inflammatory responses. Rats were injected with pilocarpine to produce status epilepticus (SE) and the following chronic epilepsy. After SE induction, TNS treatment was conducted for 4 consecutive weeks. A pilocarpine re-injection was then used to induce a seizure in the epileptic rats. The hippocampal neuronal apoptosis induced by seizure was assessed by TUNEL staining and inflammatory responses by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). The spontaneous recurrent seizure (SRS) number was counted through video monitoring, and the cognitive function assessed through Morris Water Maze (MWM) test. TNS treatment attenuated the SRS attacks and improved the cognitive impairment in epileptic rats. A pilocarpine re-injection resulted in less hippocampal neuronal apoptosis and reduced level of interleukin-1 beta (IL-1β), tumor necrosis factor-α (TNF-α), and microglial activation in epileptic rats with TNS treatment in comparison to the epileptic rats without TNS treatment. It is concluded that TNS treatment shortly after SE not only protected against the chronic spontaneous seizures but also improved cognitive impairments. These antiepileptic properties of TNS may be related to its attenuating effects on hippocampal apoptosis and pro-inflammatory responses.

  11. The Protective Effect of Bee Venom on Fibrosis Causing Inflammatory Diseases

    PubMed Central

    Lee, Woo-Ram; Pak, Sok Cheon; Park, Kwan-Kyu

    2015-01-01

    Bee venom therapy is a treatment modality that may be thousands of years old and involves the application of live bee stings to the patient’s skin or, in more recent years, the injection of bee venom into the skin with a hypodermic needle. Studies have proven the effectiveness of bee venom in treating pathological conditions such as arthritis, pain and cancerous tumors. However, there has not been sufficient review to fully elucidate the cellular mechanisms of the anti-inflammatory effects of bee venom and its components. In this respect, the present study reviews current understanding of the mechanisms of the anti-inflammatory properties of bee venom and its components in the treatment of liver fibrosis, atherosclerosis and skin disease. PMID:26580653

  12. Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway

    PubMed Central

    Latremoliere, Alban; Latini, Alexandra; Andrews, Nick; Cronin, Shane J.; Fujita, Masahide; Gorska, Katarzyna; Hovius, Ruud; Romero, Carla; Chuaiphichai, Surawee; Painter, Michio; Miracca, Giulia; Babaniyi, Olusegun; Remor, Aline Pertile; Duong, Kelly; Riva, Priscilla; Barrett, Lee B.; Ferreirós, Nerea; Naylor, Alasdair; Penninger, Josef M.; Tegeder, Irmgard; Zhong, Jian; Blagg, Julian; Channon, Keith M.; Johnsson, Kai; Costigan, Michael; Woolf, Clifford J.

    2015-01-01

    SUMMARY Human genetic studies have revealed an association between GTP cyclohydrolase 1 polymorphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients. We now show that excessive BH4 is produced in mice by both axotomized sensory neurons and macrophages infiltrating damaged nerves and inflamed tissue. Constitutive BH4 overproduction in sensory neurons increases pain sensitivity, whereas blocking BH4 production only in these cells reduces nerve injury-induced hypersensitivity without affecting nociceptive pain. To minimize risk of side effects, we targeted sepiapterin reductase (SPR), whose blockade allows minimal BH4 production through the BH4 salvage pathways. Using a structure-based design, we developed a potent SPR inhibitor and show that it reduces pain hypersensitivity effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neurons and macrophages, with no development of tolerance or adverse effects. Finally, we demonstrate that sepiapterin accumulation is a sensitive biomarker for SPR inhibition in vivo. PMID:26087165

  13. Blueberry Component Pterostilbene Protects Corneal Epithelial Cells from Inflammation via Anti-oxidative Pathway

    PubMed Central

    Li, Jin; Ruzhi Deng; Hua, Xia; Zhang, Lili; Lu, Fan; Coursey, Terry G.; Pflugfelder, Stephen C.; Li, De-Quan

    2016-01-01

    Blueberries have been recognized to possess protective properties from inflammation and various diseases, but not for eye and ocular disorders. This study explores potential benefits of pterostilbene (PS), a natural component of blueberries, in preventing ocular surface inflammation using an in vitro culture model of human corneal epithelial cells (HCECs) exposed to hyperosmotic medium at 450 mOsM. Gene expression was detected by RT-qPCR, and protein production or activity was determined by ELISA, zymography, Western blotting and immunofluorescent staining. Reactive oxygen species (ROS) production was measured using DCFDA kit. The addition of PS significantly reduced the expression of pro-inflammatory mediators, TNF-α, IL-1 β, IL-6, MMP-2 and MMP-9 in HCECs exposed to hyperosmotic medium. Pre-treatment with PS (5 to 20 μM) suppressed ROS overproduction in a dose-dependent manner. Additionally, PS significantly decreased the levels of oxidative damage biomarkers, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), aconitase-2 and 8-hydroxydeoxyguanosine (8-OHdG). Importantly, PS was found to rebalance homeostasis between oxygenases and anti-oxidative enzymes by decreasing cyclooxygenase 2 (COX2) expression and restoring the activity of antioxidant enzymes, superoxide dismutase 1 (SOD1) and peroxiredoxin-4 (PRDX4) during hyperosmotic stress. Our findings demonstrate that PS protects human cornea from hyperosmolarity-induced inflammation and oxidative stress, suggesting protective effects of PS on dry eye. PMID:26762881

  14. The role of infection in inflammatory bowel disease: initiation, exacerbation and protection.

    PubMed

    Lidar, Merav; Langevitz, Pnina; Shoenfeld, Yehuda

    2009-09-01

    Inflammatory bowel disease, a collective term for ulcerative colitis and Crohn's disease, is a chronic, immune-mediated disease of the gastrointestinal tract that develops in genetically susceptible individuals. The role of infection in the development of inflammatory bowel disease is underscored by various clinical observations, such as the delayed age of onset, suggesting that childhood exposure to pathogens is essential, and the clinical improvement that follows decreasing bacterial intestinal load. Over the years, many a pathogen has been linked to the development and exacerbation of inflammatory bowel disease, notably; Mycobacterium paratuberculosis, Escherichia coli, Listeria monocytogenes and Chlamydia as well as viruses such as measles, mumps, rubella, Epstein-Barr virus and cytomegalovirus. Presently, leading theories of disease pathogenesis suggest loss of immune tolerance to normal commensal bacteria coupled with excessive exposure to bacterial antigenic products. This review describes the most commonly implicated pathogens in the causation of IBD and presents the evidence supporting their pathogenic role as well as data that offset their importance.

  15. Gastrodin protects against chronic inflammatory pain by inhibiting spinal synaptic potentiation

    PubMed Central

    Xiao, Mei-Mei; Zhang, Yu-Qi; Wang, Wen-Ting; Han, Wen-Juan; Lin, Zhen; Xie, Rou-Gang; Cao, Zhi; Lu, Na; Hu, San-Jue; Wu, Sheng-Xi; Dong, Hui; Luo, Ceng

    2016-01-01

    Tissue injury is known to produce inflammation and pain. Synaptic potentiation between peripheral nociceptors and spinal lamina I neurons has been proposed to serve as a trigger for chronic inflammatory pain. Gastrodin is a main bioactive constituent of the traditional Chinese herbal medicine Gastrodia elata Blume, which has been widely used as an analgesic since ancient times. However, its underlying cellular mechanisms have remained elusive. The present study demonstrated for the first time that gastrodin exhibits an analgesic effect at the spinal level on spontaneous pain, mechanical and thermal pain hypersensitivity induced by peripheral inflammation, which is not dependent on opioid receptors and without tolerance. This analgesia by gastrodin is at least in part mediated by depressing spinal synaptic potentiation via blockade of acid-sensing ion channels. Further studies with miniature EPSCs and paired-pulse ratio analysis revealed the presynaptic origin of the action of gastrodin, which involves a decrease in transmitter release probability. In contrast, neither basal nociception nor basal synaptic transmission was altered. This study revealed a dramatic analgesic action of gastrodin on inflammatory pain and uncovered a novel spinal mechanism that could underlie the analgesia by gastrodin, pointing the way to a new analgesic for treating chronic inflammatory pain. PMID:27853254

  16. SIRT1 protects osteoblasts against particle-induced inflammatory responses and apoptosis in aseptic prosthesis loosening.

    PubMed

    Deng, Zhantao; Wang, Zhenheng; Jin, Jiewen; Wang, Yong; Bao, Nirong; Gao, Qian; Zhao, Jianning

    2017-02-01

    We hypothesized that SIRT1 downregulation in osteoblasts induced by wear particles was one of the reasons for particle-induced osteolysis (PIO) in total joint arthroplasty failure. In the present study, the expression of SIRT1 was examined in osteoblasts treated with TiAl6V4 particles (TiPs) and CoCrMo particles (CoPs) from materials used in prosthetics and specimens from PIO animal models. To address whether SIRT1 downregulation triggers inflammatory responses and apoptosis in osteoblasts, the effect of a SIRT1 activator, resveratrol on the expression of inflammatory cytokines and apoptosis in particle-treated osteoblasts was tested. The results demonstrated that SIRT1 expression was significantly downregulated in particle-treated osteoblasts and PIO animal models. Both pharmacological activation and overexpression of SIRT1 dramatically reduced the particle-induced expression of inflammatory cytokines and osteoblast apoptosis through NF-κB and p53 signaling, respectively. Furthermore, in PIO animal models, resveratrol significantly reduced the severity of osteolysis. Collectively, the results of the present study indicated that SIRT1 plays a vital role in the pathogenesis of aseptic loosening, and further treatment targeted at SIRT1 possibly lead to novel approaches for prevention of aseptic prosthesis loosening.

  17. Attenuation of the macrophage inflammatory activity by TiO₂ nanotubes via inhibition of MAPK and NF-κB pathways.

    PubMed

    Neacsu, Patricia; Mazare, Anca; Schmuki, Patrik; Cimpean, Anisoara

    2015-01-01

    Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro-inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO2) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO2 nanotubes on the activation of MAPK and NF-κB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH2-terminal kinase (JNK), IKKβ, and IkB-α. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-κB pathways providing a potential mechanism for their anti-inflammatory activity.

  18. Attenuation of the macrophage inflammatory activity by TiO2 nanotubes via inhibition of MAPK and NF-κB pathways

    PubMed Central

    Neacsu, Patricia; Mazare, Anca; Schmuki, Patrik; Cimpean, Anisoara

    2015-01-01

    Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro-inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO2) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO2 nanotubes on the activation of MAPK and NF-κB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH2-terminal kinase (JNK), IKKβ, and IkB-α. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-κB pathways providing a potential mechanism for their anti-inflammatory activity. PMID:26491301

  19. Peroxisome proliferator-activated receptor-γ agonist inhibits the mammalian target of rapamycin signaling pathway and has a protective effect in a rat model of status epilepticus

    PubMed Central

    SAN, YONG-ZHI; LIU, YU; ZHANG, YU; SHI, PING-PING; ZHU, YU-LAN

    2015-01-01

    Peroxisome proliferator-activated receptor γ (PPAR-γ) has a protective role in several neurological diseases. The present study investigated the effect of the PPAR-γ agonist, pioglitazone, on the mammalian target of rapamycin (mTOR) signaling pathway in a rat model of pentylenetetrazol (PTZ)-induced status epilepticus (SE). The investigation proceeded in two stages. First, the course of activation of the mTOR signaling pathway in PTZ-induced SE was examined to determine the time-point of peak activity, as reflected by phopshorylated (p)-mTOR/mTOR and p-S6/S6 ratios. Subsequently, pioglitazone was administrated intragastrically to investigate its effect on the mTOR signaling pathway, through western blot and immunochemical analyses. The levels of the interleukin (IL)-1β and IL-6 inflammatory cytokines were detected using ELISA, and neuronal loss was observed via Nissl staining. In the first stage of experimentation, the mTOR signaling pathway was activated, and the p-mTOR/mTOR and p-S6/S6 ratios peaked on the third day. Compared with the vehicle treated-SE group, pretreatment with pioglitazone was associated with the loss of fewer neurons, lower levels of IL-1β and IL-6, and inhibition of the activation of the mTOR signaling pathway. Therefore, the mTOR signaling pathway was activated in the PTZ-induced SE rat model, and the PPAR-γ agonist, pioglitazone, had a neuroprotective effect, by inhibiting activation of the mTOR pathway and preventing the increase in the levels of IL-1β and IL-6. PMID:25891824

  20. The influence of macrophage inflammatory protein-1α on protective immunity mediated by antiviral cytotoxic T cells

    PubMed Central

    Jones, Emma; Price, David A; Dahm-Vicker, Michaela; Cerundolo, Vincenzo; Klenerman, Paul; Gallimore, Awen

    2003-01-01

    Macrophage inflammatory protein 1α (MIP-1α), a member of the CC-chemokine subfamily, is known to induce chemotaxis of a variety of cell types in vivo. Although the role of MIP-1α in inflammatory responses generated following primary infection of mice with many different pathogens has been characterized, the influence of this chemokine on the generation of antigen-specific T-cell responses in vivo is less well understood. This is important, as virus-specific CD8+ T lymphocytes (CTL) play a crucial role in defence against viral infections, both acutely and in the long term. In this study, we compared the ability of wild-type and MIP-1α-deficient (MIP-1α−/−) mice to mount CTL responses specific for the immunodominant epitope derived from influenza nucleoprotein (NP366–374). Influenza-specific CTL responses were compared with respect to frequency, cytotoxic activity and ability to clear subsequent infections with recombinant vaccinia viruses expressing the influenza NP. The results indicate that antiviral CTL generated in MIP-1α−/− mice are slightly impaired in their ability to protect against a subsequent infection. However, impaired in vivo CTL-mediated antiviral protection was found to be associated with reduced cytotoxicity rather than with a failure of the CTL to migrate to peripheral sites of infection. PMID:12709019

  1. Protective effects of Lingguizhugan decoction on amyloid-beta peptide (25-35)-induced cell injury: Anti-inflammatory effects☆

    PubMed Central

    Xi, Feifei; Sang, Feng; Zhou, Chunxiang; Ling, Yun

    2012-01-01

    In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloid-β peptide (25–35), as a model of Alzheimer’s disease, to evaluate the protective effects of 10-3–10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH-SY5Y cells with amyloid-β peptide-induced injury, and lowered levels of interleukin-1β, interleukin-6, tumor necrosis factor-α and nitric oxide in the culture supernatant of activated BV-2 microglia. The effects of 10-3 g/mL Lingguizhugan decoction were more significant. These results suggest that Lingguizhugan decoction can protect SH-SY5Y cells against amyloid-β peptide (25–35)-induced injury in a dose-dependent manner by inhibiting overexpression of inflammatory factors by activated microglia. PMID:25317138

  2. Transcriptional Profiling of the Bladder in Urogenital Schistosomiasis Reveals Pathways of Inflammatory Fibrosis and Urothelial Compromise

    PubMed Central

    Ray, Debalina; Nelson, Tyrrell A.; Fu, Chi-Ling; Patel, Shailja; Gong, Diana N.; Odegaard, Justin I.; Hsieh, Michael H.

    2012-01-01

    Urogenital schistosomiasis, chronic infection by Schistosoma haematobium, affects 112 million people worldwide. S. haematobium worm oviposition in the bladder wall leads to granulomatous inflammation, fibrosis, and egg expulsion into the urine. Despite the global impact of urogenital schistosomiasis, basic understanding of the associated pathologic mechanisms has been incomplete due to the lack of suitable animal models. We leveraged our recently developed mouse model of urogenital schistosomiasis to perform the first-ever profiling of the early molecular events that occur in the bladder in response to the introduction of S. haematobium eggs. Microarray analysis of bladders revealed rapid, differential transcription of large numbers of genes, peaking three weeks post-egg administration. Many differentially transcribed genes were related to the canonical Type 2 anti-schistosomal immune response, as reflected by the development of egg-based bladder granulomata. Numerous collagen and metalloproteinase genes were differentially transcribed over time, revealing complex remodeling and fibrosis of the bladder that was confirmed by Masson's Trichrome staining. Multiple genes implicated in carcinogenesis pathways, including vascular endothelial growth factor-, oncogene-, and mammary tumor-related genes, were differentially transcribed in egg-injected bladders. Surprisingly, junctional adhesion molecule, claudin and uroplakin genes, key components for maintaining the urothelial barrier, were globally suppressed after bladder exposure to eggs. This occurred in the setting of urothelial hyperplasia and egg shedding in urine. Thus, S. haematobium egg expulsion is associated with intricate modulation of the urothelial barrier on the cellular and molecular level. Taken together, our findings have important implications for understanding host-parasite interactions and carcinogenesis in urogenital schistosomiasis, and may provide clues for novel therapeutic strategies. PMID

  3. Controlling herpetic stromal keratitis by modulating lymphotoxin-alpha-mediated inflammatory pathways.

    PubMed

    Veiga-Parga, Tamara; Giménez, Fernanda; Mulik, Sachin; Chiang, Eugene Y; Grogan, Jane L; Rouse, Barry T

    2013-01-01

    Herpes simplex virus 1 infection of the eye can result in stromal keratitis, a chronic immunoinflammatory lesion that is a significant cause of human blindness. A key to controlling the severity of lesions is to identify cellular and molecular events responsible for tissue damage. This report evaluates the role of lymphotoxin-α, a proinflammatory cytokine that could be involved during stromal keratitis. We demonstrate that after infection, both lymphotoxin-α and lymphotoxin-β transcripts are detectable at high levels 48 h postinfection, suggesting roles for the secreted homotrimer lymphotoxin-α3 and the membrane-bound lymphotoxin-α1β2 heterotrimer in stromal keratitis. Using a corneal stromal fibroblast cell line, lymphotoxin-α3 and lymphotoxin-α1β2 were found to have proinflammatory roles by stimulating production of chemokines. Treatment of mice with a depleting anti-lymphotoxin-α mAb during the clinical phase of the disease significantly attenuated stromal keratitis lesions. In treated mice, expression of proinflammatory molecules and chemokines was reduced, as were numbers of cornea-infiltrating proinflammatory cells, particularly Th1 cells. The protective effect of anti-lymphotoxin-α mAb was highly reduced with a mutant version of the mAb that lacks Fc receptor binding activity, indicating that depletion of lymphotoxin-expressing cells was mainly responsible for efficacy, with LT-α3 contributing minimally to inflammation. These data demonstrate that lymphotoxin-expressing cells, such as Th1 cells, mediate stromal keratitis.

  4. Interleukin 10 regulates inflammatory cytokine synthesis to protect against lipopolysaccharide-induced abortion and fetal growth restriction in mice.

    PubMed

    Robertson, Sarah A; Care, Alison S; Skinner, Rebecca J

    2007-05-01

    Interleukin 10 (IL10) is a potent immune-regulating cytokine and inhibitor of inflammatory cytokine synthesis. To evaluate the anti-inflammatory role of IL10 in pregnancy, the response of genetically IL10-deficient mice to low-dose lipopolysaccharide (LPS)-induced abortion was examined. When IL10-null mutant C57Bl/6 (Il10(-/-)) and control (Il10(+/+)) mice were administered low-dose LPS on Day 9.5 of gestation, IL10 deficiency predisposed to fetal loss accompanied by growth restriction in remaining viable fetuses, with an approximately 10-fold reduction in the threshold dose for 100% abortion. After LPS administration, inflammatory cytokines tumor necrosis factor-alpha (TNFA) and IL6 were markedly increased in serum, uterine, and conceptus tissues in Il10(-/-) mice compared with Il10(+/+) mice, with elevated local synthesis of Tnfa and Il6 mRNAs in the gestational tissues. IL1A and IL12p40 were similarly elevated in serum and gestational tissues, whereas interferon gamma (IFNG) and soluble TNFRII content were unchanged in the absence of IL10. Recombinant IL10 rescued the increased susceptibility to LPS-induced fetal loss in Il10(-/-) mice but did not improve outcomes in Il10(+/+) mice. IL10 genotype also influenced the responsiveness of mice to a TNFA antagonist, etanercept. Fetal loss in Il10(-/-) mice was partly alleviated by moderate or high doses of etanercept, whereas Il10(+/+) mice were refractory to high-dose etanercept, consistent with attenuation by IL10 status of TNFA bioavailability after etanercept treatment. These data show that IL10 modulates resistance to inflammatory stimuli by downregulating expression of proinflammatory cytokines TNFA, IL6, IL1A, and IL12, acting to protect against inflammation-induced pathology in the implantation site.

  5. Protective role of tumor necrosis factor (TNF) receptors in chronic intestinal inflammation: TNFR1 ablation boosts systemic inflammatory response.

    PubMed

    Wang, Yi; Han, Gencheng; Chen, Yu; Wang, Ke; Liu, Guijun; Wang, Renxi; Xiao, He; Li, Xinying; Hou, Chunmei; Shen, Beifen; Guo, Renfeng; Li, Yan; Chen, Guojiang

    2013-09-01

    Tumor necrosis factor-α (TNF-α) acts as a key factor for the development of inflammatory bowel diseases (IBDs), whose function is known to be mediated by TNF receptor 1 (TNFR1) or TNFR2. However, the precise role of the two receptors in IBD remains poorly understood. Herein, chronic colitis was established by oral administration of dextran sulfate sodium (DSS) in TNFR1 or TNFR2-/- mice. Unexpectedly, TNFR1 or TNFR2 deficiency led to exacerbation of signs of colitis compared with wild-type (WT) counterparts. Of note, TNFR1 ablation rendered significantly increased mortality compared with TNFR2 and WT mice after DSS. Aggravated pathology of colitis in TNFR1-/- or TNFR2-/- mice correlated with elevated colonic expression of proinflammatory cytokines and chemokines. Importantly, ablation of TNFR1 or TNFR2 increased apoptosis of colonic epithelial cells, which might be due to the heightened ratio of Bax/Bcl-2 and increased expression of caspase-8. Intriguingly, despite comparable intensity of intestinal inflammation in TNFR-deficient mice after DSS, systemic inflammatory response (including splenomegaly and myeloid expansion) was augmented dramatically in TNFR1-/- mice, instead of TNFR2-/- mice. Granulocyte-macrophage colony-stimulating factor (GMCSF) was identified as a key mediator in this process, as neutralization of GMCSF dampened peripheral inflammatory reaction and reduced mortality in TNFR1-/- mice. These data suggest that signaling via TNFR1 or TNFR2 has a protective role in chronic intestinal inflammation, and that lacking TNFR1 augments systemic inflammatory response in GMCSF-dependent manner.

  6. Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway

    PubMed Central

    Zu, Guo; Guo, Jing; Che, Ningwei; Zhou, Tingting; Zhang, Xiangwen

    2016-01-01

    Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients in Panax ginseng, and it attenuates inflammation and apoptosis. The aims of our study were to explore the potential of Rg1 for the treatment of intestinal I/R injury and to determine whether the protective effects of Rg1 were exerted through the Wnt/β-catenin signaling pathway. In this study, Rg1 treatment ameliorated inflammatory factors, ROS and apoptosis that were induced by intestinal I/R injury. Cell viability was increased and cell apoptosis was decreased with Rg1 pretreatment following hypoxia/reoxygenation (H/R) in the in vitro study. Rg1 activated the Wnt/β-catenin signaling pathway in both the in vivo and in vitro models, and in the in vitro study, the activation was blocked by DKK1. Our study provides evidence that pretreatment with Rg1 significantly reduces ROS and apoptosis induced by intestinal I/R injury via activation of the Wnt/β-catenin pathway. Taken together, our results suggest that Rg1 could exert its therapeutic effects on intestinal I/R injury through the Wnt/β-catenin signaling pathway and provide a novel treatment modality for intestinal I/R injury. PMID:27910952

  7. t-BHQ Provides Protection against Lead Neurotoxicity via Nrf2/HO-1 Pathway

    PubMed Central

    Ye, Fang; Li, Xiaoyi; Li, Lili; Yuan, Jing; Chen, Jun

    2016-01-01

    The neurotoxicity of lead has been well established, and oxidative stress is strongly associated with lead-induced neurotoxicity. Nrf2 is important for protection against oxidative stress in many disease models. We applied t-BHQ, which is an Nrf2 activator, to investigate the possible role of Nrf2 in the protection against lead neurotoxicity. t-BHQ significantly attenuated the oxidative stress in developmental rats by decreasing MDA level, as well as by increasing SOD activity and GSH content, in the hippocampus and frontal cortex. Furthermore, neuronal apoptosis was detected by Nissl staining, and Bax expression was inhibited in the t-BHQ-treated group. Results showed that t-BHQ suppressed ROS production and caspase 3/7 activity but increased intracellular GSH content, in SH-SY5Y cells under lead exposure. Moreover, in vivo and in vitro, t-BHQ enhanced the nuclear translocation of Nrf2 and binding to ARE areas but did not induce Nrf2 transcription. These phenomena were confirmed using RT-PCR, EMSA, Western blot, and immunofluorescence analyses. Subsequent upregulation of the expression of HO-1, NQO1, and GCLC was observed. However, knockdown of Nrf2 or HO-1 adversely affected the protective effects of t-BHQ against lead toxicity in SH-SY5Y cells. Thus, t-BHQ can protect against lead neurotoxicity, depending on the Nrf2/HO-1 pathway. PMID:26798413

  8. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury

    SciTech Connect

    Milatovic, Dejan; Gupta, Ramesh C.; Yu, Yingchun; Zaja-Milatovic, Snjezana; Aschner, Michael

    2011-11-15

    Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson's disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully understood. However, several studies suggest that oxidative damage and inflammatory processes play prominent roles in the degeneration of dopamine-containing neurons. In the present study, we assessed the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates and associated neuronal dysfunctions both in vitro and in vivo. Results from our in vitro study showed a significant (p < 0.01) increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes (F{sub 2}-IsoPs), as well as the depletion of ATP in primary rat cortical neurons following exposure to Mn (500 {mu}M) for 2 h. These effects were protected when neurons were pretreated for 30 min with 100 of an antioxidant, the hydrophilic vitamin E analog, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), or an anti-inflammatory agent, indomethacin. Results from our in vivo study confirmed a significant increase in F{sub 2}-IsoPs levels in conjunction with the progressive spine degeneration and dendritic damage of the striatal medium spiny neurons (MSNs) of mice exposed to Mn (100 mg/kg, s.c.) 24 h. Additionally, pretreatment with vitamin E (100 mg/kg, i.p.) or ibuprofen (140 {mu}g/ml in the drinking water for two weeks) attenuated the Mn-induced increase in cerebral F{sub 2}-IsoPs? and protected the MSNs from dendritic atrophy and dendritic spine loss. Our findings suggest that the mediation of oxidative stress/mitochondrial dysfunction and the control of alterations in biomarkers of oxidative injury, neuroinflammation and synaptodendritic degeneration may provide an effective, multi-pronged therapeutic strategy for protecting dysfunctional dopaminergic

  9. Downhill Running-Based Overtraining Protocol Improves Hepatic Insulin Signaling Pathway without Concomitant Decrease of Inflammatory Proteins.

    PubMed

    da Rocha, Alisson L; Pereira, Bruno C; Pauli, José R; Cintra, Dennys E; de Souza, Claudio T; Ropelle, Eduardo R; da Silva, Adelino S R

    2015-01-01

    The purpose of this study was to verify the effects of overtraining (OT) on insulin, inflammatory and gluconeogenesis signaling pathways in the livers of mice. Rodents were divided into control (CT), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR). Rotarod, incremental load, exhaustive and grip force tests were used to evaluate performance. Thirty-six hours after a grip force test, the livers were extracted for subsequent protein analyses. The phosphorylation of insulin receptor beta (pIRbeta), glycogen synthase kinase 3 beta (pGSK3beta) and forkhead box O1 (pFoxo1) increased in OTR/down versus CT. pGSK3beta was higher in OTR/up versus CT, and pFoxo1 was higher in OTR/up and OTR versus CT. Phosphorylation of protein kinase B (pAkt) and insulin receptor substrate 1 (pIRS-1) were higher in OTR/up versus CT and OTR/down. The phosphorylation of IκB kinase alpha and beta (pIKKalpha/beta) was higher in all OT protocols versus CT, and the phosphorylation of stress-activated protein kinases/Jun amino-terminal kinases (pSAPK-JNK) was higher in OTR/down versus CT. Protein levels of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) and hepatocyte nuclear factor 4alpha (HNF-4alpha) were higher in OTR versus CT. In summary, OTR/down improved the major proteins of insulin signaling pathway but up-regulated TRB3, an Akt inhibitor, and its association with Akt.

  10. Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis.

    PubMed

    Pillon, Nicolas J; Azizi, Paymon M; Li, Yujin E; Liu, Jun; Wang, Changsen; Chan, Kenny L; Hopperton, Kathryn E; Bazinet, Richard P; Heit, Bryan; Bilan, Philip J; Lee, Warren L; Klip, Amira

    2015-07-01

    Obesity is associated with inflammation and immune cell recruitment to adipose tissue, muscle and intima of atherosclerotic blood vessels. Obesity and hyperlipidemia are also associated with tissue insulin resistance and can compromise insulin delivery to muscle. The muscle/fat microvascular endothelium mediates insulin delivery and facilitates monocyte transmigration, yet its contribution to the consequences of hyperlipidemia is poorly understood. Using primary endothelial cells from human adipose tissue microvasculature (HAMEC), we investigated the effects of physiological levels of fatty acids on endothelial inflammation and function. Expression of cytokines and adhesion molecules was measured by RT-qPCR. Signaling pathways were evaluated by pharmacological manipulation and immunoblotting. Surface expression of adhesion molecules was determined by immunohistochemistry. THP1 monocyte interaction with HAMEC was measured by cell adhesion and migration across transwells. Insulin transcytosis was measured by total internal reflection fluorescence microscopy. Palmitate, but not palmitoleate, elevated the expression of IL-6, IL-8, TLR2 (Toll-like receptor 2), and intercellular adhesion molecule 1 (ICAM-1). HAMEC had markedly low fatty acid uptake and oxidation, and CD36 inhibition did not reverse the palmitate-induced expression of adhesion molecules, suggesting that inflammation did not arise from palmitate uptake/metabolism. Instead, inhibition of TLR4 to NF-κB signaling blunted palmitate-induced ICAM-1 expression. Importantly, palmitate-induced surface expression of ICAM-1 promoted monocyte binding and transmigration. Conversely, palmitate reduced insulin transcytosis, an effect reversed by TLR4 inhibition. In summary, palmitate activates inflammatory pathways in primary microvascular endothelial cells, impairing insulin transport and increasing monocyte transmigration. This behavior may contribute in vivo to reduced tissue insulin action and enhanced tissue

  11. Grapefruit-Derived Nanovectors Use an Activated Leukocyte Trafficking Pathway to Deliver Therapeutic Agents to Inflammatory Tumor Sites.

    PubMed

    Wang, Qilong; Ren, Yi; Mu, Jingyao; Egilmez, Nejat K; Zhuang, Xiaoyin; Deng, Zhongbin; Zhang, Lifeng; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2015-06-15

    Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory-driven disease mouse models, we show that grapefruit-derived nanovectors (GNV) coated with inflammatory-related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of dextran sulfate sodium-induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that chemokines are overexpressed in diseased human tissue provides the rationale for using IGNVs to more directly deliver therapeutic agents to inflammatory tumor sites and the rationale for the use of IGNVs as treatment for certain cancers in personalized medicine.

  12. Grapefruit-derived nanovectors use an activated leukocyte trafficking pathway to deliver therapeutic agents to inflammatory tumor sites

    PubMed Central

    Wang, Qilong; Ren, Yi; Mu, Jingyao; Egilmez, Nejat; Zhuang, Xiaoyin; Deng, Zhongbin; Zhang, Lifeng; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2015-01-01

    Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory driven disease mouse models, we show that grapefruit-derived nanovectors (GNVs) coated with inflammatory related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of DSS induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that there is an overexpression of chemokines in diseased human tissue provides the rationale for using IGNVs to more directed delivery of therapeutic agents to inflammatory tumor sites and the use of IGNVs as personalized medicine for treatment of certain cancers. PMID:25883092

  13. Sulforaphane protects against acrolein-induced oxidative stress and inflammatory responses: modulation of Nrf-2 and COX-2 expression

    PubMed Central

    Deng, Yu-Hui; Cui, Fa-Cai

    2016-01-01

    Introduction Acrolein (2-propenal) is a reactive α, β-unsaturated aldehyde which causes a health hazard to humans. The present study focused on determining the protection offered by sulforaphane against acrolein-induced damage in peripheral blood mononuclear cells (PBMC). Material and methods Acrolein-induced oxidative stress was determined through evaluating the levels of reactive oxygen species, protein carbonyl and sulfhydryl content, thiobarbituric acid reactive species, total oxidant status and antioxidant status (total antioxidant capacity, glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activity). Also, Nrf-2 expression levels were determined using western blot analysis. Acrolein-induced inflammation was determined through analyzing expression of cyclooxygenase-2 by western blot and PGE2 levels by ELISA. The protection offered by sulforaphane against acrolein-induced oxidative stress and inflammation was studied. Results Acrolein showed a significant (p < 0.001) increase in the levels of oxidative stress parameters and down-regulated Nrf-2 expression. Acrolein-induced inflammation was observed through upregulation (p < 0.001) of COX-2 and PGE2 levels. Pretreatment with sulforaphane enhanced the antioxidant status through upregulating Nrf-2 expression (p < 0.001) in PBMC. Acrolein-induced inflammation was significantly inhibited through suppression of COX-2 (p < 0.001) and PGE2 levels (p < 0.001). Conclusions The present study provides clear evidence that pre-treatment with sulforaphane completely restored the antioxidant status and prevented inflammatory responses mediated by acrolein. Thus the protection offered by sulforaphane against acrolein-induced damage in PBMC is attributed to its anti-oxidant and anti-inflammatory potential. PMID:27478470

  14. Pathways from marine protected area design and management to ecological success.

    PubMed

    Rudd, Murray A

    2015-01-01

    Using an international dataset compiled from 121 sites in 87 marine protected areas (MPAs) globally (Edgar et al., 2014), I assessed how various configurations of design and management conditions affected MPA ecological performance, measured in terms of fish species richness and biomass. The set-theoretic approach used Boolean algebra to identify pathways that combined up to five 'NEOLI' ( No-take, Enforced, Old, Large, Isolated) conditions and that were sufficient for achieving positive, and negative, ecological outcomes. Ecological isolation was overwhelming the most important condition affecting ecological outcomes but Old and Large were also conditions important for achieving high levels of biomass among large fishes (jacks, groupers, sharks). Solution coverage was uniformly low (<0.35) for all models of positive ecological performance suggesting the presence of numerous other conditions and pathways to ecological success that did not involve the NEOLI conditions. Solution coverage was higher (>0.50) for negative results (i.e., the absence of high biomass) among the large commercially-exploited fishes, implying asymmetries in how MPAs may rebuild populations on the one hand and, on the other, protect against further decline. The results revealed complex interactions involving MPA design, implementation, and management conditions that affect MPA ecological performance. In general terms, the presence of no-take regulations and effective enforcement were insufficient to ensure MPA effectiveness on their own. Given the central role of ecological isolation in securing ecological benefits from MPAs, site selection in the design phase appears critical for success.

  15. Pathways from marine protected area design and management to ecological success

    PubMed Central

    2015-01-01

    Using an international dataset compiled from 121 sites in 87 marine protected areas (MPAs) globally (Edgar et al., 2014), I assessed how various configurations of design and management conditions affected MPA ecological performance, measured in terms of fish species richness and biomass. The set-theoretic approach used Boolean algebra to identify pathways that combined up to five ‘NEOLI’ (No-take, Enforced, Old, Large, Isolated) conditions and that were sufficient for achieving positive, and negative, ecological outcomes. Ecological isolation was overwhelming the most important condition affecting ecological outcomes but Old and Large were also conditions important for achieving high levels of biomass among large fishes (jacks, groupers, sharks). Solution coverage was uniformly low (<0.35) for all models of positive ecological performance suggesting the presence of numerous other conditions and pathways to ecological success that did not involve the NEOLI conditions. Solution coverage was higher (>0.50) for negative results (i.e., the absence of high biomass) among the large commercially-exploited fishes, implying asymmetries in how MPAs may rebuild populations on the one hand and, on the other, protect against further decline. The results revealed complex interactions involving MPA design, implementation, and management conditions that affect MPA ecological performance. In general terms, the presence of no-take regulations and effective enforcement were insufficient to ensure MPA effectiveness on their own. Given the central role of ecological isolation in securing ecological benefits from MPAs, site selection in the design phase appears critical for success. PMID:26644975

  16. Glucagon-Like Peptide-1-Mediated Modulation of Inflammatory Pathways in the Diabetic Brain: Relevance to Alzheimer's Disease.

    PubMed

    Qin, LiMei; Chong, Thomas; Rodriguez, Richard; Pugazhenthi, Subbiah

    2016-01-01

    Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients.

  17. Bacillus anthracis peptidoglycan stimulates an inflammatory response in monocytes through the p38 mitogen-activated protein kinase pathway.

    PubMed

    Langer, Marybeth; Malykhin, Alexander; Maeda, Kenichiro; Chakrabarty, Kaushik; Williamson, Kelly S; Feasley, Christa L; West, Christopher M; Metcalf, Jordan P; Coggeshall, K Mark

    2008-01-01

    We hypothesized that the peptidoglycan component of B. anthracis may play a critical role in morbidity and mortality associated with inhalation anthrax. To explore this issue, we purified the peptidoglycan component of the bacterial cell wall and studied the response of human peripheral blood cells. The purified B. anthracis peptidoglycan was free of non-covalently bound protein but contained a complex set of amino acids probably arising from the stem peptide. The peptidoglycan contained a polysaccharide that was removed by mild acid treatment, and the biological activity remained with the peptidoglycan and not the polysaccharide. The biological activity of the peptidoglycan was sensitive to lysozyme but not other hydrolytic enzymes, showing that the activity resides in the peptidoglycan component and not bacterial DNA, RNA or protein. B. anthracis peptidoglycan stimulated monocytes to produce primarily TNFalpha; neutrophils and lymphocytes did not respond. Peptidoglycan stimulated monocyte p38 mitogen-activated protein kinase and p38 activity was required for TNFalpha production by the cells. We conclude that peptidoglycan in B. anthracis is biologically active, that it stimulates a proinflammatory response in monocytes, and uses the p38 kinase signal transduction pathway to do so. Given the high bacterial burden in pulmonary anthrax, these findings suggest that the inflammatory events associated with peptidoglycan may play an important role in anthrax pathogenesis.

  18. Characterizing the Mechanistic Pathways of the Instant Blood-Mediated Inflammatory Reaction in Xenogeneic Neonatal Islet Cell Transplantation

    PubMed Central

    Liuwantara, David; Chew, Yi Vee; Favaloro, Emmanuel J.; Hawkes, Joanne M.; Burns, Heather L.; O'Connell, Philip J.; Hawthorne, Wayne J.

    2016-01-01

    Introduction The instant blood-mediated inflammatory reaction (IBMIR) causes major loss of islets after transplantation and consequently represents the initial barrier to survival of porcine neonatal islet cell clusters (NICC) after xenotransplantation. Methods This study used novel assays designed to characterize the various immunologic components responsible for xenogeneic IBMIR to identify initiators and investigate processes of IBMIR-associated coagulation, complement activation and neutrophil infiltration. The IBMIR was induced in vitro by exposing NICC to platelet-poor or platelet-rich human plasma or isolated neutrophils. Results We found that xenogeneic IBMIR was characterized by rapid, platelet-independent thrombin generation, with addition of platelets both accelerating and exacerbating this response. Platelet-independent complement activation was observed as early as 30 minutes after NICC exposure to plasma. However, membrane attack complex formation was not observed in NICC histopathology sections until after 60 minutes. We demonstrated for the first time that NICC-mediated complement activation was necessary for neutrophil activation in the xenogeneic IBMIR setting. Finally, using the Seahorse extracellular flux analyzer, we identified substantial loss of islet function (up to 40%) after IBMIR with surviving NICC showing evidence of mitochondrial damage. Conclusions This study used novel assays to describe multiple key pathways by which xenogeneic IBMIR causes islet destruction, allowing further refinement of future interventions aimed at resolving the issue of IBMIR in xenotransplantation. PMID:27500267

  19. Molecular and Morphological Characterization of Inflammatory Infiltrate in Rosacea Reveals Activation of Th1/Th17 Pathways.

    PubMed

    Buhl, Timo; Sulk, Mathias; Nowak, Pawel; Buddenkotte, Jörg; McDonald, Ian; Aubert, Jérôme; Carlavan, Isabelle; Déret, Sophie; Reiniche, Pascale; Rivier, Michel; Voegel, Johannes J; Steinhoff, Martin

    2015-09-01

    Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, quantitative real-time reverse-transcriptase-PCR, and quantitative immunohistochemistry on facial biopsies of rosacea patients, classified according to their clinical subtype. As controls, we used samples from patients with facial lupus erythematosus and healthy controls. Our study shows significant activation of the immune system in all subtypes of rosacea, characterizing erythematotelangiectatic rosacea (ETR) already as a disease with significant influx of proinflammatory cells. The T-cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFN-γ or IL-17, for example. Chemokine expression patterns support a Th1/Th17 polarization profile of the T-cell response. Macrophages and mast cells are increased in all three subtypes of rosacea, whereas neutrophils reach a maximum in papulopustular rosacea. Our studies also provide evidence for the activation of plasma cells with significant antibody production already in ETR, followed by a crescendo pattern toward phymatous rosacea. In sum, Th1/Th17 polarized inflammation and macrophage infiltration are an underestimated hallmark in all subtypes of rosacea. Therapies directly targeting the Th1/Th17 pathway are promising candidates in the future treatment of this skin disease.

  20. Bacillus anthracis Peptidoglycan Stimulates an Inflammatory Response in Monocytes through the p38 Mitogen-Activated Protein Kinase Pathway

    PubMed Central

    Langer, Marybeth; Malykhin, Alexander; Maeda, Kenichiro; Chakrabarty, Kaushik; Williamson, Kelly S.; Feasley, Christa L.; West, Christopher M.; Metcalf, Jordan P.; Coggeshall, K. Mark

    2008-01-01

    We hypothesized that the peptidoglycan component of B. anthracis may play a critical role in morbidity and mortality associated with inhalation anthrax. To explore this issue, we purified the peptidoglycan component of the bacterial cell wall and studied the response of human peripheral blood cells. The purified B. anthracis peptidoglycan was free of non-covalently bound protein but contained a complex set of amino acids probably arising from the stem peptide. The peptidoglycan contained a polysaccharide that was removed by mild acid treatment, and the biological activity remained with the peptidoglycan and not the polysaccharide. The biological activity of the peptidoglycan was sensitive to lysozyme but not other hydrolytic enzymes, showing that the activity resides in the peptidoglycan component and not bacterial DNA, RNA or protein. B. anthracis peptidoglycan stimulated monocytes to produce primarily TNFα; neutrophils and lymphocytes did not respond. Peptidoglycan stimulated monocyte p38 mitogen-activated protein kinase and p38 activity was required for TNFα production by the cells. We conclude that peptidoglycan in B. anthracis is biologically active, that it stimulates a proinflammatory response in monocytes, and uses the p38 kinase signal transduction pathway to do so. Given the high bacterial burden in pulmonary anthrax, these findings suggest that the inflammatory events associated with peptidoglycan may play an important role in anthrax pathogenesis. PMID:19002259

  1. Is resistant starch protective against colorectal cancer via modulation of the WNT signalling pathway?

    PubMed

    Malcomson, Fiona C; Willis, Naomi D; Mathers, John C

    2015-08-01

    Epidemiological and experimental evidence suggests that non-digestible carbohydrates (NDC) including resistant starch are protective against colorectal cancer. These anti-neoplastic effects are presumed to result from the production of the SCFA, butyrate, by colonic fermentation, which binds to the G-protein-coupled receptor GPR43 to regulate inflammation and other cancer-related processes. The WNT pathway is central to the maintenance of homeostasis within the large bowel through regulation of processes such as cell proliferation and migration and is frequently aberrantly hyperactivated in colorectal cancers. Abnormal WNT signalling can lead to irregular crypt cell proliferation that favours a hyperproliferative state. Butyrate has been shown to modulate the WNT pathway positively, affecting functional outcomes such as apoptosis and proliferation. Butyrate's ability to regulate gene expression results from epigenetic mechanisms, including its role as a histone deacetylase inhibitor and through modulating DNA methylation and the expression of microRNA. We conclude that genetic and epigenetic modulation of the WNT signalling pathway may be an important mechanism through which butyrate from fermentation of resistant starch and other NDC exert their chemoprotective effects.

  2. How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario

    PubMed Central

    Arrázola, Macarena S.; Silva-Alvarez, Carmen; Inestrosa, Nibaldo C.

    2015-01-01

    Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death. Mitochondria are highly dynamic organelles, and the balance between their fusion and fission processes is essential for neuronal function. Interestingly, in AD, the process known as “mitochondrial dynamics” is also impaired by Aβo. On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling, through the Wnt3a ligand, prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling, through the Wnt5a ligand, protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders. Here we discuss the neuroprotective role of the canonical and non-canonical Wnt signaling pathways in AD and their differential modulation of mitochondrial processes, associated with mitochondrial dysfunction and neurodegeneration. PMID:25999816

  3. How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario.

    PubMed

    Arrázola, Macarena S; Silva-Alvarez, Carmen; Inestrosa, Nibaldo C

    2015-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death. Mitochondria are highly dynamic organelles, and the balance between their fusion and fission processes is essential for neuronal function. Interestingly, in AD, the process known as "mitochondrial dynamics" is also impaired by Aβo. On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling, through the Wnt3a ligand, prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling, through the Wnt5a ligand, protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders. Here we discuss the neuroprotective role of the canonical and non-canonical Wnt signaling pathways in AD and their differential modulation of mitochondrial processes, associated with mitochondrial dysfunction and neurodegeneration.

  4. Flavonoids from sea buckthorn inhibit the lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages through the MAPK and NF-κB pathways.

    PubMed

    Jiang, Fan; Guan, Haining; Liu, Danyi; Wu, Xi; Fan, Mingcheng; Han, Jianchun

    2017-03-03

    Sea buckthorn has long been used as a functional food to regulate cholesterol, relieve angina, and diminish inflammation. Flavonoids are one of the main active components in sea buckthorn. We investigated the effects of sea buckthorn flavonoid (SF) treatment on two pathways that mediate inflammation, the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, to explore the anti-inflammatory activity of SFs in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The LPS-induced over-production of nitric oxide (NO) and prostaglandin E2 (PGE2) was inhibited by SFs through a mechanism related to the modulatory effects of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes. Additionally, SFs downregulated the production and mRNA expression of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β. Moreover, SFs inhibited the phosphorylation of the p38 and stress-activated protein kinase/jun amino-terminal kinase (SAPK/JNK) MAPK pathways, and they reduced the nuclear translocation of NF-κB to prevent its activation by blocking the phosphorylation and degradation of inhibitor protein of NF-κB α (IκB-α). Based on these findings, SFs may exert their inhibitory effects on inflammation by regulating the release of inflammatory mediators through the MAPK and NF-κB pathways. SFs highlight the potential benefits of using functional foods with anti-inflammatory actions to combat inflammatory diseases.

  5. [Protective effect of quercetin against immunological liver injury through activating Nrf2/ARE signaling pathway].

    PubMed

    Wei, Caibing; Zhou, Liandi; Zhang, Yuzhen; Zhang, Jiawei; Zhang, Qihui; Tao, Kun

    2017-03-01

    Objective To observe the protective effect of quercetin against immunological liver injury induced by triptolide, and investigate the involvement of Nrf2/ARE signaling pathway in the protection. Methods Fifty C57BL/6J mice were randomly divided into five groups: control group, model group, (20, 50, 80) mg/kg quercetin pre-treatment groups. Each group included 10 mice. The mice were treated with different doses of quercetin once daily for consecutive 10 days. At the end of the experiment, triptolide (500 μg/kg) was given intragastrically to induce immunological liver injury in all groups except for the control group. Twenty-two hours later, the levels of serum ALT , AST were detected. The contents of GSH, SOD and MDA in liver tissue homogenates were measured through commercial kits. HE staining was performed to observe pathologic changes of the liver. The mRNA expressions of heme oxygenase-1 (HO-1), NQO1, glutamate-cysteine ligase catalytic subunit (GCLC) was tested by quantitative real-time PCR, and the protein expression of Nrf2 was detected by Western blotting. Results Compared with the model group, the serum activities of ALT and AST as well as MDA content remarkably decreased by the administration of quercetin (80 mg/kg), while GSH, SOD contents were elevated in liver tissues; pathologic changes of the liver was ameliorated evidently by quercetin; Nrf2 protein expression in the nucleus as well as mRNA expressions of HO-1, NQO1, GCLC increased. Moreover, the protective effect of 50 mg/kg quercetin was not as good as that of 80 mg/kg quercetin, and 20 mg/kg quercetin did little against the immunological liver injury. Conclusion High-dose quercetin can inhibit immunological liver injury induced by triptolide, and the mechanism may be associated with the activation of Nrf2/ARE signaling pathway.

  6. ET-1 Promotes Differentiation of Periodontal Ligament Stem Cells into Osteoblasts through ETR, MAPK, and Wnt/β-Catenin Signaling Pathways under Inflammatory Microenvironment.

    PubMed

    Liang, Li; Zhou, Wei; Yang, Nan; Yu, Jifeng; Liu, Hongchen

    2016-01-01

    Periodontitis is a kind of chronic inflammatory disease that affects the tooth-supporting tissues. ET-1 is related to periodontitis and involved in the regulation of cytokines, but the mechanisms remain unclear. The aim of this study is to investigate how ET-1 affects proinflammatory cytokine expression and differentiation in human periodontal ligament stem cells (PDLSCs). PDLSCs were isolated from the periodontal ligament tissues of periodontitis patients and then treated with ET-1 (1, 10, or 100 nM) for 12 h, 24 h, or 72 h. The osteogenic potential of PDLSCs was tested using ALP staining. TNF-α, IL-1β, and IL-6 levels were evaluated by ELISA and western blot. Runx2, OCN, and COL1 mRNA and western levels were detected by RT-PCR and western blot, respectively. To examine the signaling pathways and molecular mechanisms involved in ET-1-mediated cytokine expression and osteogenic differentiation, ETR pathway, MAPKs pathway, Wnt/β-catenin pathway, and Wnt/Ca(2+) pathway were detected by RT-PCR and western blot, respectively. ET-1 promoted differentiation of PDLSCs into osteoblasts by increasing secretion of TNF-α, IL-1β, and IL-6 in a dose- and time-dependent manner. ET-1 also increased expression of Runx2, OCN, and COL1. ET-1 promotes differentiation of PDLSCs into osteoblasts through ETR, MAPK, and Wnt/β-catenin signaling pathways under inflammatory microenvironment.

  7. 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

  8. Tenuigenin exhibits protective effects against LPS-induced acute kidney injury via inhibiting TLR4/NF-κB signaling pathway.

    PubMed

    Fu, Haiyan; Hu, Zhansheng; Di, Xingwei; Zhang, Qiuhong; Zhou, Rongbin; Du, Hongyang

    2016-11-15

    Tenuigenin (TNG) has been reported to have various pharmacological activities, such as anti-oxidative and anti-inflammatory activities. However, the protective effects of TNG on lipopolysaccharides (LPS)-induced acute kidney injury (AKI) are still not clear. The aim of this study was to investigate the protective effects and mechanism of TGN on LPS-induced AKI in mice. The kidney histological change, levels of blood urea nitrogen (BUN), and creatinine were measured to assess the protective effects of TNG on LPS-induced AKI. The levels of TNF-α, IL-1β, and IL-6 in serum and kidney tissues were detected by ELISA. The extent of nuclear factor kappa-B (NF-κB) p65 and the expression of Toll-like receptor-4 (TLR4) were detected by western blot analysis. The results showed that TNG markedly attenuated the histological alterations, BUN and creatinine levels in kidney. TNG also suppressed LPS-induced TNF-α, IL-1β, and IL-6 production. Furthermore, the expression of TLR4 and NF-κB activation induced by LPS were markedly inhibited by TNG. In conclusion, this study demonstrated that TNG protected against LPS-induced AKI by inhibiting TLR4/NF-κB signaling pathway.

  9. A natural compound macelignan protects midbrain dopaminergic neurons from inflammatory degeneration via microglial arginase-1 expression.

    PubMed

    Kiyofuji, Kana; Kurauchi, Yuki; Hisatsune, Akinori; Seki, Takahiro; Mishima, Satoshi; Katsuki, Hiroshi

    2015-08-05

    Inflammatory events involving activated microglia have been recognized to play an important role in pathogenesis of various neurodegenerative disorders including Parkinson disease. Compounds regulating activation profiles of microglia may provide therapeutic benefits for Parkinson disease characterized by degeneration of midbrain dopaminergic neurons. Here we examined the effect of macelignan, a compound derived from nutmeg, on inflammatory degeneration of midbrain dopaminergic neurons. Treatment of midbrain slice cultures with interferon (IFN)-γ and lipopolysaccharide (LPS) caused a substantial decrease in viable dopaminergic neurons and an increase in nitric oxide (NO) production indicated by extracellular nitrite accumulation. Application of macelignan (10 μM) concomitantly with LPS prevented the loss of dopaminergic neurons. Besides nitrite accumulation, up-regulation of inducible NO synthase protein expression in response to IFN-γ/LPS was confirmed by Western blotting, and immunohistochemical examination revealed expression of inducible NO synthase in a subpopulation of Iba-1-poitive microglia. However, macelignan did not affect any of these NO-related parameters. On the other hand, macelignan promoted expression of arginase-1 in midbrain slice cultures irrespective of the presence or the absence of IFN-γ/LPS treatment. Arginase-1 expression was mainly localized in a subpopulation of Iba-1-positive cells. Importantly, the neuroprotective effect of macelignan was antagonized by N(ω)-hydroxy-nor-L-arginine, a specific arginase inhibitor. The neuroprotective effect of macelignan was also prevented by GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Overall, these results indicate that macelignan, a compound with PPARγ agonist activity, can provide neuroprotective effect on dopaminergic neurons in an arginase-dependent but NO-independent manner.

  10. Roles of NAD in Protection of Axon against Degeneration via SIRT1 Pathways.

    PubMed

    Zhang, Jing; Guo, Wei-Hua; Qi, Xiao-Xia; Li, Gui-Bao; Hu, Yan-Lai; Wu, Qi; Ding, Zhao-Xi; Li, Hong-Yu; Hao, Jing; Sun, Jin-Hao

    2016-04-30

    Axonal degeneration is a common pathological change of neurogenical disease which often arises before the neuron death. But it had not found any effective method to protect axon from degeneration. In this study we intended to confirm the protective effect of nicotinamide adenine dinucleotide (NAD), investigate the optimal administration dosage and time of NAD, and identify the relationship between silence signal regulating factor 1 (SIRT1) and axonal degeneration. An axonal degeneration model was established using dorsal root ganglion (DRG) neurons injured by vincristine to observe the protective effects of NAD to the injured axons. In addition, the potential contribution of the SIRT1 in axonal degeneration was also investigated. Through the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunochemistry staining, axons counting and length measuring, transmission electron microscope (TEM) observation, we demonstrated that NAD played an important role in preventing axonal degeneration. Further study revealed that the expression of SIRT1 and phosphorylated Akt1 (p-Akt1) was up-regulated when NAD was added into the culturing medium. Taking together, our results demonstrated that NAD might delay the axonal degeneration through SIRT1/Akt1 pathways.

  11. Suppression of Inflammatory Responses by Black Rice Extract in RAW 264.7 Macrophage Cells via Downregulation of NF-kB and AP-1 Signaling Pathways.

    PubMed

    Limtrakul, Pornngarm; Yodkeeree, Supachai; Pitchakarn, Pornsiri; Punfa, Wanisa

    2015-01-01

    Anthocyanin, a phenolic compound, has been reported to have an anti-inflammatory effect against lipopolysaccharide (LPS) induced changes in immune cells. However, little is known about the molecular mechanisms underlying its anti-inflammatory effects. Few research studies have concerned the anti-inflammation properties of colored rice extract as a functional material. Therefore, the purpose of this study was to examine anti-inflammatory effects of the polar fraction of black rice whole grain extracts (BR-WG-P) that features a high anthocyanin content. Our results showed that BR-WG-P significantly inhibited LPS-induced pro- inflammatory mediators, including production of NO and expression of iNOS and COX-2. In addition, secretion of pro-inflammatory cytokines including TNF-α and IL-6 was also significantly inhibited. Moreover, BR-WG-P and anthocyanin inhibited NF-kB and AP-1 translocation into the nucleus. BR-WG-P also decreased the phosphorylation of ERK, p38 and JNK in a dose dependent manner. These results suggested that BR-WG-P might suppress LPS-induced inflammation via the inhibition of the MAPK signaling pathway leading to decrease of NF-kB and AP-1 translocation. All of these results indicate that BR-WG-P exhibits therapeutic potential associated with the anthocyanin content in the extract for treating inflammatory diseases associated with cancer.

  12. Potent Anti-inflammatory and Analgesic Actions of the Chloroform Extract of Dendropanax morbifera Mediated by the Nrf2/HO-1 Pathway.

    PubMed

    Akram, Muhammad; Kim, Kyeong-A; Kim, Eun-Sun; Syed, Ahmed Shah; Kim, Chul Young; Lee, Jong Soo; Bae, Ok-Nam

    2016-01-01

    Dendropanax morbifera LEVEILLE (DP) has been used in traditional Korean medicines to treat a variety of inflammatory diseases. Although the in vitro anti-inflammatory potential of this plant is understood, its in vivo efficacy and underlying molecular mechanism of anti-inflammatory effects are largely unknown. We elucidated the anti-inflammatory and analgesic activities and the underlying molecular mechanisms of DP using in vitro and in vivo models. Lipopolysaccharide (LPS)-stimulated murine macrophages were used to analyze the in vitro anti-inflammatory potential of DP extract and to elucidate the underlying mechanisms. In vivo animal models of phorbol 12-myristate 13-acetate (TPA)-induced ear edema and acetic acid-induced writhing response tests were used to analyze the in vivo anti-inflammatory effects and anti-nociceptive effects of DP extract, respectively. Methanolic extract of DP (DPME) significantly inhibited the release of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-activated macrophages. Among the five sub-fractions, the chloroform fraction (DP-C) showed the most potent suppressive effects against pro-inflammatory mediators and cytokines in LPS-stimulated macrophages. These effects were attributed to inhibition of nuclear factor-κB (NF-κB) nuclear translocation and c-Jun N terminal kinase (JNK) 1/2 phosphorylation and to activation of NF-E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling. DP-C exhibited strong protective in vivo effects in TPA-induced ear edema mouse model and acetic acid-induced writhing response test. Our data suggest that DP-C has potent anti-inflammatory and analgesic activities and may be a promising treatment against a variety of inflammatory diseases.

  13. Moderate exercise training provides modest protection against adipose tissue inflammatory gene expression in response to high‐fat feeding

    PubMed Central

    Linden, Melissa A.; Pincu, Yair; Martin, Stephen A.; Woods, Jeffrey A.; Baynard, Tracy

    2014-01-01

    Abstract As white adipose tissue (WAT) expands under obesogenic conditions, local WAT hypoxia may contribute to the chronic low‐grade inflammation observed in obesity. Aerobic exercise training is beneficial in treating WAT inflammation after obesity is established, but it remains unknown whether exercise training, while on a concomitant high‐fat (HF) diet, influences WAT inflammation during the development of obesity. We sought to determine the effects of 4, 8, and 12 weeks of HF feeding and/or moderate intensity treadmill exercise training (EX) on the relationship between inflammatory and hypoxic gene expression within mouse WAT. Male C57Bl6/J mice (n = 113) were randomized into low‐fat (LF)/sedentary (SED), LF/EX, HF/SED, or HF/EX groups. The low‐fat and high‐fat diets contained 10% and 60% energy from fat, respectively. Exercise training consisted of treadmill running 5 days/week at 12 m/min, 8% incline, 40 min/day. Quantitative real‐time PCR was used to assess gene expression. HF diet impaired glucose regulation, and upregulated WAT gene expression of inflammation (IL‐1β, IL‐1ra, TNFα), macrophage recruitment and infiltration (F4/80 and monocyte chemoattractant protein), and M1 (CD11c) and M2 (CD206 and Arginase‐1) macrophage polarization markers. Treadmill training resulted in a modest reduction of WAT macrophage and inflammatory gene expression. HF diet had little effect on hypoxia‐inducible factor‐1α and vascular endothelial growth factor, suggesting that WAT inflammatory gene expression may not be driven by hypoxia within the adipocytes. Treadmill training may provide protection by preventing WAT expansion and macrophage recruitment. PMID:25347855

  14. MyD88 Mediates Instructive Signaling in Dendritic Cells and Protective Inflammatory Response during Rickettsial Infection

    PubMed Central

    Bechelli, Jeremy; Smalley, Claire; Zhao, Xuemei; Judy, Barbara; Valdes, Patricia; Walker, David H.

    2016-01-01

    Spotted fever group rickettsiae cause potentially life-threatening infections throughout the world. Several members of the Toll-like receptor (TLR) family are involved in host response to rickettsiae, and yet the mechanisms by which these TLRs mediate host immunity remain incompletely understood. In the present study, we found that host susceptibility of MyD88−/− mice to infection with Rickettsia conorii or Rickettsia australis was significantly greater than in wild-type (WT) mice, in association with severely impaired bacterial clearance in vivo. R. australis-infected MyD88−/− mice showed significantly lower expression levels of gamma interferon (IFN-γ), interleukin-6 (IL-6), and IL-1β, accompanied by significantly fewer inflammatory infiltrates of macrophages and neutrophils in infected tissues, than WT mice. The serum levels of IFN-γ, IL-12, IL-6, and granulocyte colony-stimulating factor were significantly reduced, while monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, and RANTES were significantly increased in infected MyD88−/− mice compared to WT mice. Strikingly, R. australis infection was incapable of promoting increased expression of MHC-IIhigh and production of IL-12p40 in MyD88−/− bone marrow-derived dendritic cells (BMDCs) compared to WT BMDCs, although costimulatory molecules were upregulated in both types of BMDCs. Furthermore, the secretion levels of IL-1β by Rickettsia-infected BMDCs and in the sera of infected mice were significantly reduced in MyD88−/− mice compared to WT controls, suggesting that in vitro and in vivo production of IL-1β is MyD88 dependent. Taken together, our results suggest that MyD88 signaling mediates instructive signals in DCs and secretion of IL-1β and type 1 immune cytokines, which may account for the protective inflammatory response during rickettsial infection. PMID:26755162

  15. Evaluation of In Vitro Anti-Inflammatory Activities and Protective Effect of Fermented Preparations of Rhizoma Atractylodis Macrocephalae on Intestinal Barrier Function against Lipopolysaccharide Insult

    PubMed Central

    Bose, Shambhunath; Kim, Hojun

    2013-01-01

    Lipopolysaccharide (LPS), a potent inducer of systemic inflammatory responses, is known to cause impairment of intestinal barrier function. Here, we evaluated the in vitro protective effect of an unfermented formulation of Rhizoma Atractylodis Macrocephalae (RAM), a traditional Chinese herbal medicine widely used in the treatment of many digestive and gastrointestinal disorders, and two fermented preparations of RAM, designated as FRAM-1 (prepared in Luria-Bertani broth) and FRAM-2 (prepared in glucose), on intestinal epithelial cells (IECs) against LPS insult. In general, fermented formulations, especially FRAM-2, but not unfermented RAM, exerted an appreciable protective effect on IECs against LPS-induced perturbation of membrane resistance and permeability. Both fermented formulations exhibited appreciable anti-inflammatory activities in terms of their ability to inhibit LPS-induced gene expression and induced production of a number of key inflammatory mediators and cytokines in RAW 264.7 macrophage cells. However, in most cases, FRAM-2 exhibited stronger anti-inflammatory effects than FRAM-1. Our findings also suggest that suppression of nuclear factor-κβ (NF-κβ) activity might be one of the possible mechanisms by which the fermented RAM exerts its anti-inflammatory effects. Collectively, our results highlight the benefits of using fermented products of RAM to protect against LPS-induced inflammatory insult and impairment in intestinal barrier function. PMID:23573125

  16. Inhibiting HMGB1 with Glycyrrhizic Acid Protects Brain Injury after DAI via Its Anti-Inflammatory Effect

    PubMed Central

    Pang, Honggang; Huang, Tinqin; Li, Dandong; Zhao, Yonglin; Ma, Xudong

    2016-01-01

    High-mobility group box 1 (HMGB1), a nuclear protein that has endogenous cytokine-like activity, is involved in several neurological diseases by mediating inflammatory response. In this study, a lateral head rotation device was used to establish a rat diffuse axonal injury (DAI) model. The dynamic expression of HMGB1, apoptosis-associated proteins, and proinflammatory cytokines were detected by Western blot, and neuronal apoptosis was observed by TUNEL staining. The extracellular release of HMGB1 and the accumulation of β-APP were observed by immunofluorescence and immunohistochemistry, respectively. The brain injury was indicated by modified neurological severity score (mNSS), brain water content (BWC), and the extravasation of Evans blue. We showed that HMGB1 level obviously decreased within 48 h after DAI, accompanied by neuronal apoptosis, the activation of caspases 3 and 9, and the phosphorylation of BCL-2. Inhibiting HMGB1 with glycyrrhizic acid (GL) can suppress the activation of apoptosis-associated proteins and inhibit the expression of proinflammatory cytokines, which ameliorated motor and cognitive deficits, reduced neuronal apoptosis, and protected the integrity of blood brain barrier (BBB) and axonal injury after experimental DAI in rats. Thus, HMGB1 may be involved in the inflammatory response after DAI, and inhibition of HMGB1 release with GL can notably alleviate the brain injury after DAI. PMID:27041825

  17. 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.

  18. Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways

    PubMed Central

    Singh, Bhupendra; Shoulson, Rivka; Chatterjee, Anwesha; Ronghe, Amruta; Bhat, Nimee K.; Dim, Daniel C.; Bhat, Hari K.

    2014-01-01

    The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17β-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in protection against oxidative DNA damage was increased in Res- and Res + E2-treated mammary tissues. Resveratrol also prevented E2-mediated inhibition of detoxification genes AOX1 and FMO1. Inhibition of E2-mediated alterations in NRF2 promoter methylation and expression of NRF2 targeting miR-93 after Res treatment indicated Res-mediated epigenetic regulation of NRF2 during E2-induced breast carcinogenesis. Resveratrol treatment also induced apoptosis and inhibited E2-mediated increase in DNA damage in mammary tissues. Increased apoptosis and decreased DNA damage, cell migration, colony and mammosphere formation in Res- and Res + E2-treated MCF-10A cells suggested a protective role of Res against E2-induced mammary carcinogenesis. Small-interfering RNA-mediated silencing of NRF2 inhibited Res-mediated preventive effects on the colony and mammosphere formation. Taken together, these results suggest that Res inhibits E2-induced breast carcinogenesis via induction of NRF2-mediated protective

  19. Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFκB Pathway Suppression

    PubMed Central

    Zhou, Zhong'e; Tang, Yong; Chen, Chengjun; Lu, Yi; Liu, Liang

    2016-01-01

    Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) mRNA expression, RAGE expression, and NFκB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects. In conclusion, metformin inhibits AGEs-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression. PMID:27761470

  20. Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFκB Pathway Suppression.

    PubMed

    Zhou, Zhong'e; Tang, Yong; Jin, Xian; Chen, Chengjun; Lu, Yi; Liu, Liang; Shen, Chengxing

    2016-01-01

    Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) mRNA expression, RAGE expression, and NFκB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects. In conclusion, metformin inhibits AGEs-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression.

  1. Ectopic Tertiary Lymphoid Tissue in Inflammatory Bowel Disease: Protective or Provocateur?

    PubMed Central

    McNamee, Eóin N.; Rivera-Nieves, Jesús

    2016-01-01

    Organized lymphoid tissues like the thymus first appeared in jawed vertebrates around 500 million years ago and have evolved to equip the host with a network of specialized sites, strategically located to orchestrate strict immune-surveillance and efficient immune responses autonomously. The gut-associated lymphoid tissues maintain a mostly tolerant environment to dampen our responses to daily dietary and microbial products in the intestine. However, when this homeostasis is perturbed by chronic inflammation, the intestine is able to develop florid organized tertiary lymphoid tissues (TLT), which heralds the onset of regional immune dysregulation. While TLT are a pathologic hallmark of Crohn’s disease (CD), their role in the overall process remains largely enigmatic. A critical question remains; are intestinal TLT generated by the immune infiltrated intestine to modulate immune responses and rebuild tolerance to the microbiota or are they playing a more sinister role by generating dysregulated responses that perpetuate disease? Herein, we discuss the main theories of intestinal TLT neogenesis and focus on the most recent findings that open new perspectives to their role in inflammatory bowel disease. PMID:27579025

  2. Melatonin enhances pro-inflammatory cytokine levels and protects against Chagas disease.

    PubMed

    Santello, Fabricia Helena; Frare, Eduardo Osório; Caetano, Leony Cristina; AlonsoToldo, Míriam Paula; do Prado, José Clóvis

    2008-08-01

    Pro-inflammatory and modulatory cytokines have an essential role in host defense against human and murine Trypanosoma cruzi infection. Control of T. cruzi parasitism during the acute phase of infection is considered to be critically dependent on direct macrophage activation by cytokines. Melatonin has been proposed to regulate the immune system by affecting cytokine production in immunocompetent cells, enhancing the production of several T helper (Th)1 cytokines. The aims of this work were to evaluate in rats, the influences of exogenous melatonin treatment on T. cruzi-infected host's immune responses. With this in mind, several immunological parameters were analyzed, including tumor necrosis factor-alpha, gamma-interferon, interleukin-12, nitric oxide (NO) and macrophage count. The melatonin therapy was provided in one of two different treatment regimens, that is, either beginning 7 days prior to infection or concomitant with the infection. Both treatments triggered an up-regulation of the immune response, with the concomitant treatment being more effective; in this case all cytokines studied, with exception of NO, displayed enhanced concentrations and there was a higher number of peritoneal macrophages, which displayed reduced concentrations under melatonin therapy. We conclude that melatonin plays a pivotal role in up-regulating the Th1 immune response thus controlling parasite replication.

  3. An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways.

    PubMed

    Maes, Michael

    2011-04-29

    There is a significant 'comorbidity' between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Depressive symptoms frequently occur during the course of ME/CFS. Fatigue and somatic symptoms (F&S), like pain, muscle tension, and a flu-like malaise, are key components of depression. At the same time, depression and ME/CFS show major clinical differences, which allow to discriminate them with a 100% accuracy. This paper aims to review the shared pathways that underpin both disorders and the pathways that discriminate them. Numerous studies have shown that depression and ME/CFS are characterized by shared aberrations in inflammatory, oxidative and nitrosative (IO&NS) pathways, like systemic inflammation and its long-term sequels, including O&NS-induced damage to fatty acids, proteins and DNA; dysfunctional mitochondria; lowered antioxidant levels, like zinc and coenzyme Q10; autoimmune responses to neoepitopes formed by O&NS; lowered omega-3 polyunsaturated fatty acid levels; and increased translocation of gram-negative bacteria. Some IO&NS-related pathways, like the induction of indoleamine 2-3-dioxygenase, neurodegeneration and decreased neurogenesis, are more specific to depression, whereas other pathways, like the 2'-5' oligoadenylate synthetase/RNase L pathway, are specific to ME/CFS. Most current animal models of depression, e.g. those induced by cytokines, are not reminiscent of human depression but reflect a mixture of depressive and F&S symptoms. The latter symptoms, sometimes called sickness behavior, differ from depression and ME/CFS because the former is a (sub)acute response to infection-induced pro-inflammatory cytokines that aims to enhance recovery, whereas the latter are characterized by long-term sequels in multiple IO&NS pathways. Depression and ME/CFS are not 'comorbid' disorders, but should be regarded as 'co-associated disorders' that are clinical manifestations of shared pathways.

  4. CCR2+ Inflammatory Dendritic Cells and Translocation of Antigen by Type III Secretion Are Required for the Exceptionally Large CD8+ T Cell Response to the Protective YopE69-77 Epitope during Yersinia Infection

    PubMed Central

    Zhang, Yue; Tam, Jason W.; Mena, Patricio; van der Velden, Adrianus W. M.; Bliska, James B.

    2015-01-01

    During Yersinia pseudotuberculosis infection of C57BL/6 mice, an exceptionally large CD8+ T cell response to a protective epitope in the type III secretion system effector YopE is produced. At the peak of the response, up to 50% of splenic CD8+ T cells recognize the epitope YopE69-77. The features of the interaction between pathogen and host that result in this large CD8+ T cell response are unknown. Here, we used Y. pseudotuberculosis strains defective for production, secretion and/or translocation of YopE to infect wild-type or mutant mice deficient in specific dendritic cells (DCs). Bacterial colonization of organs and translocation of YopE into spleen cells was measured, and flow cytometry and tetramer staining were used to characterize the cellular immune response. We show that the splenic YopE69-77-specific CD8+ T cells generated during the large response are polyclonal and are produced by a “translocation-dependent” pathway that requires injection of YopE into host cell cytosol. Additionally, a smaller YopE69-77-specific CD8+ T cell response (~10% of the large expansion) can be generated in a “translocation-independent” pathway in which CD8α+ DCs cross present secreted YopE. CCR2-expressing inflammatory DCs were required for the large YopE69-77-specific CD8+ T cell expansion because this response was significantly reduced in Ccr2-/- mice, YopE was translocated into inflammatory DCs in vivo, inflammatory DCs purified from infected spleens activated YopE69-77-specific CD8+ T cells ex vivo and promoted the expansion of YopE69-77-specific CD8+ T cells in infected Ccr2-/- mice after adoptive transfer. A requirement for inflammatory DCs in producing a protective CD8+ T cell response to a bacterial antigen has not previously been demonstrated. Therefore, the production of YopE69-77-specific CD8+ T cells by inflammatory DCs that are injected with YopE during Y. pseudotuberculosis infection represents a novel mechanism for generating a massive and protective

  5. Polydatin Protects Bone Marrow Stem Cells against Oxidative Injury: Involvement of Nrf 2/ARE Pathways

    PubMed Central

    Chen, Meihui; Hou, Yu; Lin, Dingkun

    2016-01-01

    Polydatin, a glucoside of resveratrol, has been reported to possess potent antioxidative effects. In the present study, we aimed to investigate the effects of polydatin in bone marrow-derived mesenchymal stem cells (BMSCs) death caused by hydrogen peroxide (H2O2), imitating the microenvironment surrounding transplanted cells in the injured spinal cord in vitro. In our study, MTT results showed that polydatin effectively prevented the decrease of cell viability caused by H2O2. Hochest 33258, Annexin V-PI, and Western blot assay showed H2O2-induced apoptosis in BMSCs, which was attenuated by polydatin. Further studies indicated that polydatin significantly protects BMSCs against apoptosis due to its antioxidative effects and the regulation of Nrf 2/ARE pathway. Taken together, our results indicate that polydatin could be used in combination with BMSCs for the treatment of spinal cord injury by improving the cell survival and oxidative stress microenvironments. PMID:27022401

  6. 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.

  7. High glucose induces inflammatory cytokine through protein kinase C-induced toll-like receptor 2 pathway in gingival fibroblasts

    SciTech Connect

    Jiang, Shao-Yun; Wei, Cong-Cong; Shang, Ting-Ting; Lian, Qi; Wu, Chen-Xuan; Deng, Jia-Yin

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer High glucose significantly induced TLR2 expression in gingival fibroblasts. Black-Right-Pointing-Pointer High glucose increased NF-{kappa}B p65 nuclear activity, IL-1{beta} and TNF-{alpha} levels. Black-Right-Pointing-Pointer PKC-{alpha}/{delta}-TLR2 pathway is involved in periodontal inflammation under high glucose. -- Abstract: Toll-like receptors (TLRs) play a key role in innate immune response and inflammation, especially in periodontitis. Meanwhile, hyperglycemia can induce inflammation in diabetes complications. However, the activity of TLRs in periodontitis complicated with hyperglycemia is still unclear. In the present study, high glucose (25 mmol/l) significantly induced TLR2 expression in gingival fibroblasts (p < 0.05). Also, high glucose increased nuclear factor kappa B (NF-{kappa}B) p65 nuclear activity, tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-l{beta} (IL-1{beta}) levels. Protein kinase C (PKC)-{alpha} and {delta} knockdown with siRNA significantly decreased TLR2 and NF-{kappa}B p65 expression (p < 0.05), whereas inhibition of PKC-{beta} had no effect on TLR2 and NF-{kappa}B p65 under high glucose (p < 0.05). Additional studies revealed that TLR2 knockdown significantly abrogated high-glucose-induced NF-{kappa}B expression and inflammatory cytokine secretion. Collectively, these data suggest that high glucose stimulates TNF-{alpha} and IL-1{beta} secretion via inducing TLR2 through PKC-{alpha} and PKC-{delta} in human gingival fibroblasts.

  8. Ischemic preconditioning protects the brain against injury via inhibiting CaMKII-nNOS signaling pathway.

    PubMed

    Wang, Mei; Qi, Da-Shi; Zhou, Cui; Han, Dong; Li, Pei-Pei; Zhang, Fang; Zhou, Xiao-Yan; Han, Meng; Di, Jie-Hui; Ye, Jun-Song; Yu, Hong-Min; Song, Yuan-Jian; Zhang, Guang-Yi

    2016-03-01

    Although studies have shown that cerebral ischemic preconditioning (IPC) can ameliorate ischemia/reperfusion (I/R) induced brain damage, but its precise mechanisms remain unknown. Therefore, the aim of this study was to investigate the neuroprotective mechanisms of IPC against ischemic brain damage induced by cerebral I/R and to explore whether the Calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated up-regulation of nNOS ser847-phosphorylation signaling pathway contributed to the protection provided by IPC. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with 3 min of IPC alone or KN62 (selective antagonist of CaMKII) treatment before IPC, after reperfusion for 3 days, 6 min ischemia was induced. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting was performed to measure the phosphorylation of CaMKII, nNOS, c-Jun and the expression of FasL. Immunoprecipitation was used to examine the binding between PSD95 and nNOS. The results showed that IPC could significantly protect neurons against cerebral I/R injury, furthermore, the combination of PSD95 and nNOS was increased, coinstantaneously the phosphorylation of CaMKII and nNOS (ser847) were up-regulated, however the activation of c-Jun and FasL were reduced. Conversely, KN62 treatment before IPC reversed all these effects of IPC. Taken together, the results suggest that IPC could diminish ischemic brain injury through CaMKII-mediated up-regulation of nNOS ser847-phosphorylation signaling pathway.

  9. Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways.

    PubMed

    Lin, Musen; Zhai, Xiaohan; Wang, Guangzhi; Tian, Xiaofeng; Gao, Dongyan; Shi, Lei; Wu, Hang; Fan, Qing; Peng, Jinyong; Liu, Kexin; Yao, Jihong

    2015-02-01

    Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury.

  10. Meta-analysis of genetic and environmental Parkinson's disease models reveals a common role of mitochondrial protection pathways.

    PubMed

    Soreq, Lilach; Ben-Shaul, Yoram; Israel, Zvi; Bergman, Hagai; Soreq, Hermona

    2012-03-01

    Both genetic and environmental factors trigger risks of and protection from Parkinson's disease, the second most common neurodegenerative syndrome, but possible inter-relationships between these risk and protection processes were not yet explored. By examining gene expression changes in the brains of mice under multiple treatments that increase or attenuate PD symptoms we detected underlying disease and protection-associated genes and pathways. In search for potential links between these different genes and pathways, we conducted meta-analysis on 131 brain region transcriptomes from mice over-expressing native or mutated α-synuclein (SNCA) with or without the protective HSP70 chaperone, or exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with or without the protective acetylcholinesterase (AChE-R) variant. All these models showed shared risk-inducible and protection-suppressible transcript modifications. Self-organized map (SOM) classification revealed risk- and protection-associated alterations in nuclear and mitochondrial metal ion-regulated transcripts, respectively; Gene Ontology based analysis validated these pathways. To complement this approach, and identify potential outcome damages, we further searched for shared functional enrichments in the lists of genes detected in young SNCA mutant or in old SNCA mutants and MPTP-exposed mice. This post-hoc functional analysis identified early-onset changes in Parkinsonian, immune and alternative splicing pathways which shifted into late-onset or exposure-associated NFkB-mediated neuro-inflammation. Our study suggests metal ions-mediated cross-talk between nuclear and mitochondrial pathways by both environmental and genetic risk and protective factors involved in Parkinson's disease, which eventually culminates in neuro-inflammation. Together, these findings offer new insights and novel targets for therapeutic interference with the gene-environment interactions underlying

  11. Reducing canonical Wingless/Wnt signaling pathway confers protection against mutant Huntingtin toxicity in Drosophila.

    PubMed

    Dupont, Pascale; Besson, Marie-Thérèse; Devaux, Jérôme; Liévens, Jean-Charles

    2012-08-01

    Huntington's disease (HD) is a genetic neurodegenerative disease characterized by movement disorders, cognitive decline and neuropsychiatric symptoms. HD is caused by expanded CAG tract within the coding region of Huntingtin protein. Despite major insights into the molecular mechanisms leading to HD, no effective cure is yet available. Mutant Huntingtin (mHtt) has been reported to alter the stability and levels of β-Catenin, a key molecule in cell adhesion and signal transduction in Wingless (Wg)/Wnt pathway. However it remains to establish whether manipulation of Wg/Wnt signaling can impact HD pathology. We here investigated the phenotypic interactions between mHtt and Wg/Wnt signaling by using the power of Drosophila genetics. We provide compelling evidence that reducing Armadillo/β-Catenin levels confers protection and that this beneficial effect is correlated with the inactivation of the canonical Wg/Wnt signaling pathway. Knockdowns of Wnt ligands or of the downstream transcription factor Pangolin/TCF both ameliorate the survival of HD flies. Similarly, overexpression of one Armadillo/β-Catenin destruction complex component (Axin, APC2 or Shaggy/GSK-3β) increases the lifespan of HD flies. Loss of functional Armadillo/β-Catenin not only abolishes neuronal intrinsic but also glia-induced alterations in HD flies. Our findings highlight that restoring canonical Wg/Wnt signaling may be of therapeutic value.

  12. Autophagy confers DNA damage repair pathways to protect the hematopoietic system from nuclear radiation injury

    PubMed Central

    Lin, Weiwei; Yuan, Na; Wang, Zhen; Cao, Yan; Fang, Yixuan; Li, Xin; Xu, Fei; Song, Lin; Wang, Jian; Zhang, Han; Yan, Lili; Xu, Li; Zhang, Xiaoying; Zhang, Suping; Wang, Jianrong

    2015-01-01

    Autophagy is essentially a metabolic process, but its in vivo role in nuclear radioprotection remains unexplored. We observed that ex vivo autophagy activation reversed the proliferation inhibition, apoptosis, and DNA damage in irradiated hematopoietic cells. In vivo autophagy activation improved bone marrow cellularity following nuclear radiation exposure. In contrast, defective autophagy in the hematopoietic conditional mouse model worsened the hematopoietic injury, reactive oxygen species (ROS) accumulation and DNA damage caused by nuclear radiation exposure. Strikingly, in vivo defective autophagy caused an absence or reduction in regulatory proteins critical to both homologous recombination (HR) and non-homologous end joining (NHEJ) DNA damage repair pathways, as well as a failure to induce these proteins in response to nuclear radiation. In contrast, in vivo autophagy activation increased most of these proteins in hematopoietic cells. DNA damage assays confirmed the role of in vivo autophagy in the resolution of double-stranded DNA breaks in total bone marrow cells as well as bone marrow stem and progenitor cells upon whole body irradiation. Hence, autophagy protects the hematopoietic system against nuclear radiation injury by conferring and intensifying the HR and NHEJ DNA damage repair pathways and by removing ROS and inhibiting apoptosis. PMID:26197097

  13. Protective Role of Fucoidan in Cerebral Ischemia-Reperfusion Injury through Inhibition of MAPK Signaling Pathway.

    PubMed

    Che, Nan; Ma, Yijie; Xin, Yinhu

    2016-11-25

    Fucoidan has been reported to exhibit various beneficial activities ranging from to antivirus and anticancer properties. However, little information is available about the effects of fucoidan on cerebral ischemia-reperfusion injury (IRI). Our study aimed to explore the effects of fucoidan on cerebral IRI, as well as the underlying mechanisms. Sprague-Dawley (SD) rats were randomly subjected to four groups: Sham, IRI+saline (IRI+S), IRI+80 mg/kg fucoidan (IRI+F80), and IRI+160 mg/kg fucoidan (IRI+F160). Fucoidan (80 mg/kg or 160 mg/kg) was intraperitoneally injected from 7 days before the rats were induced to cerebral IRI model with middle cerebral artery occlusion (MCAO) method. At 24 h after reperfusion, neurological deficits and the total infarct volume were determined. The levels of inflammation-associated cytokines (interleukin (IL)-1β, IL-6, myeloperoxidase (MPO), and tumor necrosis factor (TNF)-α), oxidative stress-related proteins (malondialdehyde (MDA) and superoxide dismutase (SOD)) in the ischemic brain were measured by enzyme-linked immunosorbent assay (ELISA). Besides, the levels of apoptosis-related proteins (p-53, Bax, and B-cell lymphoma (Bcl)-2) and mitogen-activated protein kinase (MAPK) pathway (phosphorylation-extracellular signalregulated kinase (p-ERK), p-c-Jun N-terminal kinase (JNK), and p-p38) were measured. Results showed that administration of fucoidan significantly reduced the neurological deficits and infarct volume compared to the IRI+S group in a dose-dependent manner. Also, fucoidan statistically decreased the levels of inflammation-associated cytokines, and oxidative stress-related proteins, inhibited apoptosis, and suppressed the MAPK pathway. So, Fucoidan plays a protective role in cerebral IRI might be by inhibition of MAPK pathway.

  14. TWEAK protects cardiomyocyte against apoptosis in a PI3K/AKT pathway dependent manner

    PubMed Central

    Yang, Bin; Yan, Ping; Gong, Hui; Zuo, Lin; Shi, Ying; Guo, Jian; Guo, Rui; Xie, Jun; Li, Bao

    2016-01-01

    Myocyte apoptosis is a key determinant of cardiac recovery and prognosis of patients with acute myocardial infarction (AMI). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of TNF superfamily, is a pro-inflammatory and pro-angiogenic cytokine implicated in physiological tissue regeneration and wound repair and is closely related to cardiac remodeling, dysfunction and fibrosis. However, the role of TWEAK and its receptor Fn14 in the cardiomyocyte apoptosis is still poorly understood. The present study aimed to investigate whether the TWEAK enhanced the cardiomyocyte apoptosis in AMI. The apoptosis of the cardiomyocyte cell line H9C2 was induced by hypoxia/reoxygenation. The apoptosis of H9C2 cells was evaluated by flow cytometry and caspase-3 activity assay under treatment with TWEAK at different concentrations. The phosphorylated signaling molecules and the expression involved in the surprising protection of TWEAK against the apoptosis with a dose-dependent manner (≥50 ng/ml). Furthermore, a rat myocardial ischemia and reperfusion (I/R) model was established by TWEAK preconditioning through injecting the TWEAK into the scar and border after ischemia immediately induced by ligating the left anterior descending coronary artery for 50 min and followed by different reperfusion times. The heart function was significantly improved in TWEAK preconditioning rats compared with controls as well as the infarct size was significantly reduced 21 days after reperfusion. Meanwhile, TWEAK protected the cardiac apoptosis by activation of cardioprotective signaling PI3K/AKT during I/R. Our findings suggest that TWEAK may represent a cardioprotective factor that inhibits the myocyte death of myocardial IRI. PMID:27725864

  15. Pinellia ternata lectin exerts a pro-inflammatory effect on macrophages by inducing the release of pro-inflammatory cytokines, the activation of the nuclear factor-κB signaling pathway and the overproduction of reactive oxygen species.

    PubMed

    Yu, Hong-Li; Zhao, Teng-Fei; Wu, Hao; Pan, Yao-Zong; Zhang, Qian; Wang, Kui-Long; Zhang, Chen-Chao; Jin, Yang-Ping

    2015-10-01

    Pinellia ternata (PT) is a widely used traditional Chinese medicine. The raw material has a throat-irritating toxicity that is associated with the PT lectin (PTL). PTL is a monocot lectin isolated from the tubers of PT, which exhibits mouse peritoneal acute inflammatory effects in vivo. The present study aimed to investigate the pro-inflammatory effect of PTL on macrophages. PTL (50 µg/ml)‑stimulated macrophages enhanced the chemotactic activity of neutrophils. PTL (50, 100, 200 and 400 µg/ml) significantly elevated the production of cytokines [tumor necrosis factor‑α (TNF-α) , interleukin (IL)‑1β and IL‑6]. PTL (25, 50 and 100 µg/ml) induced intracellular reactive oxygen species (ROS) overproduction. PTL also caused transfer of p65 from the macrophage cytoplasm to the nucleus and activated the nuclear factor‑κB (NF‑κB) signaling pathway. Scanning electron microscope images revealed severe cell swelling and membrane integrity defection of macrophages following PTL (100 µg/ml) stimulation, which was also associated with inflammation. PTL had pro‑inflammatory activity, involving induced neutrophil migration, cytokine release, ROS overproduction and the activation of the NF-κB signaling pathway, which was associated with the activation of macrophages.

  16. Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway

    PubMed Central

    Li, Qing-rong; Wang, Zhuo; Zhou, Wei; Fan, Shou-rui; Ma, Run; Xue, Li; Yang, Lu; Li, Ya-shan; Tan, Hong-li; Shao, Qing-hua; Yang, Hong-ying

    2016-01-01

    Epalrestat is a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy. This study assumed that epalrestat had a protective effect on diabetic peripheral nerve injury by suppressing the expression of aldose reductase in peripheral nerves of diabetes mellitus rats. The high-fat and high-carbohydrate model rats were established by intraperitoneal injection of streptozotocin. Peripheral neuropathy occurred in these rats after sustaining high blood glucose for 8 weeks. At 12 weeks after streptozotocin injection, rats were intragastrically administered epalrestat 100 mg/kg daily for 6 weeks. Transmission electron microscope revealed that the injuries to myelinated nerve fibers, non-myelinated nerve fibers and Schwann cells of rat sciatic nerves had reduced compared to rats without epalrestat administuation. Western blot assay and immunohistochemical results demonstrated that after intervention with epalrestat, the activities of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase gradually increased, but aldose reductase protein expression gradually diminished. Results confirmed that epalrestat could protect against diabetic peripheral neuropathy by relieving oxidative stress and suppressing the polyol pathway. PMID:27073391

  17. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.

    PubMed

    Rialdi, Alex; Campisi, Laura; Zhao, Nan; Lagda, Arvin Cesar; Pietzsch, Colette; Ho, Jessica Sook Yuin; Martinez-Gil, Luis; Fenouil, Romain; Chen, Xiaoting; Edwards, Megan; Metreveli, Giorgi; Jordan, Stefan; Peralta, Zuleyma; Munoz-Fontela, Cesar; Bouvier, Nicole; Merad, Miriam; Jin, Jian; Weirauch, Matthew; Heinz, Sven; Benner, Chris; van Bakel, Harm; Basler, Christopher; García-Sastre, Adolfo; Bukreyev, Alexander; Marazzi, Ivan

    2016-05-27

    The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. We identified topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses as well as bacterial products. Therapeutic pharmacological inhibition of Top1 protected mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life-threatening infections characterized by an acutely exacerbated immune response.

  18. The blocking of uPAR suppresses lipopolysaccharide‐induced inflammatory osteoclastogenesis and the resultant bone loss through attenuation of integrin β3/Akt pathway

    PubMed Central

    Ishisaki, Akira; Miyashita, Mei; Matsuo, Osamu

    2016-01-01

    Abstract Introduction Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, cause the bone destruction by promotion of the differentiation of monocyte/macrophage lineage cells into mature osteoclasts (OCs) with active bone‐resorbing character. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of urokinase plasminogen activator receptor (uPAR) in the bone destruction caused by chronic inflammation. Methods We investigated that the effect of uPAR on inflammatory OC formation induced by lipopolysaccharide (LPS) in inflammatory diseases. Results We found that the LPS more weakly induced OC formation and the resultant bone loss in uPAR‐deficient mice than in wild‐type mice. Additionally, we demonstrated that uPAR significantly potentiated LPS‐induced OC formation of RAW264.7 mouse monocyte/macrophage linage cells in integrin β3/Akt‐dependent manner. Moreover, we showed that the blocking of uPAR function by the administration of anti‐uPAR neutralizing antibody significantly attenuated the LPS‐induced OC formation and the resultant bone loss in mice. Conclusions These results strongly suggest that uPAR negatively regulates the LPS‐induced inflammatory OC formation and the resultant bone loss mediated through the integrin β3/Akt pathway. Our findings partly clarify the molecular mechanisms underlying bone destruction caused by chronic inflammatory diseases, and would benefit research on identifying antibody therapy for the treatment of these diseases. PMID:27621816

  19. Physical activity, by enhancing parasympathetic tone and activating the cholinergic anti-inflammatory pathway, is a therapeutic strategy to restrain chronic inflammation and prevent many chronic diseases.

    PubMed

    Lujan, Heidi L; DiCarlo, Stephen E

    2013-05-01

    Chronic diseases are the leading cause of death in the world and chronic inflammation is a key contributor to many chronic diseases. Accordingly, interventions that reduce inflammation may be effective in treating multiple adverse chronic conditions. In this context, physical activity is documented to reduce systemic low-grade inflammation and is acknowledged as an anti-inflammatory intervention. Furthermore, physically active individuals are at a lower risk of developing chronic diseases. However the mechanisms mediating this anti-inflammatory phenotype and range of health benefits are unknown. We hypothesize that the "cholinergic anti-inflammatory pathway" (CAP) mediates the anti-inflammatory phenotype and range of health benefits associated with physical activity. The CAP is an endogenous, physiological mechanism by which acetylcholine from the vagus nerve, interacts with the innate immune system to modulate and restrain the inflammatory cascade. Importantly, higher levels of physical activity are associated with enhanced parasympathetic (vagal) tone and lower levels of C-reactive protein, a marker of low-grade inflammation. Accordingly, physical activity, by enhancing parasympathetic tone and activating the CAP, may be a therapeutic strategy to restrain chronic inflammation and prevent many chronic diseases.

  20. Chlorin e6-Mediated Photodynamic Therapy Suppresses P. acnes-Induced Inflammatory Response via NFκB and MAPKs Signaling Pathway

    PubMed Central

    Wang, Yoon-Young; Ryu, A-Reum; Jin, Solee; Jeon, Yu-Mi; Lee, Mi-Young

    2017-01-01

    Photodynamic therapy (PDT), consisting of photosensitizer, light, and oxygen has been used for the treatment of various diseases including cancers, microbial infections and skin disorders. In this study, we examined the anti-inflammatory effect of chlorin e6-mediated PDT in P. acnes-infected HaCaT cells using photosensitizer chlorin e6 (Ce6) and halogen light. The live and heat-killed P. acnes triggered an upregulation of inflammatory molecules such as iNOS, NO, and inflammatory cytokine in HaCaT cells and mouse model. Ce6-mediated PDT notably downregulated the expression of these inflammatory molecules in vitro and in vivo. Similarly, chlorin e6-mediated PDT was capable of regulating inflammatory response in both live and heat killed S. epidermidis exposed HaCaT cells. Moreover, phosphorylation of p38, JNK, and ERK were reduced by Ce6-mediated PDT. Ce6-mediated PDT also reduced the phosphorylation of IKKα/β, IĸBα and NFκB p65 in P. acnes-stimulated HaCaT cells. In addition, the dramatic increase in the nuclear translocation of NFκB p65 observed upon stimulation with P. acnes was markedly impaired by Ce6-based PDT. This is the first suggestion that Ce6-mediated PDT suppresses P. acnes-induced inflammation through modulating NFκB and MAPKs signaling pathways. PMID:28118375

  1. Protective Effects of Green Tea Polyphenol Against Renal Injury Through ROS-Mediated JNK-MAPK Pathway in Lead Exposed Rats

    PubMed Central

    Wang, Haidong; Li, Deyuan; Hu, Zhongze; Zhao, Siming; Zheng, Zhejun; Li, Wei

    2016-01-01

    To investigate the potential therapeutic effects of polyphenols in treating Pb induced renal dysfunction and intoxication and to explore the detailed underlying mechanisms. Wistar rats were divided into four groups: control groups (CT), Pb exposure groups (Pb), Pb plus Polyphenols groups (Pb+PP) and Polyphenols groups (PP). Animals were kept for 60 days and sacrificed for tests of urea, serum blood urea nitrogen (BUN) and creatinine. Histological evaluations were then performed. In vitro studies were performed using primary kidney mesangial cells to reveal detailed mechanisms. Cell counting kit-8 (CCK-8) was used to evaluate cell viability. Pb induced cell apoptosis was measured by flow cytometry. Reactive oxygen species (ROS) generation and scavenging were tested by DCFH-DA. Expression level of tumor necrosis factor-α (TNF-α), interleukin-1-β (IL-1-β) and IL-6 were assayed by ELISA. Western blot and qPCR were used to measure the expression of ERK1/2, JNK1/2 and p38. Polyphenols have obvious protective effects on Pb induced renal dysfunction and intoxication both in vivo and in vitro. Polyphenols reduced Pb concentration and accumulation in kidney. Polyphenols also protected kidney mesangial cells from Pb induced apoptosis. Polyphenols scavenged Pb induced ROS generation and suppressed ROS-mediated ERK/JNK/p38 pathway. Downstream pro-inflammatory cytokines were inhibited in consistency. Polyphenol is protective in Pb induced renal intoxication and inflammatory responses. The underlying mechanisms lie on the antioxidant activity and ROS scavenging activity of polyphenols. PMID:27239812

  2. Edible blue-green algae reduce the production of pro-inflammatory cytokines by inhibiting NF-κB pathway in macrophages and splenocytes

    PubMed Central

    Ku, Chai Siah; Pham, Tho X.; Park, Youngki; Kim, Bohkyung; Shin, Min; Kang, Insoo; Lee, Jiyoung

    2013-01-01

    Background Chronic inflammation contributes to the development of pathological disorders including insulin resistance and atherosclerosis. Identification of anti-inflammatory natural products can prevent the inflammatory diseases. Methods Anti-inflammatory effects of blue-green algae (BGA), i.e., Nostoc commune var. Sphaeroides Kützing (NO) and Spirulina Platensis (SP), were compared in RAW 264.7 and mouse bone marrow-derived macrophages (BMM) as well as splenocytes from apolipoprotein E knockout (apoE−/−) mice fed BGA. Results When macrophages pretreated with 100 μg/ml NO lipid extract (NOE) or SP lipid extract (SPE) were activated by lipopolysaccharide (LPS), expression and secretion of pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), and IL-6, were significantly repressed. NOE and SPE also significantly repressed the expression of TNFα and IL-1β in BMM. LPS-induced secretion of IL-6 was lower in splenocytes from apoE−/− fed an atherogenic diet containing 5% NO or SP for 12 weeks. In RAW 264.7 macrophages, NOE and SPE markedly decreased nuclear translocation of NF-κB. The degree of repression of pro-inflammatory gene expression by algal extracts was much stronger than that of SN50, an inhibitor of NF-κB nuclear translocation. Trichostatin A, a pan histone deacetylase inhibitor, increased basal expression of IL-1β and attenuated the repression of the gene expression by SPE. SPE significantly down-regulated mRNA abundance of 11 HDAC isoforms, consequently increasing acetylated histone 3 levels. Conclusion NOE and SPE repress pro-inflammatory cytokine expression and secretion in macrophages and splenocytes via inhibition of NF-κB pathway. Histone acetylation state is likely involved in the inhibition. General significance This study underscores natural products can exert anti-inflammatory effects by epigenetic modifications such as histone acetylation. PMID:23357040

  3. Sulodexide down-regulates the release of cytokines, chemokines, and leukocyte colony stimulating factors from human macrophages: role of glycosaminoglycans in inflammatory pathways of chronic venous disease.

    PubMed

    Mannello, Ferdinando; Ligi, Daniela; Canale, Matteo; Raffetto, Joseph D

    2014-01-01

    Chronic venous disease (CVeD) is a debilitating condition that affects millions of individuals worldwide. The condition can result in varicose veins, or advance to severe skin changes and venous ulceration. The fundamental basis for CVeD is inflammation within the venous circulation and that it is subjected to increased hydrostatic pressure resulting in increased ambulatory venous pressure. The inflammation involves leukocytes, in particular macrophages and monocytes, inflammatory modulators and chemokines, cytokine expression, growth factors, metalloproteinase (MMP) activity, and many regulatory pathways that perpetuate inflammation. Sulodexide (SDX) is a glycosaminoglycan with pro-fibrinolytic and anti-thrombotic properties. We have previously demonstrated that SDX inhibits the secretion of pro-zymogen MMP-9 from human leukocytes without displacing high molecular complexes of MMP-9. The anti-inflammatory properties of SDX on activated leukocytes have not been well established. We hypothesized that SDX will reduce the secretion of inflammatory mediators from lipopolysaccharide (LPS)-stimulated macrophages. Therefore, we evaluated the effects of SDX on LPS-stimulated macrophage secretion of various inflammatory and anti-inflammatory cytokines, chemokines, and colony stimulating factors. We used microplatebased multiplex immunoassays. LPS-stimulated macrophages in vitro caused a substantial increase of interleukins, tumor necrosis factor, interferon, chemokines and colony stimulating factors. The addition of SDX caused both a dose-dependent and dose-independent decrease in nearly all of the inflammatory cytokines, chemokines and colony stimulating factors. These findings suggest that SDX has a significant effect on the release of inflammatory mediators from macrophages, and may be useful in the treatment of early and advanced CVeD.

  4. CXC195 suppresses proliferation and inflammatory response in LPS-induced human hepatocellular carcinoma cells via regulating TLR4-MyD88-TAK1-mediated NF-κB and MAPK pathway

    SciTech Connect

    Wang, Yiting; Tu, Qunfei; Yan, Wei; Xiao, Dan; Zeng, Zhimin; Ouyang, Yuming; Huang, Long; Cai, Jing; Zeng, Xiaoli; Chen, Ya-Jie; Liu, Anwen

    2015-01-02

    Highlights: • CXC195 exhibited significant anti-proliferative effect and induced cell cycle arrest in LPS-induced HepG2 cells. • CXC195 suppressed the release of pro-inflammatory mediators in LPS-induced HepG2 cells. • CXC195 regulated TLR4-MyD88-TAK1-mediated NF-κB and MAPK pathway in LPS-induced HepG2 cells. - Abstract: CXC195 showed strong protective effects in neuronal apoptosis by exerting its antioxidant activity. However, the anti-cancer effects of CXC195 is still with limited acquaintance. Here, we investigated the role of CXC195 in lipopolysaccharide (LPS)-induced human hepatocellular carcinoma (HCC) cells lines (HepG2) and the possible signaling pathways. CXC195 exhibited significant anti-proliferative effect and induced cell cycle arrest in LPS-induced HepG2 cells. In addition, CXC195 suppressed the release of pro-inflammatory mediators in LPS-induced HepG2 cells, including TNF-α, iNOS, IL-1β, IL-6, CC chemokine ligand (CCL)-2, CCL-22 and epidermal growth factor receptor (EGFR). Moreover, CXC195 inhibited the expressions and interactions of TLR4, MyD88 and TAK1, NF-κB translocation to nucleus and its DNA binding activity, phosphorylation of ERK1/2, p38 and JNK. Our results suggested that treatment with CXC195 could attenuate the TLR4-mediated proliferation and inflammatory response in LPS-induced HepG2 cells, thus might be beneficial for the treatment of HCC.

  5. Pro-inflammatory cytokine TNF-α is a key inhibitory factor for lactose synthesis pathway in lactating mammary epithelial cells.

    PubMed

    Kobayashi, Ken; Kuki, Chinatsu; Oyama, Shoko; Kumura, Haruto

    2016-01-15

    Lactose is a milk-specific carbohydrate synthesized by mammary epithelial cells (MECs) in mammary glands during lactation. Lactose synthesis is downregulated under conditions causing inflammation such as mastitis, in which MECs are exposed to high concentrations of inflammatory cytokines. In this study, we investigated whether inflammatory cytokines (TNF-α, IL-1β, and IL-6) directly influence the lactose synthesis pathway by using two types of murine MEC culture models: the monolayer culture of MECs to induce lactogenesis; and the three-dimensional culture of MECs surrounded by Matrigel to induce reconstitution of the alveolar structure in vitro. TNF-α caused severe down-regulation of lactose synthesis-related genes concurrently with the degradation of glucose transporter 1 (GLUT1) from the basolateral membranes in MECs. IL-1β also caused degradation of GLUT1 along with a decrease in the expression level of β-1,4-galactosylransferase 3. IL-6 caused both up-regulation and down-regulation of the expression levels of lactose synthesis-related genes in MECs. These results indicate that TNF-α, IL-1β, and IL-6 have different effects on the lactose synthesis pathway in MECs. Furthermore, TNF-α triggered activation of NFκB and inactivation of STAT5, suggesting that NFκB and STAT5 signaling pathways are involved in the multiple adverse effects of TNF-α on the lactose synthesis pathway.

  6. Wild bitter gourd protects against alcoholic fatty liver in mice by attenuating oxidative stress and inflammatory responses.

    PubMed

    Lu, Kuan-Hung; Tseng, Hui-Chun; Liu, Chun-Ting; Huang, Ching-Jang; Chyuan, Jong-Ho; Sheen, Lee-Yan

    2014-05-01

    Bitter gourd (Momordica charantia L.) is a common vegetable grown widely in Asia that is used as a traditional medicine. The objective of this study was to investigate whether wild bitter gourd possessed protective effects against chronic alcohol-induced liver injury in mice. C57BL/6 mice were fed an alcohol-containing liquid diet for 4 weeks to induce alcoholic fatty liver. Meanwhile, mice were treated with ethanol extracts from four different wild bitter gourd cultivars: Hualien No. 1', Hualien No. 2', Hualien No. 3' and Hualien No. 4'. The results indicated that the daily administration of 500 mg kg body weight(-1) of a Hualien No. 3' extract (H3E) or a Hualien No. 4' extract (H4E) markedly reduced the steatotic alternation of liver histopathology. In addition, the activation of serum aminotransferases (AST and ALT) and the accumulation of hepatic TG content caused by alcohol were ameliorated. The hepatoprotective effects of H3E and H4E involved the enhancement of the antioxidant defence system (GSH, GPx, GRd, CAT and SOD), inhibition of lipid peroxidation (MDA) and reduction of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in the liver. Moreover, H3E and H4E supplementation suppressed the alcohol-induced elevation of CYP2E1, SREBP-1, FAS and ACC protein expression. These results demonstrated that ethanol extracts of Hualien No. 3' and Hualien No. 4' have beneficial effects against alcoholic fatty liver, in which they attenuate oxidative stress and inflammatory responses.

  7. Gingerol protects against experimental liver fibrosis in rats via suppression of pro-inflammatory and profibrogenic mediators.

    PubMed

    Algandaby, Mardi M; El-Halawany, Ali M; Abdallah, Hossam M; Alahdal, Abdulrahman M; Nagy, Ayman A; Ashour, Osama M; Abdel-Naim, Ashraf B

    2016-04-01

    6-Gingerol (Gin) is known to possess hepatoprotective effects. Liver fibrosis is a major health concern that results in significant morbidity and mortality. There is no FDA-approved medication for liver fibrosis. The present work aimed at exploring the beneficial effects of Gin against liver fibrosis in rats. Experimental fibrosis was induced by challenging animals with CCl4 for 6 weeks. Gin significantly ameliorated the increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, albumin, total cholesterol (TC) and triglyceride (TG) concentrations, and liver index. These effects were confirmed by light and electron microscopic examinations. The antifibrotic effects were confirmed by examining Masson trichrome-stained liver sections which indicated reduced collagen deposition in Gin-treated animals. Further, Gin administration hampered alpha-smooth muscle actin (α-SMA) expression and significantly reduced hepatic content of transforming growth factor-beta (TGF-β). Also, Gin elicited profound antioxidant actions as indicated by preventing reduced glutathione (GSH) depletion and lipid peroxide accumulation. The observed antifibrotic activities involved decreased production of nuclear factor κB (NF-κB), tumor necrosis factor alpha (TNF-α), expression of toll-like receptor 4 (TLR4), intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM). Involvement of Gin anti-inflammatory activity was verified by the decreased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in livers of animals treated with Gin. Thus, it can be concluded that Gin protects against CCl4-induced liver fibrosis in rats. This can be ascribed, at least partly, to its antioxidant, anti-inflammatory effects as well as the inhibition of NF-κB/TLR-4 expression.

  8. Inflammatory and fibrotic processes are involved in the cardiotoxic effect of sunitinib: Protective role of L-carnitine.

    PubMed

    Blanca, Antonio J; Ruiz-Armenta, María V; Zambrano, Sonia; Miguel-Carrasco, José L; Arias, José L; Arévalo, Miguel; Mate, Alfonso; Aramburu, Oscar; Vázquez, Carmen M

    2016-01-22

    Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of l-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400mg LC/kg/day; (3) rats treated with 25mg Su/kg/day; and (4) rats treated with LC+Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-κB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-κB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co-administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-κB inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-κB; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment.

  9. Oral azathioprine leads to higher incorporation of 6-thioguanine in DNA of skin than liver: the protective role of the Keap1/Nrf2/ARE pathway.

    PubMed

    Kalra, Sukirti; Zhang, Ying; Knatko, Elena V; Finlayson, Stewart; Yamamoto, Masayuki; Dinkova-Kostova, Albena T

    2011-10-01

    Azathioprine is a widely used anti-inflammatory, immunosuppressive, and anticancer agent. However, chronic treatment with this drug is associated with a profoundly increased risk (in certain cases by more than 100-fold) of developing squamous cell carcinoma of the skin. Incorporation of its ultimate metabolite, thio-dGTP, in DNA results in partial substitution of guanine with 6-thioguanine which, combined with exposure to UVA radiation, creates a source of synergistic mutagenic damage to DNA. We now report that oral treatment with azathioprine leads to a much greater incorporation of 6-thioguanine in DNA of mouse skin than liver. These higher levels of 6-thioguanine, together with the fact that the skin is constantly exposed to UV radiation from the sun, may be responsible, at least in part, for the increased susceptibility of this organ to tumor development. Genetic upregulation of the Keap1/Nrf2/ARE pathway, a major cellular regulator of the expression of a network of cytoprotective genes, reduces the incorporation of 6-thioguanine in DNA of both skin and liver following treatment with azathioprine. Similarly, pharmacologic activation of the pathway by the potent inducer sulforaphane results in lower 6-thioguanine incorporation in DNA and protects 6-thioguanine-treated cells against oxidative stress following exposure to UVA radiation. Protection is accompanied by increased levels of glutathione and induction of multidrug resistance-associated protein 4, an organic anion efflux pump that also exports nucleoside monophosphate analogues. Our findings suggest that activation of the Keap1/Nrf2/ARE pathway could reduce the risk for skin cancer in patients receiving long-term azathioprine therapy.

  10. Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway

    PubMed Central

    Kalra, Sukirti; Zhang, Ying; Knatko, Elena V.; Finlayson, Stewart; Yamamoto, Masayuki; Dinkova-Kostova, Albena T.

    2011-01-01

    Azathioprine is a widely used anti-inflammatory, immunosuppressive, and anticancer agent. However, chronic treatment with this drug is associated with a profoundly increased risk (in certain cases by more than 100-fold) of developing squamous cell carcinoma of the skin. Incorporation of its ultimate metabolite, thio-dGTP, in DNA results in partial substitution of guanine with 6-thioguanine which, combined with exposure to ultraviolet A (UVA) radiation, creates a source of synergistic mutagenic damage to DNA. We now report that oral treatment with azathioprine leads to a much greater incorporation of 6-thioguanine in DNA of mouse skin than liver. These higher levels of 6-thioguanine, together with the fact that the skin is constantly exposed to UV radiation from the sun, may be responsible, at least in part, for the increased susceptibility of this organ to tumor development. Genetic upregulation of the Keap1/Nrf2/ARE pathway, a major cellular regulator of the expression of a network of cytoprotective genes, reduces the incorporation of 6-thioguanine in DNA of both skin and liver following treatment with azathioprine. Similarly, pharmacological activation of the pathway by the potent inducer sulforaphane results in lower 6-thioguanine incorporation in DNA, and protects 6-thioguanine-treated cells against oxidative stress following exposure to UVA radiation. Protection is accompanied by increased levels of glutathione and induction of multidrug resistance-associated protein 4 (MRP4), an organic anion efflux pump that also exports nucleoside monophosphate analogues. Our findings suggest that activation of the Keap1/Nrf2/ARE pathway could reduce the risk for skin cancer in patients receiving long-term azathioprine therapy. PMID:21803983

  11. Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

    PubMed Central

    Tao, Min; Liu, Lu; Shen, Meng; Zhi, Qiaoming; Gong, Fei-Ran; Zhou, Binhua P.; Wu, Yadi; Liu, Haiyan; Chen, Kai; Shen, Bairong; Wu, Meng-Yao; Shou, Liu-Mei; Li, Wei

    2016-01-01

    ABSTRACT Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Acα and PP2Acβ isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-κB (NF-κB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Acα overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-κB pathway in vitro. LPS and MCM induced IKK and IκB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKα attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-κB pathway–dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-κB–dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-κB pathway–dependent PP2Ac repression. PMID:26761431

  12. Immunobiotic Lactobacillus jensenii elicits anti-inflammatory activity in porcine intestinal epithelial cells by modulating negative regulators of the Toll-like receptor signaling pathway.

    PubMed

    Shimazu, Tomoyuki; Villena, Julio; Tohno, Masanori; Fujie, Hitomi; Hosoya, Shoichi; Shimosato, Takeshi; Aso, Hisashi; Suda, Yoshihito; Kawai, Yasushi; Saito, Tadao; Makino, Seiya; Ikegami, Shuji; Itoh, Hiroyuki; Kitazawa, Haruki

    2012-01-01

    The effect of Lactobacillus jensenii TL2937 on the inflammatory immune response triggered by enterotoxigenic Escherichia coli (ETEC) and lipopolysaccharide (LPS) in a porcine intestinal epitheliocyte cell line (PIE cells) was evaluated. Challenges with ETEC or LPS elicited Toll-like receptor 4 (TLR4)-mediated inflammatory responses in cultured PIE cells, indicating that our cell line may be useful for studying inflammation in the guts of weaning piglets. In addition, we demonstrated that L. jensenii TL2937 attenuated the expression of proinflammatory cytokines and chemokines caused by ETEC or LPS challenge by downregulating TLR4-dependent nuclear factorκB (NF-κB) and mitogen-activated protein kinase (MAPK) activation. Furthermore, we demonstrated that L. jensenii TL2937 stimulation of PIE cells upregulated three negative regulators of TLRs: A20, Bcl-3, and MKP-1, deepening the understanding of an immunobiotic mechanism of action. L. jensenii TL2937-mediated induction of negative regulators of TLRs would have a substantial physiological impact on homeostasis in PIE cells, because excessive TLR inflammatory signaling would be downregulated. These results indicated that PIE cells can be used to study the mechanisms involved in the protective activity of immunobiotics against intestinal inflammatory damage and may provide useful information for the development of new immunologically functional feeds that help to prevent inflammatory intestinal disorders, including weaning-associated intestinal inflammation.

  13. Role of Genetic Polymorphisms in NFKB-Mediated Inflammatory Pathways in Response to Primary Chemoradiation Therapy for Rectal Cancer

    SciTech Connect

    Dzhugashvili, Maia; Luengo-Gil, Ginés; García, Teresa; González-Conejero, Rocío; Conesa-Zamora, Pablo; Escolar, Pedro Pablo; Calvo, Felipe; Vicente, Vicente; Ayala de la Peña, Francisco

    2014-11-01

    Purpose: To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Methods and Materials: Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. Results: The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95% confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Conclusions: Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment.

  14. Peroxiredoxin IV regulates pro-inflammatory responses in large yellow croaker (Pseudosciaena crocea) and protects against bacterial challenge.

    PubMed

    Yu, Suhong; Mu, Yinnan; Ao, Jingqun; Chen, Xinhua

    2010-03-05

    In this study, we applied a comparative proteomic approach to the analysis of differentially expressed proteins in the spleens of large yellow croaker following treatment with an inactivated trivalent bacterial vaccine. Twenty-four altered proteins were identified by MALDI-TOF or MALDI-TOF-TOF, including immune-related proteins, antioxidant proteins, signal transducers, protein biosynthesis and catabolism modulators, and carbonic anhydrases. Three Prx family members, namely, Prx I, Prx II, and Prx IV, were upregulated after treatment with the vaccine, indicating potentially important roles for these antioxidant proteins in the antibacterial immune response. Large yellow croaker Prx IV (LycPrxIV), which has thiol-dependent peroxidase activity, was constitutively expressed in all tissues examined. Immunoelectron microscopy showed that LycPrxIV was primarily localized to the rER or peroxisome in spleen cells of healthy fish, and its synthesis on the rER increased following treatment with bacterial vaccine. Suppression of LycPrxIV by siRNA resulted in an increase in NF-kappaB activity in spleen tissues, while in vivo administration of recombinant LycPrxIV (rLycPrxIV) caused a decrease in NF-kappaB activity, indicating that LycPrxIV negatively regulates NF-kappaB activation. Likewise, siRNA-mediated knockdown of LycPrxIV increased the expression of TNF-alpha and CC chemokine, and downregulated the expression of IL-10. However, injection of fish with rLycPrxIV induced the opposite expression pattern of these cytokines, suggesting a role for LycPrxIV in regulating pro-inflammatory responses. Bacterial challenge experiments showed that suppression of LycPrxIV expression by siRNA significantly increased fish mortality as compared to controls, whereas rLycPrxIV provided a protective effect. Together, our data suggest that LycPrxIV may regulate pro-inflammatory responses to protect large yellow croaker from bacterial challenge, revealing a novel antibacterial mechanism in

  15. Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm?

    PubMed

    Ahmed, Asif; Ramma, Wenda

    2015-03-01

    Pre-eclampsia is a vascular disorder of pregnancy where anti-angiogenic factors, systemic inflammation and oxidative stress predominate, but none can claim to cause pre-eclampsia. This review provides an alternative to the 'two-stage model' of pre-eclampsia in which abnormal spiral arteries modification leads to placental hypoxia, oxidative stress and aberrant maternal systemic inflammation. Very high maternal soluble fms-like tyrosine kinase-1 (sFlt-1 also known as sVEGFR) and very low placenta growth factor (PlGF) are unique to pre-eclampsia; however, abnormal spiral arteries and excessive inflammation are also prevalent in other placental disorders. Metaphorically speaking, pregnancy can be viewed as a car with an accelerator and brakes, where inflammation, oxidative stress and an imbalance in the angiogenic milieu act as the 'accelerator'. The 'braking system' includes the protective pathways of haem oxygenase 1 (also referred as Hmox1 or HO-1) and cystathionine-γ-lyase (also known as CSE or Cth), which generate carbon monoxide (CO) and hydrogen sulphide (H2S) respectively. The failure in these pathways (brakes) results in the pregnancy going out of control and the system crashing. Put simply, pre-eclampsia is an accelerator-brake defect disorder. CO and H2S hold great promise because of their unique ability to suppress the anti-angiogenic factors sFlt-1 and soluble endoglin as well as to promote PlGF and endothelial NOS activity. The key to finding a cure lies in the identification of cheap, safe and effective drugs that induce the braking system to keep the pregnancy vehicle on track past the finishing line.

  16. ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway.

    PubMed

    Shan, Weiwei; Wang, Chao; Zhang, Zhenbo; Luo, Xuezhen; Ning, Chengcheng; Yu, Yinhua; Feng, Youji; Gu, Chao; Chen, Xiaojun

    2015-03-01

    The purpose of the study was to explore the role and mechanism of ataxia-telangiectasia mutated (ATM) protein in endometrial carcinogenesis. A reverse-phase protein array (RPPA) was used to analyze the expression of ATM signal pathway proteins in Ishikawa and progesterone-insensitive Ishikawa. ATM expression was detected in endometrium specimens by immunohistochemistry, including 8 cases with proliferative endometrium, 6 cases with secretory endometrium, 10 cases with simple hyperplasia (SH), 13 cases of complex hyperplasia (CH), 11 cases of endometrial atypical hyperplasia (EAH), and 83 cases with type I endometrial cancer. The relationship between ATM expression and other clinicopathological indicators was also examined in type I endometrial cancer patients. The mechanisms of ATM were explored in vitro with the endometrial cell lines Ishikawa and RL95-2. A cell counting kit-8 (CCK-8) test and Western blot analysis were performed to test proliferation and protein expression. Statistical analysis was performed with SPSS19.0. The significance level was set at 0.05. ATM was increased with medroxyprogesterone acetate (MPA) stimulation in Ishikawa in RPPA. ATM expression gradually decreased in endometrial hyperplasic lesions compared with the normal proliferative and secretory endometrium and was the lowest in type I endometrial cancer. ATM expression was negatively correlated with pathological grades in type I endometrial cancer. In vitro, ATM silencing retarded proliferation inhibition in Ishikawa and RL95-2 treated with MPA. ATM silencing could down-regulate the MPA-stimulated signal proteins, including Chk2, P53, and caspase-3 in vitro. MPA might exert its role through activating the ATM-associated pathway, ATM-Chk2-P53-caspase-3 (active), preserving normal endometrium and protecting it from malignancies. ATM might be a promising indicator for endometrial hyperplasia and cancer.

  17. Molecular hydrogen protects mice against polymicrobial sepsis by ameliorating endothelial dysfunction via an Nrf2/HO-1 signaling pathway.

    PubMed

    Chen, Hongguang; Xie, Keliang; Han, Huanzhi; Li, Yuan; Liu, Lingling; Yang, Tao; Yu, Yonghao

    2015-09-01

    Endothelial injury is a primary cause of sepsis and sepsis-induced organ damage. Heme oxygenase-1 (HO-1) plays an essential role in endothelial cellular defenses against inflammation by activating nuclear factor E2-related factor-2 (Nrf2). We found that molecular hydrogen (H2) exerts an anti-inflammatory effect. Here, we hypothesized that H2 attenuates endothelial injury and inflammation via an Nrf2-mediated HO-1 pathway during sepsis. First, we detected the effects of H2 on cell viability and cell apoptosis in human umbilical vein endothelial cells (HUVECs) stimulated by LPS. Then, we measured cell adhesion molecules and inflammatory factors in HUVECs stimulated by LPS and in a cecal ligation and puncture (CLP)-induced sepsis mouse model. Next, the role of Nrf2/HO-1 was investigated in activated HUVECs, as well as in wild-type and Nrf(-/-) mice with sepsis. We found that both 0.3 mmol/L and 0.6 mmol/L (i.e., saturated) H2-rich media improved cell viability and cell apoptosis in LPS-activated HUVECs and that 0.6mmol/L (i.e., saturated) H2-rich medium exerted an optimal effect. H2 could suppress the release of cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1), and pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and high-mobility group box 1 protein (HMGB1). Furthermore, H2 could elevate anti-inflammatory cytokine IL-10 levels in LPS-stimulated HUVECs and in lung tissue from CLP mice. H2 enhanced HO-1 expression and activity in vitro and in vivo. HO-1 inhibition reversed the regulatory effects of H2 on cell adhesion molecules and inflammatory factors. H2 regulated endothelial injury and the inflammatory response via Nrf2-mediated HO-1 levels. These results suggest that H2 could suppress excessive inflammatory responses and endothelial injury via an Nrf2/HO-1 pathway.

  18. EPO protects Müller cell under high glucose state through BDNF/TrkB pathway

    PubMed Central

    Wang, Ping; Xia, Fei

    2015-01-01

    Neurotrophic factor decreased in the early stage of diabetic retinal nerve cells. Neurons damage brain derived neurotrophic factor (BDNF) and receptor TrkB expression reduced. Erythropoietin (EPO) plays an important role in protecting early diabetic retinopathy. The rats were euthanized at 24 h after EPO vitreous injection and the retina was separated. HE staining was applied to observe the pathological tissue morphology. Immunohistochemistry, immunofluorescence, and Western blot were used to detect BDNF, TrkB, extracellular signal-regulated kinase (ERK), and glial fibrillary acidic portein (GFAP) expression. Retinal structure was clear in group C, while the retinal thickness and RGCs number decreased in group B at 24 w. Retinal thickness in group E was greater than in group B but lower than in group C. GFAP and ERK expression increased in both group B and E, whereas the latter was significantly lower than the former. TrkB protein level was in group E > B > C at 4 w, while it was in group C > group E > group B at 24 w. BDNF expression in group B was higher than in group C at 4 w, whereas it was opposite at 24 w. BDNF expression increased in group E at 4 w, and it was similar in group E compared with group C at 24 w. EPO vitreous injection can increase BDNF and TrkB expression, while reduce GFAP and ERK expression in diabetes rat retina. It could protect Müller cells through BDNF/TrkB pathway to play a role of nerve nutrition. PMID:26339375

  19. Glucosamine protects nucleus pulposus cells and induces autophagy via the mTOR-dependent pathway.

    PubMed

    Jiang, LiBo; Jin, YongLong; Wang, HuiRen; Jiang, YunQi; Dong, Jian

    2014-11-01

    Although glucosamine has been suggested to be effective in the treatment of osteoarthritis, its effect on disc degeneration remains unclear. We sought to explore whether glucosamine can activate autophagy in rat nucleus pulposus (NP) cells and protect cells treated with IL-1β or hydrogen peroxide (H2 O2 ). Autophagy in cells was examined by detecting for LC3, Beclin-1, m-TOR, and p70S6K, as well as by analyzing autophagosomes. To inhibit autophagy, 3-methyladenine (3-MA) was used. In the cells treated with IL-1β, the levels of Adamts-4, Mmp-13, aggrecan, and Col2a1 were analyzed by real-time PCR and immunofluorescence. Apoptosis was analyzed by TUNEL. Cell senescence under H2 O2 was revealed by SA-β-Gal staining. Glucosamine could activate autophagy in a dose-dependent manner within 24 h and inhibit the phosphorylation of m-TOR and p70S6K. Autophagy in IL-1β or H2 O2 -treated cells was increased by glucosamine. Glucosamine attenuated the decrease of aggrecan and prevented the apoptosis of the NP cells induced by IL-1β, whereas 3-MA partly reversed these effects. The percentage of SA-β-Gal-positive cells induced by H2 O2 treatment was decreased by glucosamine, accompanied by the decline of p70S6K phosphorylation. Glucosamine protects NP cells and up-regulates autophagy by inhibiting the m-TOR pathway, which might point a potential therapeutic agent for disc degeneration.

  20. EPO protects Müller cell under high glucose state through BDNF/TrkB pathway.

    PubMed

    Wang, Ping; Xia, Fei

    2015-01-01

    Neurotrophic factor decreased in the early stage of diabetic retinal nerve cells. Neurons damage brain derived neurotrophic factor (BDNF) and receptor TrkB expression reduced. Erythropoietin (EPO) plays an important role in protecting early diabetic retinopathy. The rats were euthanized at 24 h after EPO vitreous injection and the retina was separated. HE staining was applied to observe the pathological tissue morphology. Immunohistochemistry, immunofluorescence, and Western blot were used to detect BDNF, TrkB, extracellular signal-regulated kinase (ERK), and glial fibrillary acidic portein (GFAP) expression. Retinal structure was clear in group C, while the retinal thickness and RGCs number decreased in group B at 24 w. Retinal thickness in group E was greater than in group B but lower than in group C. GFAP and ERK expression increased in both group B and E, whereas the latter was significantly lower than the former. TrkB protein level was in group E > B > C at 4 w, while it was in group C > group E > group B at 24 w. BDNF expression in group B was higher than in group C at 4 w, whereas it was opposite at 24 w. BDNF expression increased in group E at 4 w, and it was similar in group E compared with group C at 24 w. EPO vitreous injection can increase BDNF and TrkB expression, while reduce GFAP and ERK expression in diabetes rat retina. It could protect Müller cells through BDNF/TrkB pathway to play a role of nerve nutrition.

  1. Naringenin Inhibits Superoxide Anion-Induced Inflammatory Pain: Role of Oxidative Stress, Cytokines, Nrf-2 and the NO−cGMP−PKG−KATPChannel Signaling Pathway

    PubMed Central

    Manchope, Marília F.; Calixto-Campos, Cássia; Coelho-Silva, Letícia; Zarpelon, Ana C.; Pinho-Ribeiro, Felipe A.; Georgetti, Sandra R.; Baracat, Marcela M.; Casagrande, Rúbia; Verri, Waldiceu A.

    2016-01-01

    In the present study, the effect and mechanism of action of the flavonoid naringenin were evaluated in superoxide anion donor (KO2)-induced inflammatory pain in mice. Naringenin reduced KO2-induced overt-pain like behavior, mechanical hyperalgesia, and thermal hyperalgesia. The analgesic effect of naringenin depended on the activation of the NO−cGMP−PKG−ATP-sensitive potassium channel (KATP) signaling pathway. Naringenin also reduced KO2-induced neutrophil recruitment (myeloperoxidase activity), tissue oxidative stress, and cytokine production. Furthermore, naringenin downregulated KO2-induced mRNA expression of gp91phox, cyclooxygenase (COX)-2, and preproendothelin-1. Besides, naringenin upregulated KO2-reduced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mRNA expression coupled with enhanced heme oxygenase (HO-1) mRNA expression. In conclusion, the present study demonstrates that the use of naringenin represents a potential therapeutic approach reducing superoxide anion-driven inflammatory pain. The antinociceptive, anti-inflammatory and antioxidant effects are mediated via activation of the NO−cGMP−PKG−KATP channel signaling involving the induction of Nrf2/HO-1 pathway. PMID:27045367

  2. Anti-inflammatory function of Withangulatin A by targeted inhibiting COX-2 expression via MAPK and NF-kappaB pathways.

    PubMed

    Sun, Lijuan; Liu, Jianwen; Cui, Daling; Li, Jiyu; Yu, Youjun; Ma, Lei; Hu, Lihong

    2010-02-15

    Withangulatin A (WA), an active component isolated from Physalis angulata L., has been reported to possess anti-tumor and trypanocidal activities in model systems via multiple biochemical mechanisms. The aim of this study is to investigate its anti-inflammatory potential and the possible underlying mechanisms. In the current study, WA significantly suppressed mice T lymphocytes proliferation stimulated with LPS in a dose- and time-dependent manner and inhibited pro-inflammation cytokines (IL-2, IFN-gamma, and IL-6) dramatically. Moreover, WA targeted inhibited COX-2 expression mediated by MAPKs and NF-kappaB nuclear translocation pathways in mice T lymphocytes, and this result was further confirmed by the COX-1/2 luciferase reporter assay. Intriguingly, administration of WA inhibited the extent of mice ear swelling and decreased pro-inflammatory cytokines production in mice blood serum. Based on these evidences, WA influences the mice T lymphocytes function through targeted inhibiting COX-2 expression via MAPKs and NF-kappaB nuclear translocation signaling pathways, and this would make WA a strong candidate for further study as an anti-inflammatory agent.

  3. Protective effects of pogostone against LPS-induced acute lung injury in mice via regulation of Keap1-Nrf2/NF-κB signaling pathways.

    PubMed

    Sun, Chao-Yue; Xu, Lie-Qiang; Zhang, Zhen-Biao; Chen, Chao-Hui; Huang, Yong-Zhong; Su, Zu-Qing; Guo, Hui-Zhen; Chen, Xiao-Ying; Zhang, Xie; Liu, Yu-Hong; Chen, Jian-Nan; Lai, Xiao-Ping; Li, Yu-Cui; Su, Zi-Ren

    2016-03-01

    Pogostone, a major component of Pogostemon cablin, has been demonstrated to possess antibacterial, anti-fungal, immunosuppressive and anti-inflammatory properties. To investigate the potential therapeutic effect of pogostone on lipopolysaccharide (LPS)-induced acute lung injury (ALI), mice were pretreated with pogostone prior to LPS exposure. After LPS challenge, the lungs were excised and the histological changes, wet to dry weight ratios, MPO activity reflecting neutrophil infiltration, and MDA activity reflecting oxidative stress were examined. The inflammatory cytokines in the BALF were determined by ELISA assay. Moreover, the expressions of p65 and phosphorylated p65 subunit of NF-κB, and Nrf2 in the nucleus in lung tissues were measured by Western blot analysis, and meanwhile the dependent genes of NF-κB and Nrf2 were assessed by RT-qPCR. The results showed that pretreatment with pogostone markedly improved survival rate, attenuated the histological alterations in the lung, reduced the MPO and MDA levels, decreased the wet/dry weight ratio of lungs, down-regulated the level of pro-inflammatory mediators including TNF-a, IL-1β and IL-6. Furthermore, pretreatment with pogostone enhanced the Nrf2 dependent genes including NQO-1, GCLC and HO-1 but suppressed NF-κB regulated genes including TNF-α, IL-1β and IL-6. The mechanism behind the protective effect was correlated with its regulation on the balance between Keap1-Nrf2 and NF-κB signaling pathways. Therefore, pogostone may be considered as a potential therapeutic agent for preventing and treating ALI.

  4. Hypertensive nephropathy treatment by heart-protecting musk pill: a study of anti-inflammatory therapy for target organ damage of hypertension

    PubMed Central

    Tian, Dengke; Ling, Shuang; Chen, Gangling; Li, Yajuan; Liu, Jun; Ferid, Murad; Bian, Ka

    2011-01-01

    This study was designed to investigate the protective effect of the heart-protecting musk pill (HMP) on inflammatory injury of kidney from spontaneously hypertensive rat (SHR). Male SHRs aged 4 weeks were divided into SHR model group, HMP low-dosage group (13.5 mg/kg), and HMP high-dosage group (40 mg/kg). Age-matched Wistar–Kyoto rats were used as normal control. All rats were killed at 12 weeks of age. Tail-cuff method and enzyme-linked immunosorbent assay were used to determine rat systolic blood pressure and angiotensin II (Ang II) contents, respectively. Renal inflammatory damage was evaluated by the following parameters: protein expressions of inflammatory cytokines, carbonyl protein contents, nitrite concentration, infiltration of monocytes/macrophages in interstitium and glomeruli, kidney pathological changes, and excretion rate of urinary protein. HMP did not prevent the development of hypertension in SHR. However, this Chinese medicinal compound decreased renal Ang II content. Consistent with the change of renal Ang II, all the parameters of renal inflammatory injury were significantly decreased by HMP. This study indicates that HMP is a potent suppressor of renal inflammatory damage in SHR, which may serve as a basis for the advanced preventive and therapeutic investigation of HMP in hypertensive nephropathy. PMID:21475627

  5. Friedelane-type triterpenoids as selective anti-inflammatory agents by regulation of differential signaling pathways in LPS-stimulated macrophages.

    PubMed

    Villar-Lorenzo, Andrea; Ardiles, Alejandro E; Arroba, Ana I; Hernández-Jiménez, Enrique; Pardo, Virginia; López-Collazo, Eduardo; Jiménez, Ignacio A; Bazzocchi, Isabel L; González-Rodríguez, Águeda; Valverde, Ángela M

    2016-12-15

    A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB). Instead, C18 enhanced and prolonged nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased the expression of its target genes including hemeoxigenase 1 (HO1). C25 efficiently inhibited LPS-mediated phosphorylation of JNK, p38 and ERK, without affecting NFκB or Nrf2 signaling pathways. Both compounds reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1β (IL1β) proform, reflecting their ability to target the inflammasome. C25 also counteracted LPS effects on iNOS expression and pro-inflammatory cytokines mRNA levels in Bv-2 microglial cells. The anti-inflammatory effect of both compounds was also assessed in human macrophages. Our results suggest that triterpenoids C18 and C25 possess anti-inflammatory effects, which may be therapeutically relevant for diseases linked to inflammation.

  6. A glycoprotein from Porphyra yezoensis produces anti-inflammatory effects in liposaccharide-stimulated macrophages via the TLR4 signaling pathway.

    PubMed

    Shin, Eun-Soon; Hwang, Hye-Jung; Kim, In-Hye; Nam, Taek-Jeong

    2011-11-01

    The purpose of this study was to investigate the antioxidant and anti-inflammatory effects of a glycoprotein isolated from the alga Porphyra yezoensis in LPS-stimulated RAW 264.7 mouse macrophages. First, we extracted a novel material with antioxidant activity from P. yezoensis, confirmed by SDS-PAGE to be a glycoprotein, which we named P. yezoensis glycoprotein (PGP). PGP inhibited the production of NO and ROS and expression of iNOS, COX-2, TNF-α and IL-1β, which are involved in the pathogenesis of many inflammation-associated human diseases, including septic shock, hemorrhagic shock and rheumatoid arthritis. Next, we determined the mechanisms behind the antioxidant and anti-inflammatory activities of PGP. We focused on the Toll-like receptor 4 (TLR4) signaling pathway because it is well-known to induce the pro-inflammatory proteins that trigger MAPK and NF-κB activation in lipopolysaccharide (LPS)-induced oxidative events. PGP treatment reduced the formation of the TLR4-IRAK4 and TLR4-TRIF binding complexes in response to LPS. Moreover, it inhibited LPS-induced activation and nuclear translocation of NF-κB by abrogating IκB phosphorylation. PGP also suppressed the phosphorylation of ERK1/2 and JNK in a dose-dependent manner. These results suggest that PGP exerts its anti-inflammatory effects by modulating TLR4 signaling and thus inhibiting the activation of NF-κB and MAP kinases.

  7. Astragalin suppresses inflammatory responses via down-regulation of NF-κB signaling pathway in lipopolysaccharide-induced mastitis in a murine model.

    PubMed

    Li, Fengyang; Liang, Dejie; Yang, Zhengtao; Wang, Tiancheng; Wang, Wei; Song, Xiaojing; Guo, Mengyao; Zhou, Ershun; Li, Depeng; Cao, Yongguo; Zhang, Naisheng

    2013-10-01

    Mastitis is a prevalent and economic disease around the world and defined as infection and inflammation of the mammary gland. Astragalin, a bioactive component isolated from persimmon or Rosa agrestis, has been reported to have anti-inflammatory properties. To investigate the potential therapeutic effect of astragalin in mastitis, a murine model of mastitis was induced by administration of LPS in mammary gland. Astragalin was applied 1h before and 12h after LPS treatment. The results showed that astragalin attenuated the infiltration of inflammatory cells, the activity of myeloperoxidase (MPO) and the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in a dose-dependent manner. Additionally, Western blotting results showed that astragalin efficiently blunt decreased nuclear factor-kappaB (NF-κB) activation by inhibiting the degradation and phosphorylation of IκBα and the nuclear translocation of p65. These results suggested that astragalin exerts anti-inflammatory properties in LPS-mediated mastitis, possibly through inhibiting inhibition of the NF-κB signaling pathway, which mediates the expression of pro-inflammatory cytokines. Astragalin may be a potential therapeutic agent against mastitis.

  8. 2-Phenylnaphthalene Derivatives Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Mediators by Downregulating of MAPK/NF-κB Pathways in RAW 264.7 Macrophage Cells

    PubMed Central

    Chang, Chi-Fen; Liao, Kang-Chun; Chen, Chung-Hwan

    2017-01-01

    The anti-inflammatory pharmacological effect of eight 2-phenylnaphthalenes (PNAP-1−PNAP-8) on lipopolysaccharide (LPS)-induced RAW 264.7 (a mouse cell line) was investigated. Among them, 6,7-dihydroxy-2-(4′-hydroxyphenyl)naphthalene (PNAP-6) and 2-(4′-aminophenyl)-6,7-dimethoxynaphthalene (PNAP-8) exhibited the best anti-inflammatory activity in this study. PNAP-6 and PNAP-8 not only significantly decreased the expression of inducible nitric oxide synthase and cyclooxygenase-II, but also inhibited the production of nitric oxide, interleukin-6, and tumor necrosis factor-α in LPS stimulated cells. Moreover, PNAP-6 and PNAP-8 inhibited nuclear factor (NF)-κB activation by decreasing the degradation of IκB and nuclear translocation of NF-κB subunit (p65). In addition, PNAP-6 and PNAP-8 also attenuated the phosphorylation of ERK, p38, and JNK. These results suggest that PNAP-6 and PNAP-8 exert anti-inflammatory activities by down regulating NF-κB activation and the mitogen-activated protein kinase signaling pathway in LPS-stimulated Raw 264.7 cells. This is the first study demonstrating that PNAPs can inhibit LPS-induced pro-inflammatory mediators in macrophages cells. PMID:28060845

  9. Sub-seismic Deformation Prediction of Potential Pathways and Seismic Validation - The Joint Project PROTECT

    NASA Astrophysics Data System (ADS)

    Krawczyk, C. M.; Kolditz, O.

    2013-12-01

    The joint project PROTECT (PRediction Of deformation To Ensure Carbon Traps) aims to determine the existence and characteristics of sub-seismic structures that can potentially link deep reservoirs with the surface in the framework of CO2 underground storage. The research provides a new approach of assessing the long-term integrity of storage reservoirs. The objective is predicting and quantifying the distribution and the amount of sub-/seismic strain caused by fault movement in the proximity of a CO2 storage reservoir. The study is developing tools and workflows which will be tested at the CO2CRC Otway Project Site in the Otway Basin in south-western Victoria, Australia. For this purpose, we are building a geometrical kinematic 3-D model based on 2-D and 3-D seismic data that are provided by the Australian project partner, the CO2CRC Consortium. By retro-deforming the modeled subsurface faults in the inspected subsurface volume we can determine the accumulated sub-seismic deformation and thus the strain variation around the faults. Depending on lithology, the calculated strain magnitude and its orientation can be used as an indicator for fracture density. Furthermore, from the complete 3D strain tensor we can predict the orientation of fractures at sub-seismic scale. In areas where we have preliminary predicted critical deformation, we will acquire in November this year new near- surface, high resolution P- and S-wave 2-D seismic data in order to verify and calibrate our model results. Here, novel and parameter-based model building will especially benefit from extracting velocities and elastic parameters from VSP and other seismic data. Our goal is to obtain a better overview of possible fluid migration pathways and communication between reservoir and overburden. Thereby, we will provide a tool for prediction and adapted time-dependent monitoring strategies for subsurface storage in general including scientific visualization capabilities. Acknowledgement This work

  10. Potential Mechanisms underlying the Protective Effect of Pregnancy against Breast Cancer: A Focus on the IGF Pathway

    PubMed Central

    Katz, Tiffany A.

    2016-01-01

    A first full-term birth at an early age protects women against breast cancer by reducing lifetime risk by up to 50%. The underlying mechanism resulting in this protective effect remains unclear, but many avenues have been investigated, including lobular differentiation, cell fate, and stromal composition. A single pregnancy at an early age protects women for 30–40 years, and this long-term protection is likely regulated by a relatively stable yet still modifiable method, such as epigenetic reprograming. Long-lasting epigenetic modifications have been shown to be induced by pregnancy and to target the IGF pathway. Understanding how an early first full-term pregnancy protects against breast cancer and the role of epigenetic reprograming of the IGF system may aid in developing new preventative strategies for young healthy women in the future. PMID:27833901

  11. Potential Mechanisms underlying the Protective Effect of Pregnancy against Breast Cancer: A Focus on the IGF Pathway.

    PubMed

    Katz, Tiffany A

    2016-01-01

    A first full-term birth at an early age protects women against breast cancer by reducing lifetime risk by up to 50%. The underlying mechanism resulting in this protective effect remains unclear, but many avenues have been investigated, including lobular differentiation, cell fate, and stromal composition. A single pregnancy at an early age protects women for 30-40 years, and this long-term protection is likely regulated by a relatively stable yet still modifiable method, such as epigenetic reprograming. Long-lasting epigenetic modifications have been shown to be induced by pregnancy and to target the IGF pathway. Understanding how an early first full-term pregnancy protects against breast cancer and the role of epigenetic reprograming of the IGF system may aid in developing new preventative strategies for young healthy women in the future.

  12. Sodium Ferulate Protects against Angiotensin II-Induced Cardiac Hypertrophy in Mice by Regulating the MAPK/ERK and JNK Pathways

    PubMed Central

    Hu, Bo; Song, Jian-Tao; Ji, Xian-Fei; Liu, Zun-Qi; Cong, Mu-Lin

    2017-01-01

    Background and Objective. It has been reported that sodium ferulate (SF) has hematopoietic function against anemia and immune regulation, inflammatory reaction inhibition, inhibition of tumor cell proliferation, cardiovascular and cerebrovascular protection, and other functions. Thus, this study aimed to investigate the effects of SF on angiotensin II- (AngII-) induced cardiac hypertrophy in mice through the MAPK/ERK and JNK signaling pathways. Methods. Seventy-two male C57BL/6J mice were selected and divided into 6 groups: control group, PBS group, model group (AngII), model + low-dose SF group (AngII + 10 mg/kg SF), model + high-dose SF group (AngII + 40 mg/kg SF), and model + high-dose SF + agonist group (AngII + 40 mg/kg SCU + 10 mg/kg TBHQ). After 7 d/14 d/28 days of treatments, the changes of blood pressure and heart rates of mice were compared. The morphology of myocardial tissue and the apoptosis rate of myocardial cells were observed. The mRNA and protein expressions of atrial natriuretic peptide (ANP), transforming growth factor-β (TGF-β), collagen III (Col III), and MAPK/ERK and JNK pathway-related proteins were detected after 28 days of treatments. Results. SF improved the mice's cardiac abnormality and decreased the apoptosis rate of myocardial cells in a time- and dose-dependent manner (all P < 0.05). MAPK/ERK pathway activator inhibited the protective effect of SF in myocardial tissue of mice (P < 0.05). SF could inhibit the expression of p-ERK, p-p38MAPK, and p-JNK and regulate the expressions of ANP, TGF-β, and Col III (all P < 0.05). Conclusion. Our findings provide evidence that SF could protect against AngII-induced cardiac hypertrophy in mice by downregulating the MAPK/ERK and JNK pathways. PMID:28164119

  13. Autophagy protects intestinal epithelial cells against deoxynivalenol toxicity by alleviating oxidative stress via IKK signaling pathway.

    PubMed

    Tang, Yulong; Li, Jianjun; Li, Fengna; Hu, Chien-An A; Liao, Peng; Tan, Kunrong; Tan, Bie; Xiong, Xia; Liu, Gang; Li, Tiejun; Yin, Yulong

    2015-12-01

    Autophagy is an intracellular process of homeostatic degradation that promotes cell survival under various stressors. Deoxynivalenol (DON), a fungal toxin, often causes diarrhea and disturbs the homeostasis of the intestinal system. To investigate the function of intestinal autophagy in response to DON and associated mechanisms, we firstly knocked out ATG5 (autophagy-related gene 5) in porcine intestinal epithelial cells (IPEC-J2) using CRISPR-Cas9 technology. When treated with DON, autophagy was induced in IPEC-J2 cells but not in IPEC-J2.Atg5ko cells. The deficiency in autophagy increased DON-induced apoptosis in IPEC-J2.atg5ko cells, in part, through the generation of reactive oxygen species (ROS). The cellular stress response can be restored in IPEC-J2.atg5ko cells by overexpressing proteins involved in protein folding. Interestingly, we found that autophagy deficiency downregulated the expression of endoplasmic reticulum folding proteins BiP and PDI when IPEC-J2.atg5ko cells were treated with DON. In addition, we investigated the molecular mechanism of autophagy involved in the IKK, AMPK, and mTOR signaling pathway and found that Bay-117082 and Compound C, specific inhibitors for IKK and AMPK, respectively, inhibited the induction of autophagy. Taken together, our results suggest that autophagy is pivotal for protection against DON in pig intestinal cells.

  14. The Protective Effect of Gangliosides on Lead (Pb)-Induced Neurotoxicity Is Mediated by Autophagic Pathways.

    PubMed

    Meng, Hongtao; Wang, Lan; He, Junhong; Wang, Zhufeng

    2016-03-25

    Lead (Pb) is a ubiquitous environmental and industrial pollutant and can affect intelligence development and the learning ability and memory of children. Therefore, necessary measures should be taken to protect the central nervous system (CNS) from Pb toxicity. Gangliosides are sialic acid-containing glycosphingolipids that are constituents of mammalian cell membranes and are more abundantly expressed in the CNS. Studies have shown that gangliosides constitute a useful tool in the attempt to promote functional recovery of CNS and can reverse Pb-induced impairments of synaptic plasticity in rats. However, the detailed mechanisms have yet to be fully understood. In our present study, we tried to investigate the role of gangliosides in Pb-induced injury in hippocampus neurons and to further confirm the detailed mechanism. Our results show that Pb-induced injuries in the spatial reference memory were associated with a reduction of cell viability and cell apoptosis, and treatment with gangliosides markedly ameliorated the Pb-induced injury by inhibition of apoptosis action. Gangliosides further attenuated Pb-induced the abnormal autophagic process by regulation of mTOR pathways. In summary, our study establishes the efficacy of gangliosides as neuroprotective agents and provides a strong rationale for further studies on the underlying mechanisms of their neuroprotective functions.

  15. Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways.

    PubMed

    Roth, W; Kermer, P; Krajewska, M; Welsh, K; Davis, S; Krajewski, S; Reed, J C

    2003-10-01

    The bifunctional apoptosis regulator (BAR) is a multidomain protein that was originally identified as an inhibitor of Bax-induced apoptosis. Immunoblot analysis of normal human tissues demonstrated high BAR expression in the brain, compared to low or absent expression in other organs. Immunohistochemical staining of human adult tissues revealed that the BAR protein is predominantly expressed by neurons in the central nervous system. Immunofluorescence microscopy indicated that BAR localizes mainly to the endoplasmic reticulum (ER) of cells. Overexpression of BAR in CSM 14.1 neuronal cells resulted in significant protection from a broad range of cell death stimuli, including agents that activate apoptotic pathways involving mitochondria, TNF-family death receptors, and ER stress. Downregulation of BAR by antisense oligonucleotides sensitized neuronal cells to induction of apoptosis. Moreover, the search for novel interaction partners of BAR identified several candidate proteins that might contribute to the regulation of neuronal apoptosis (HIP1, Hippi, and Bap31). Taken together, the expression pattern and functional data suggest that the BAR protein is involved in the regulation of neuronal survival.

  16. Schisandra Lignan Extract Protects against Carbon Tetrachloride-Induced Liver Injury in Mice by Inhibiting Oxidative Stress and Regulating the NF-κB and JNK Signaling Pathways

    PubMed Central

    Chen, Qingshan; Zhan, Qi; Li, Ying; Sun, Sen; Zhao, Liang

    2017-01-01

    Schisandra chinensis (S. chinensis) is a traditional Chinese herbal medicine widely used for the treatment of liver disease, whose main active components are lignans. However, the action mechanisms of the lignans in S. chinensis remain unclear. This study aimed to investigate the protective effect and related molecular mechanism of Schisandra lignan extract (SLE) against carbon tetrachloride- (CCl4-) induced acute liver injury in mice. Different doses of SLE at 50, 100, and 200 mg/kg were administered daily by gavage for 5 days before CCl4 treatment. The results showed that SLE significantly decreased the activities of serum ALT/AST and reduced liver pathologic changes induced by CCl4. Pretreatment with SLE not only decreased the content of MDA but increased SOD, GSH, and GSH-Px activities in the liver, suggesting that SLE attenuated CCl4-induced oxidative stress. The expression levels of inflammatory cytokines TNF-a, IL-1β, and IL-6 were decreased after oral administration of SLE, probably because lignans inhibited the NF-κB activity. Additionally, SLE also inhibited hepatocyte apoptosis by suppressing JNK activation and regulating Bcl-2/Bax signaling pathways. In conclusion, these results suggested that SLE prevented CCl4-induced liver injury through a combination of antioxidative stress, anti-inflammation, and antihepatocyte apoptosis and alleviated inflammation and apoptosis by regulating the NF-κB, JNK, and Bcl-2/Bax signaling pathways. PMID:28246539

  17. Host cell-induced components of the sulfate assimilation pathway are major protective antigens of Mycobacterium tuberculosis.

    PubMed

    Pinto, Rachel; Leotta, Lisa; Shanahan, Erin R; West, Nicholas P; Leyh, Thomas S; Britton, Warwick; Triccas, James A

    2013-03-01

    New therapies to control tuberculosis are urgently required because of the inability of the only available vaccine, BCG, to adequately protect against tuberculosis. Here we demonstrate that proteins of the Mycobacterium tuberculosis sulfate-assimilation pathway (SAP) represent major immunogenic targets of the bacillus, as defined by strong T-cell recognition by both mice and humans infected with M. tuberculosis. SAP proteins displayed increased expression when M. tuberculosis was resident within host cells, which may account in part for their ability to stimulate anti-M. tuberculosis host immunity. Vaccination with the first enzyme in this pathway, adenosine-5'-triphosphate sulfurylase, conferred significant protection against murine tuberculosis and boosted BCG-induced protective immunity in the lung. Therefore, we have identified SAP components as a new family of M. tuberculosis antigens, and we have demonstrated that these components are promising candidate for inclusion in new vaccines to control tuberculosis in humans.

  18. Host Cell–Induced Components of the Sulfate Assimilation Pathway Are Major Protective Antigens of Mycobacterium tuberculosis

    PubMed Central

    Pinto, Rachel; Leotta, Lisa; Shanahan, Erin R.; West, Nicholas P.; Leyh, Thomas S.; Britton, Warwick; Triccas, James A.

    2013-01-01

    New therapies to control tuberculosis are urgently required because of the inability of the only available vaccine, BCG, to adequately protect against tuberculosis. Here we demonstrate that proteins of the Mycobacterium tuberculosis sulfate-assimilation pathway (SAP) represent major immunogenic targets of the bacillus, as defined by strong T-cell recognition by both mice and humans infected with M. tuberculosis. SAP proteins displayed increased expression when M. tuberculosis was resident within host cells, which may account in part for their ability to stimulate anti-M. tuberculosis host immunity. Vaccination with the first enzyme in this pathway, adenosine-5′-triphosphate sulfurylase, conferred significant protection against murine tuberculosis and boosted BCG-induced protective immunity in the lung. Therefore, we have identified SAP components as a new family of M. tuberculosis antigens, and we have demonstrated that these components are promising candidate for inclusion in new vaccines to control tuberculosis in humans. PMID:23225904

  19. Carvacrol protects neuroblastoma SH-SY5Y cells against Fe2+-induced apoptosis by suppressing activation of MAPK/JNK-NF-κB signaling pathway

    PubMed Central

    Cui, Zhen-wen; Xie, Zheng-xing; Wang, Bao-feng; Zhong, Zhi-hong; Chen, Xiao-yan; Sun, Yu-hao; Sun, Qing-fang; Yang, Guo-yuan; Bian, Liu-guan

    2015-01-01

    Aim: Carvacrol (2-methyl-5-isopropylphenol), a phenolic monoterpene in the essential oils of the genera Origanum and Thymus, has been shown to exert a variety of therapeutic effects. Here we examined whether carvacrol protected neuroblastoma SH-SY5Y cells against Fe2+-induced apoptosis and explored the underlying mechanisms. Methods: Neuroblastoma SH-SY5Y cells were incubated with Fe2+ for 24 h, and the cell viability was assessed with CCK-8 assay. TUNEL assay and flow cytometric analysis were performed to evaluate cell apoptosis. The mRNA levels of pro-inflammatory cytokines and NF-κB p65 were determined using qPCR. The expression of relevant proteins was determined using Western blot analysis or immunofluorescence staining. Results: Treatment of SH-SY5Y cells with Fe2+ (50–200 μmol/L) dose-dependently decreased the cell viability, which was significantly attenuated by pretreatment with carvacrol (164 and 333 μmol/L). Treatment with Fe2+ increased the Bax level and caspase-3 activity, and decreased the Bcl-2 level, resulting in cell apoptosis. Furthermore, treatment with Fe2+ significantly increased the gene expression of IL-1β, IL-6 and TNF-α, and induced the nuclear translocation of NF-κB. Treatment with Fe2+ also significantly increased the phosphorylation of p38, ERK, JNK and IKK in the cells. Pretreatment with carvacrol significantly inhibited Fe2+-induced activation of NF-κB, expression of the pro-inflammatory cytokines, and cell apoptosis. Moreover, pretreatment with carvacrol inhibited Fe2+-induced phosphorylation of JNK and IKK, but not p38 and ERK in the cells. Conclusion: Carvacrol protects neuroblastoma SH-SY5Y cells against Fe2+-induced apoptosis, which may result from suppressing the MAPK/JNK-NF-κB signaling pathways. PMID:26592517

  20. GBE50 Attenuates Inflammatory Response by Inhibiting the p38 MAPK and NF-κB Pathways in LPS-Stimulated Microglial Cells

    PubMed Central

    He, Gai-ying; Yuan, Chong-gang; Hao, Li; Xu, Ying; Zhang, Zhi-xiong

    2014-01-01

    Overactivated microglia contribute to a variety of pathological conditions in the central nervous system. The major goal of the present study is to evaluate the potential suppressing effects of a new type of Ginko biloba extract, GBE50, on activated microglia which causes proinflammatory responses and to explore the underlying molecular mechanisms. Murine BV2 microglia cells, with or without pretreatmentof GBE50 at various concentrations, were activated by incubation with lipopolysaccharide (LPS). A series of biochemical and microscopic assays were performed to measure cell viability, cell morphology, release of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and signal transduction via the p38 MAPK and nuclear factor-kappa B (NF-κB) p65 pathways. We found that GBE50 pretreatment suppressed LPS-induced morphological changes in BV2 cells. Moreover, GBE50 treatment significantly reduced the release of proinflammatory cytokines, TNF-α and IL-1β, and inhibited the associated signal transduction through the p38 MAPK and NF-κB p65 pathways. These results demonstrated the anti-inflammatory effect of GBE50 on LPS-activated BV2 microglia cells, and indicated that GBE50 reduced the LPS-induced proinflammatory TNF-α and IL-1β release by inhibiting signal transduction through the NF-κB p65 and p38 MAPK pathways. Our findings reveal, at least in part, the molecular basis underlying the anti-inflammatory effects of GBE50. PMID:24782908

  1. Intracellular Uptake of Curcumin-Loaded Solid Lipid Nanoparticles Exhibit Anti-Inflammatory Activities Superior to Those of Curcumin Through the NF-κB Signaling Pathway.

    PubMed

    Wang, Jiao; Zhu, Rongrong; Sun, Dongmei; Sun, Xiaoyu; Geng, Zhengsong; Liu, Hui; Wang, Shi-Long

    2015-03-01

    Curcumin (Cur) is a naturally derived, novel anti-inflammatory agent, but its poor solubility limits its clinical use. The aim of the present study was to encapsulate Cur into solid lipid nanoparticles (SLNs) to improve its anti-inflammatory activity. The Cur-loaded SLNs (Cur-SLNs) were prepared using emulsification and low-temperature solidification methods. In contrast to free Cur, the particles were well dispersed in aqueous medium, showing a narrow size distribution with a range of 55 : 1.2 nm, a zeta potential value of -26.2 ± 1.3 mV, and a high drug loading efficiency of 37% ± 2.5%. The sustained release of Cur was observed for up to 6 days. The particles displayed enhanced stability in phosphate-buffered saline by protecting the encapsulated Cur against hydrolysis and biotransformation, as well as increasing biocompatibility. Cur-SLNs were more effective than free Cur at reducing the expression levels of several pro- inflammatory mediators, including inflammatory cytokines (IL-6, TNF-α, and IL-1β) and nitric oxide (NO), under in vitro conditions. By Western blotting, we found that Cur-SLNs were more active than free Cur in inhibiting the LPS-induced activation of the inflammatory transcription factor NF-κB through the suppression of IκB kinase activation. Compared to free Cur, Cur-SLNs had an increased intracellular uptake over time (observed after 24 h) in RAW264.7 cells. Moreover, the Cur-SLNs (≥ 20 μM) significantly improved RAW264.7 cell viability by inhibiting apoptosis. Thus, these results demonstrated that SLNs could be used as potential anti-inflammatory drug carriers for the treatment of various chronic diseases.

  2. Raphanus sativus L. seeds prevent LPS-stimulated inflammatory response through negative regulation of the p38 MAPK-NF-κB pathway.

    PubMed

    Kook, Sung-Ho; Choi, Ki-Choon; Lee, Young-Hoon; Cho, Hyoung-Kwon; Lee, Jeong-Chae

    2014-12-01

    The seeds of Raphanus sativus L. (RSL) have long been used as anti-inflammatory traditional medicine. However, scientific bases for the purported potential of the medicine and the associated mechanisms were barely defined. This study investigated the effects of RSL seeds on lipopolysaccharide (LPS)-stimulated inflammatory responses in vitro and in vivo. Treatment with 100 μg/ml ethyl acetate fraction (REF), which was isolated from water extract of the seeds, significantly inhibited LPS-stimulated production of nitric oxide (P < 0.05), interleukin-6 (P < 0.001), and tumor necrosis factor (TNF)-α (P < 0.001) in RAW264.7 cells. Oral supplementation with 30 mg/kg REF protected mice by 90% against LPS-induced septic death and prevented the increases of serum TNF-α and interferon-γ levels in LPS-injected mice. When REF was divided into four sub-fractions (REF-F1-F4), REF-F3 showed the greatest activity to suppress LPS-stimulated production of inflammatory mediators. We subsequently isolated an active fraction from the REF-F3 and identified sinapic acid as the main constituent. The addition of 50 μg/ml active fraction markedly inhibited LPS-stimulated production of inflammatory mediators by suppressing p38 MAPK and nuclear factor-κB activation. Furthermore, supplementation with the active fraction (10 mg/kg) improved the survival rate of LPS-injected mice by 80% of the untreated control. Additional experiments revealed that sinapic acid was the active component responsible for the anti-inflammatory potential of RSL seeds. Collectively, our current results suggest that both RSL seeds and sinapic acid may be attractive materials for treating inflammatory disorders caused by endotoxins.

  3. Icariin inhibits TNF-α/IFN-γ induced inflammatory response via inhibition of the substance P and p38-MAPK signaling pathway in human keratinocytes.

    PubMed

    Kong, Lingwen; Liu, Jiaqi; Wang, Jia; Luo, Qingli; Zhang, Hongying; Liu, Baojun; Xu, Fei; Pang, Qi; Liu, Yingchao; Dong, Jingcheng

    2015-12-01

    Pro-inflammatory cytokines play a crucial role in the etiology of atopic dermatitis. We demonstrated that Herba Epimedii has anti-inflammatory potential in an atopic dermatitis mouse model; however, limited research has been conducted on the anti-inflammatory effects and mechanism of icariin, the major active ingredient in Herba Epimedii, in human keratinocytes. In this study, we evaluated the anti-inflammatory potential and mechanisms of icariin in the tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-induced inflammatory response in human keratinocytes (HaCaT cells) by observing these cells in the presence or absence of icariin. We measured IL-6, IL-8, IL-1β, MCP-1 and GRO-α production by ELISA; IL-6, IL-8, IL-1β, intercellular adhesion molecule-1 (ICAM-1) and tachykinin receptor 1 (TACR1) mRNA expression by real-time PCR; and P38-MAPK, P-ERK and P-JNK signaling expression by western blot in TNF-α/IFN-γ-stimulated HaCaT cells before and after icariin treatment. The expression of TNF-α-R1 and IFN-γ-R1 during the stimulation of the cell models was also evaluated before and after icariin treatment. We investigated the effect of icariin on these pro-inflammatory cytokines and detected whether this effect occurred via the mitogen-activated protein kinase (MAPK) signal transduction pathways. We further specifically inhibited the activity of two kinases with 20μM SB203580 (a p38 kinase inhibitor) and 50μM PD98059 (an ERK1/2 kinase inhibitor) to determine the roles of the two signal pathways involved in the inflammatory response. We found that icariin inhibited TNF-α/IFN-γ-induced IL-6, IL-8, IL-1β, and MCP-1 production in a dose-dependent manner; meanwhile, the icariin treatment inhibited the gene expression of IL-8, IL-1β, ICAM-1 and TACR1 in HaCaT cells in a time- and dose-dependent manner. Icariin treatment resulted in a reduced expression of p-P38 and p-ERK signal activation induced by TNF-α/IFN-γ; however, only SB203580, the p38 alpha

  4. Toll-like 4 receptor /NFκB inflammatory/miR-146a pathway contributes to the ART-correlated preterm birth outcome

    PubMed Central

    Liu, Peiwen; He, Wenzhi; Xiong, Zhongtang; Chang, Weijie; Zhu, Jiandong; Cui, Qiliang

    2016-01-01

    Assisted reproductive technology (ART) is widely used for the women with infertility conditions to achieve pregnancy. However, the adverse effects of ART may lead to poor perinatal and neonatal outcomes, e.g., preterm birth and low body weight. In this study, we investigated the inflammatory molecular factors and microRNA that might be involved in ART related preterm birth. We found the elevation of Toll-like 4 receptor (TLR4), activation of NFκB pathway and down-regulation of microRNA-146a (miR-146a), a negative regulator of NFκB, in the placenta of preterm birth and ART, indicating preterm birth and ART were associated with inflammation signaling activation. In vitro experiments demonstrated that miR-146a suppressed NFκB pathway and shifted the balance of cytokines in the cord blood toward a repertoire of pro-inflammatory outcomes by down-regulating IRAK1 and TRAF6. The pro-inflammatory cytokines IL-6, IFNγ and TNFα in the cord blood were highly expressed in the preterm and ART, while anti-inflammatory cytokine IL-10 was the lower in the preterm and ART. In summary, we firstly uncovered that TLR4/NFκB mediated inflammation signaling and miR-146a participated in ART-related preterm birth patients, which suggests that importance of TLR4/NFκB/miR-146a signaling in clinical interventions and biomarkers of ART-related perinatal or neonatal outcomes. PMID:27636999

  5. Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

    PubMed Central

    Ramasamy, Selvi; Saez, Borja; Mukhopadhyay, Subhankar; Ding, Daching; Ahmed, Alwiya M.; Chen, Xi; Pucci, Ferdinando; Yamin, Rae’e; Wang, Jianfeng; Pittet, Mikael J.; Kelleher, Cassandra M.; Scadden, David T.; Sweetser, David A.

    2016-01-01

    Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1Δ/Δ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression. PMID:26831087

  6. Anti-inflammatory effects of galangin on lipopolysaccharide-activated macrophages via ERK and NF-κB pathway regulation.

    PubMed

    Jung, Yun Chan; Kim, Mi Eun; Yoon, Ju Hwa; Park, Pu Reum; Youn, Hwa-Young; Lee, Hee-Woo; Lee, Jun Sik

    2014-12-01

    Inflammation is the major symptom of the innate immune response to microbial infection. Macrophages, immune response-related cells, play a role in the inflammatory response. Galangin is a member of the flavonols and is found in Alpinia officinarum, galangal root and propolis. Previous studies have demonstrated that galangin has antioxidant, anticancer, and antineoplastic activities. However, the anti-inflammatory effects of galangin are still unknown. In this study, we investigated the anti-inflammatory effects of galangin on RAW 264.7 murine macrophages. Galagin was not cytotoxic to RAW 264.7 cells, and nitric oxide (NO) production induced by lipopolysaccharide (LPS)-stimulated macrophages was significantly decreased by the addition of 50 μM galangin. Moreover, galangin treatment reduced mRNA levels of cytokines, including IL-1β and IL-6, and proinflammatory genes, such as iNOS in LPS-activated macrophages in a dose-dependent manner. Galangin treatment also decreased the protein expression levels of iNOS in activated macrophages. Galangin was found to elicit anti-inflammatory effects by inhibiting ERK and NF-κB-p65 phosphorylation. In addition, galangin-inhibited IL-1β production in LPS-activated macrophages. These results suggest that galangin elicits anti-inflammatory effects on LPS-activated macrophages via the inhibition of ERK, NF-κB-p65 and proinflammatory gene expression.

  7. Protective effect of thymoquinone improves cardiovascular function, and attenuates oxidative stress, inflammation and apoptosis by mediating the PI3K/Akt pathway in diabetic rats.

    PubMed

    Liu, Hui; Liu, Hong-Yang; Jiang, Yi-Nong; Li, Nan

    2016-03-01

    Thymoquinone is the main active monomer extracted from black cumin and has anti‑inflammatory, antioxidant and anti‑apoptotic functions. However, the protective effects of thymoquinone on cardiovascular function in diabetes remain to be fully elucidated. The present study aimed to investigate the molecular mechanisms underling the beneficial effects of thymoquinone on the cardiovascular function in streptozotocin‑induced diabetes mellitus (DM) rats. Supplement thymoquinone may recover the insulin levels and body weight, inhibit blood glucose levels and reduce the heart rate in DM‑induced rats. The results indicated that the heart, liver and lung to body weight ratios, in addition to the blood pressure levels, were similar for each experimental group. Treatment with thymoquinone significantly reduced oxidative stress damage, inhibited the increased endothelial nitric oxide synthase protein expression and suppressed the elevation of cyclooxygenase‑2 levels in DM‑induced rats. In addition, thymoquinone significantly suppressed the promotion of tumor necrosis factor‑α and interleukin‑6 levels in the DM‑induced rats. Furthermore, administration of thymoquinone significantly reduced caspase‑3 activity and the promotion of phosphorylated‑protein kinase B (Akt) protein expression levels in DM‑induced rats. These results suggest that the protective effect of thymoquinone improves cardiovascular function and attenuates oxidative stress, inflammation and apoptosis by mediating the phosphatidylinositol 3‑kinase/Akt pathway in DM‑induced rats.

  8. Citrulline Protects Streptococcus pyogenes from Acid Stress Using the Arginine Deiminase Pathway and the F1Fo-ATPase

    PubMed Central

    Cusumano, Zachary T.

    2015-01-01

    ABSTRACT A common stress encountered by both pathogenic and environmental bacteria is exposure to a low-pH environment, which can inhibit cell growth and lead to cell death. One major defense mechanism against this stress is the arginine deiminase (ADI) pathway, which catabolizes arginine to generate two ammonia molecules and one molecule of ATP. While this pathway typically relies on the utilization of arginine, citrulline has also been shown to enter into the pathway and contribute to protection against acid stress. In the pathogenic bacterium Streptococcus pyogenes, the utilization of citrulline has been demonstrated to contribute to pathogenesis in a murine model of soft tissue infection, although the mechanism underlying its role in infection is unknown. To gain insight into this question, we analyzed a panel of mutants defective in different steps in the ADI pathway to dissect how arginine and citrulline protect S. pyogenes in a low-pH environment. While protection provided by arginine utilization occurred through the buffering of the extracellular environment, citrulline catabolism protection was pH independent, requiring the generation of ATP via the ADI pathway and a functional F1Fo-ATP synthase. This work demonstrates that arginine and citrulline catabolism protect against acid stress through distinct mechanisms and have unique contributions to virulence during an infection. IMPORTANCE An important aspect of bacterial pathogenesis is the utilization of host-derived nutrients during an infection for growth and virulence. Previously published work from our lab identified a unique role for citrulline catabolism in Streptococcus pyogenes during a soft tissue infection. The present article probes the role of citrulline utilization during this infection and its contribution to protection against acid stress. This work reveals a unique and concerted action between the catabolism of citrulline and the F1Fo-ATPase that function together to provide protection for

  9. Aβ and Inflammatory Stimulus Activate Diverse Signaling Pathways in Monocytic Cells: Implications in Retaining Phagocytosis in Aβ-Laden Environment

    PubMed Central

    Savchenko, Ekaterina; Malm, Tarja; Konttinen, Henna; Hämäläinen, Riikka H.; Guerrero-Toro, Cindy; Wojciechowski, Sara; Giniatullin, Rashid; Koistinaho, Jari; Magga, Johanna

    2016-01-01

    Background: Accumulation of amyloid β (Aβ) is one of the main hallmarks of Alzheimer’s disease (AD). The enhancement of Aβ clearance may provide therapeutic means to restrict AD pathology. The cellular responses to different forms of Aβ in monocytic cells are poorly known. We aimed to study whether different forms of Aβ induce inflammatory responses in monocytic phagocytes and how Aβ may affect monocytic cell survival and function to retain phagocytosis in Aβ-laden environment. Methods: Monocytic cells were differentiated from bone marrow hematopoietic stem cells (HSC) in the presence of macrophage-colony stimulating factor. Monocytic cells were stimulated with synthetic Aβ42 and intracellular calcium responses were recorded with calcium imaging. The formation of reactive oxygen species (ROS), secretion of cytokines and cell viability were also assessed. Finally, monocytic cells were introduced to native Aβ deposits ex vivo and the cellular responses in terms of cell viability, pro-inflammatory activation and phagocytosis were determined. The ability of monocytic cells to phagocytose Aβ plaques was determined after intrahippocampal transplantation in vivo. Results: Freshly solubilized Aβ induced calcium oscillations, which persisted after removal of the stimulus. After few hours of aggregation, Aβ was not able to induce oscillations in monocytic cells. Instead, lipopolysaccharide (LPS) induced calcium responses divergent from Aβ-induced response. Furthermore, while LPS induced massive production of pro-inflammatory cytokines, neither synthetic Aβ species nor native Aβ deposits were able to induce pro-inflammatory activation of monocytic cells, contrary to primary microglia. Finally, monocytic cells retained their viability in the presence of Aβ and exhibited phagocytic activity towards native fibrillar Aβ deposits and congophilic Aβ plaques. Conclusion: Monocytic cells carry diverse cellular responses to Aβ and inflammatory stimulus LPS. Even

  10. Elevated cerebral cortical CD24 levels in patients and mice with traumatic brain injury: a potential negative role in nuclear factor κb/inflammatory factor pathway.

    PubMed

    Li, Wei; Ling, Hai-Ping; You, Wan-Chun; Liu, Huan-Dong; Sun, Qing; Zhou, Meng-Liang; Shen, Wei; Zhao, Jin-Bing; Zhu, Lin; Hang, Chun-Hua

    2014-02-01

    Increasing evidence indicates that sterile inflammatory response contributes to secondary brain injury following traumatic brain injury (TBI). However, the specific mechanisms remain largely unknown, as is whether CD24, known as an important regulator in the non-infectious inflammatory response, plays a role in secondary brain injury after TBI. Here, the expression of CD24 was detected in samples from patients with TBI by quantitative real-time polymerase chain reaction (PCR), western blotting, immunohistochemistry and immunofluorescence. RNA interference was used to investigate the effects of CD24 on inflammatory response in a mouse model of TBI. Nuclear factor kappa B (NF-κB) DNA-binding activity was measured by electrophoretic mobility shift assay, and the levels of downstream pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and Interleukin 1β (IL-1β) were detected by real-time PCR. The results indicated that both the mRNA and protein levels of CD24 were markedly elevated after TBI in humans and mice, showing a time-dependent expression. The expression of CD24 could be observed in neurons, astrocytes and microglia in both humans and mice. Meanwhile, downregulation of CD24 significantly induced an increase of NF-κB DNA-binding activity and mRNA levels of TNF-α and IL-1β. These findings indicated that CD24 expression could negatively regulate the NF-κB/inflammatory factor pathway after experimental TBI in mice, thus providing a novel target for therapeutic intervention of TBI.

  11. Anti-Inflammatory Activity of Bee Venom in BV2 Microglial Cells: Mediation of MyD88-Dependent NF-κB Signaling Pathway

    PubMed Central

    Kim, Su Jung; Hong, Seung Bok; Park, Jin-Kyu

    2016-01-01

    Bee venom has long been used as a traditional folk medicine in Korea. It has been reportedly used for the treatment of arthritis, cancer, and inflammation. Although its anti-inflammatory activity in lipopolysaccharide- (LPS-) stimulated inflammatory cells has been reported, the exact mechanism of its anti-inflammatory action has not been fully elucidated. Therefore, the aim of this study was to investigate the anti-inflammatory mechanism of bee venom in BV2 microglial cells. We first investigated whether NO production in LPS-activated BV2 cells was inhibited by bee venom, and further iNOS mRNA and protein expressions were determined. The mRNA and protein levels of proinflammatory cytokines were examined using semiquantitative RT-PCR and immunoblotting, respectively. Moreover, modulation of the transcription factor NF-κB by bee venom was also investigated using a luciferase assay. LPS-induced NO production in BV2 microglial cells was significantly inhibited in a concentration-dependent manner upon pretreatment with bee venom. Bee venom markedly reduced the mRNA expression of COX-2, TNF-α, IL-1β, and IL-6 and suppressed LPS-induced activation of MyD88 and IRAK1 and phosphorylation of TAK1. Moreover, NF-κB translocation by IKKα/β phosphorylation and subsequent IκB-α degradation were also attenuated. Thus, collectively, these results indicate that bee venom exerts its anti-inflammatory activity via the IRAK1/TAK1/NF-κB signaling pathway. PMID:27563334

  12. Protective Role of Curcumin and Flunixin Against Acetic Acid-Induced Inflammatory Bowel Disease via Modulating Inflammatory Mediators and Cytokine Profile in Rats.

    PubMed

    Gopu, Boobalan; Dileep, Rasakatla; Rani, Matukumalli Usha; Kumar, C S V Satish; Kumar, Matham Vijay; Reddy, Alla Gopala

    2015-01-01

    Ulcerative colitis is a chronically recurrent inflammatory bowel disease of unknown origin. The present study is to evaluate the effect of flunixin and curcumin in experimentally induced ulcerative colitis in rats. Animals were randomly divided into four groups, each consisting of 12 animals: normal control group, acetic acid group, curcumin-treated group, and flunixin-treated group. Induction of colitis by intracolonic administration of 4% acetic acid produced severe macroscopic inflammation in the colon, 14 days after acetic acid administration as assessed by the colonic damage score. Microscopically, colonic tissues showed ulceration, edema, and inflammatory cells infiltration. Biochemical studies revealed increased serum levels of lactate dehydrogenase (LDH), colonic alkaline phosphatase (ALP), and myeloperoxidase (MPO). Oxidative stress was indicated by elevated lipid peroxide formation and depleted reduced glutathione concentrations in colonic tissues. After induction of colitis, treatment with curcumin (50 mg/kg daily, p.o.) and flunixin (2.5 mg/kg daily, s.c.) decreased serum LDH, ALP, interleukin (IL)-1β, and tumor necrosis factor-α levels, as well as colonic MPO and lipid peroxide levels, whereas increased colonic prostaglandin E2 and IL-10 concentrations were observed. Moreover, effective doses of curcumin and flunixin were effective in restoring the histopathological changes induced by acetic acid administration. The findings of the present study provide evidence that flunixin may be beneficial in patients with inflammatory bowel disease.

  13. C-Phycocyanin protects against acute tributyltin chloride neurotoxicity by modulating glial cell activity along with its anti-oxidant and anti-inflammatory property: A comparative efficacy evaluation with N-acetyl cysteine in adult rat brain.

    PubMed

    Mitra, Sumonto; Siddiqui, Waseem A; Khandelwal, Shashi

    2015-08-05

    Spirulina is a widely used health supplement and is a dietary source of C-Phycocyanin (CPC), a potent anti-oxidant. We have previously reported the neurotoxic potential of tributyltin chloride (TBTC), an environmental pollutant and potent biocide. In this study, we have evaluated the protective efficacy of CPC against TBTC induced neurotoxicity. To evaluate the extent of neuroprotection offered by CPC, its efficacy was compared with the degree of protection offered by N-acetylcysteine (NAC) (a well known neuroprotective drug, taken as a positive control). Male Wistar rats (28 day old) were administered with 20mg/kg TBTC (oral) and 50mg/kg CPC or 50mg/kg NAC (i.p.), alone or in combination, and various parameters were evaluated. These include blood-brain barrier (BBB) damage; redox parameters (ROS, GSH, redox pathway associated enzymes, oxidative stress markers); inflammatory, cellular, and stress markers; apoptotic proteins and in situ cell death assay (TUNEL). We observed increased CPC availability in cortical tissue following its administration. Although BBB associated proteins like claudin-5, p-glycoprotein and ZO-1 were restored, CPC/NAC failed to protect against TBTC induced overall BBB permeability (Evans blue extravasation). Both CPC and NAC remarkably reduced oxidative stress and inflammation. NAC effectively modulated redox pathway associated enzymes whereas CPC countered ROS levels efficiently. Interestingly, CPC and NAC were equivalently capable of reducing apoptotic markers, astroglial activation and cell death. This study illustrates the various pathways involved in CPC mediated neuroprotection against this environmental neurotoxicant and highlights its capability to modulate glial cell activity.

  14. Resveratrol preconditioning protects hepatocytes against hepatic ischemia reperfusion injury via Toll-like receptor 4/nuclear factor-κB signaling pathway in vitro and in vivo.

    PubMed

    He, Diao; Guo, Zhen; Pu, Jun-Liang; Zheng, Dao-Feng; Wei, Xu-Fu; Liu, Rui; Tang, Cheng-Yong; Wu, Zhong-Jun

    2016-06-01

    The purpose of this study was to investigate the protective effect of resveratrol against hepatic ischemia reperfusion injury (HIRI) and explore the potential underlying mechanism. Resveratrol-pretreated BRL-3A (rat liver) cells and rats underwent hypoxia/reoxygenation and hepatic ischemia/reperfusion, respectively. BRL-3A cell damage was evaluated, and the mRNA and protein expression of related signal molecules was assessed in cell model. The protein expression of related signal molecules was also assessed in rat model. Inflammatory cytokines levels were determined in the cell supernatant and rat serum while rat liver function and hepatocyte apoptosis were assessed. The results revealed that resveratrol significantly enhanced cell viability, inhibited cell apoptosis, and decreased levels of lactate dehydrogenase (LDH) and production of tumor necrosis factor-α (TNF-α) and interleukin-(IL)-1β in the cell supernatant. In addition, resveratrol ameliorated elevated Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and the depressed inhibitor of NF-κB (IκB)-α caused by hypoxia/reoxygenation stimulation in BRL-3A cells. Moreover, resveratrol inhibited the translocation of NF-κB p65 after the stimulation of hypoxia/reoxygenation in BRL-3A cells. In vivo assays revealed that resveratrol reduced levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and liver pathological changes, while it alleviated hepatocyte apoptosis, negatively mediated the production of TNF-α and IL-1β in serum, and reversed TLR4/NF-κB signaling pathway caused by hepatic ischemia/reperfusion stimulation in liver tissues. The results indicate that resveratrol protected hepatocytes against HIRI, which may be mediated in part via the TLR4/NF-κB signaling pathway.

  15. Interleukin-4 regulates macrophage polarization via the MAPK signaling pathway to protect against atherosclerosis.

    PubMed

    Zhao, X N; Li, Y N; Wang, Y T

    2016-02-22

    Our study aimed to investigate the effects of interleukin-4 (IL-4) on macrophage polarization, as well as its role in the development of atherosclerosis. Human peripheral blood mononuclear cells (PBMCs) were isolated and randomly divided into 3 groups: control group, ox-LDL group, and ox-LDL + IL-4 groups. The expression of M1/M2 macrophage surface markers such as TNF-α, CD68, and CD206 were analyzed by western blot. Cell viability was determined using the MTT assay. Measurement of CD86/CD206 expression ratio (M1/M2 ratio) was performed via flow cytometry. In addition, ApoE(-/-) mice on a C57BL/6 background were subjected to high-fat diets, and were used as a model of atherosclerosis. Atherosclerotic lesion area was quantified after mice were treated with ox-LDL and IL-4. Finally, expression of phosphorylated MAPK signaling molecules such as p-ERK and p-JNK was quantified using western blot. The expression of TNF-α and CD86 markedly increased after cells were treated with ox-LDL, whereas the expression of CD206 markedly increased after PBMCs were treated with IL-4. It is possible that IL-4 could decrease ox-LDL-induced cell viability and the CD86/CD206 (M1/M2) ratio. Additionally, IL-4 intervention attenuated ox-LDL-induced atherosclerotic lesions in ApoE(-/-) mice, and decreased ox- LDL-induced expression of p-ERK and p-JNK. Our findings indicate that IL-4 may induce macrophages to take on an M2 phenotype in order to resolve inflammation via inhibition of MAPK signaling pathways, thereby protecting against atherosclerosis. IL-4 may serve as an intervention target for atherosclerosis.

  16. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2.

    PubMed

    Schlacher, Katharina; Wu, Hong; Jasin, Maria

    2012-07-10

    Genes mutated in patients with Fanconi anemia (FA) interact with the DNA repair genes BRCA1 and BRCA2/FANCD1 to suppress tumorigenesis, but the molecular functions ascribed to them cannot fully explain all of their cellular roles. Here, we show a repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation. Fork protection is surprisingly rescued in FANCD2-deficient cells by elevated RAD51 levels or stabilized RAD51 filaments. Moreover, FANCD2-mediated fork protection is epistatic with RAD51 functions, revealing an unanticipated fork protection pathway that connects FA genes to RAD51 and the BRCA1/2 breast cancer suppressors. Collective results imply a unified molecular mechanism for repair-independent functions of FA, RAD51, and BRCA1/2 proteins in preventing genomic instability and suppressing tumorigenesis.

  17. Anti-inflammatory and hepatoprotective effects of glycyrrhetinic acid on CCl4-induced damage in precision-cut liver slices from Jian carp (Cyprinus carpio var. jian) through inhibition of the nf-kƁ pathway.

    PubMed

    Cao, Liping; Ding, Weidong; Jia, Rui; Du, Jingliang; Wang, Tao; Zhang, Chunyun; Gu, Zhengyan; Yin, Guojun

    2017-03-10

    In order to evaluate the antioxidant and anti-inflammatory effects of glycyrrhetinic acid (GA) on carbon tetrachloride (CCl4)-induced damage in precision-cut liver slices (PCLS) from Jian carp (Cyprinus carpio. Jian), an acute liver damage model was established in this study. The viability of PCLS, levels of anti-oxidases in liver homogenates, expression of inflammation-related genes including nuclear factor-κB (nf-κB)/c-rel, inducible nitric oxide synthase (inos), interleukin-1β (il-1β), interleukin-6 (il-6) and interleukin-8 (il-8), and protein levels of (nf-κB)/c-rel in liver tissues were measured. The results showed that pretreatment of PCLS with GA at 5 and 10 μg/mL for 6 h significantly inhibited the cytotoxicity of CCl4. GA attenuated CCl4-induced oxidative stress in PCLS through promoting the recovery of superoxide dismutase (SOD) and glutathione (GSH) levels, and inhibiting malondialdehyde (MDA) synthesis. In inflammatory response, GA at both 5 and 10 μg/mL significantly inhibited the increase in mRNA levels of inflammatory cytokines including nf-kƁ/c-rel, inos, il-1β, il-6 and il-8, and the protein level of Nf-kƁ/C-rel induced by CCl4. Furthermore, treatment with pyrrolyl dithiocarbamate (PDTC, 4 μg/mL), an inhibitor of nuclear transcription factor nf-kB, significantly inhibited nf-kB levels, and transcription of downstream cytokines inos, il-1β, il-6 and il-8, also the viability of PCLS was significantly increased. These results indicated that GA suppressed inflammation and reduced cytotoxicity by inhibiting the nf-kƁ signaling pathway, and plays a role in liver protection.

  18. Tim-4 protects mice against lipopolysaccharide-induced endotoxic shock by suppressing the NF-κB signaling pathway.

    PubMed

    Xu, Liyun; Zhao, Peiqing; Xu, Yong; Gao, Lishuang; Wang, Hongxing; Jia, Xiaoxia; Ma, Hongxin; Liang, Xiaoxong; Ma, Chunxong; Gao, Lifen

    2016-11-01

    Endotoxic shock is the primary cause of morbidity and mortality in hospital patients, creating an urgent need to explore the mechanisms involved in sepsis. Our previous studies showed that T-cell immunoglobulin- and mucin-domain-containing molecule-4 (Tim-4) attenuated the inflammatory response through regulating the functions of macrophages. However, the mechanism by which Tim-4 does this has not been fully elucidated. In this study, we found that Tim-4 expression was increased in lipopolysaccharide (LPS)-induced endotoxic shock. Interestingly, the survival rate of mice in the Tim-4 overexpression group was higher than that of the control group after LPS administration. To investigate the function of Tim-4 in LPS-induced inflammation, we further demonstrated that Tim-4 attenuated LPS-induced endotoxic shock by inhibiting cytokine production by macrophages. Blocking expression of Tim-4 and nuclear factor-kappa B (NF-κB) signal inhibition showed that Tim-4 inhibited cytokine production via NF-κB signaling pathway. This study indicates that Tim-4 may exert its immune modulation by regulating inflammatory factor secretion and might act as a novel potential target for inflammatory diseases, especially endotoxic shock.

  19. Impact of a lung-protective ventilatory strategy on systemic and pulmonary inflammatory responses during laparoscopic surgery: is it really helpful?

    PubMed

    Kokulu, Serdar; Günay, Ersin; Baki, Elif Doğan; Ulasli, Sevinc Sarinc; Yilmazer, Mehmet; Koca, Buğra; Arıöz, Dagistan Tolga; Ela, Yüksel; Sivaci, Remziye Gül

    2015-02-01

    Laparoscopic surgery is performed by carbon dioxide (CO2) insufflation, but this may induce stress responses. The aim of this study is to compare the level of inflammatory mediators in patients receiving low tidal volume (VT) versus traditional VT during gynecological laparoscopic surgery. Forty American Society of Anesthesiologists (ASA) physical status 1 and 2 subjects older than 18 years old undergoing laparoscopic gynecological surgery were included. Systemic inflammatory response was assessed with serum IL-6, TNF-alpha, IL-8, and IL-1β in patients receiving intraoperative low VT and traditional VT during laparoscopic surgery [within the first 5 min after endotracheal intubation (T1), 60 min after the initiation of mechanical ventilation (T2), and in the postanesthesia care unit 30 min after tracheal extubation (T3)]. Additionally, inflammatory response was assessed with bronchoalveolar lavage (BAL) at T1 and T3 periods. An increase in the serum levels of IL-6, TNF-alpha, IL-8, and IL-1β was observed in both groups during the time periods of T1, T2, and T3. No significant differences were found in the serum and BAL levels of inflammatory mediators during time periods between groups. The results of the present study suggested that the lung-protective ventilation and traditional strategies are not different in terms of lung injury and inflammatory response during conventional laparoscopic gynecological surgery.

  20. IL-17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer

    PubMed Central

    Loncle, Celine; Bonjoch, Laia; Folch-Puy, Emma; Lopez-Millan, Maria Belen; Lac, Sophie; Molejon, Maria Inés; Chuluyan, Eduardo; Cordelier, Pierre; Dubus, Pierre; Lomberk, Gwen; Urrutia, Raul; Closa, Daniel; Iovanna, Juan L

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering “druggable” molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL-17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL-17 functions during this transition are currently unclear. In this study, we demonstrate that IL-17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early PanIN lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiological role for REG3β during pancreatitis and PDAC initiation. PMID:26404002

  1. The anti-malarial artemisinin inhibits pro-inflammatory cytokines via the NF-κB canonical signaling pathway in PMA-induced THP-1 monocytes.

    PubMed

    Wang, Yue; Huang, Zhouqing; Wang, Liansheng; Meng, Shu; Fan, Yuqi; Chen, Ting; Cao, Jiatian; Jiang, Rujia; Wang, Changqian

    2011-02-01

    Several kinds of sesquiterpene lactones have been proven to inhibit NF-κB and to retard atherosclerosis by reducing lesion size and changing plaque composition. The anti-malarial artemisinin (Art) is a pure sesquiterpene lactone extracted from the Chinese herb Artemisia annua (qinghao, sweet wormwood). In the present study, we demonstrate that artemisinin inhibits the secretion and the mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in a dose-dependent manner in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 human monocytes. We also found that the NF-κB specific inhibitor, Bay 11-7082, inhibited the expression of these pro-inflammatory cytokines, suggesting that the NF-κB pathway may be involved in the decreased cytokine release. At all time-points (1-6 h), artemisinin impeded the phosphorylation of IKKα/ß, the phosphorylation and degradation of IκBα and the nuclear translocation of the NF-κB p65 subunit. Additionally, artemisinin inhibited the translocation of the NF-κB p65 subunit as demonstrated by confocal laser scanning microscopic analysis and by NF-κB binding assays. Our data indicate that artemisinin exerts an anti-inflammatory effect on PMA-induced THP-1 monocytes, suggesting the potential role of artemisinin in preventing the inflammatory progression of atherosclerosis.

  2. Anti-inflammatory activity of n-propyl gallate through down-regulation of NF-κB and JNK pathways.

    PubMed

    Jung, Hyun-Joo; Kim, Su-Jung; Jeon, Woo-Kwang; Kim, Byung-Chul; Ahn, Kisup; Kim, Kyunghoon; Kim, Young-Myeong; Park, Eun-Hee; Lim, Chang-Jin

    2011-10-01

    The present study aimed to assess anti-inflammatory activity and underlying mechanism of n-propyl gallate, the n-propyl ester of gallic acid. n-Propyl gallate was shown to contain anti-inflammatory activity using two experimental animal models, acetic acid-induced permeability model in mice, and air pouch model in rats. It suppressed production of nitric oxide and induction of inducible nitric oxide synthase and cyclooxygenase-2 in the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. It was able to diminish reactive oxygen species level elevated in the LPS-stimulated RAW264.7 macrophage cells. It also suppressed gelatinolytic activity of matrix metalloproteinase-9 enhanced in the LPS-stimulated RAW264.7 macrophage cells. It inhibited inhibitory κB-α degradation and enhanced NF-κB promoter activity in the stimulated macrophage cells. It was able to suppress phosphorylation of c-Jun NH(2)-terminal kinase 1/2 (JNK1/2) and activation of c-Jun promoter activity in the stimulated macrophage cells. In brief, n-propyl gallate possesses anti-inflammatory activity via down-regulation of NF-κB and JNK pathways.

  3. Anti-inflammatory effects of physalin E from Physalis angulata on lipopolysaccharide-stimulated RAW 264.7 cells through inhibition of NF-κB pathway.

    PubMed

    Yang, Yan-Jun; Yi, Lang; Wang, Qing; Xie, Bing-Bing; Dong, Yan; Sha, Cong-Wei

    2017-04-01

    Physalin E is a naturally occurring seco-steroid isolated from the stems and aerial parts of Physalis angulata L. (Solanaceae). This study was aimed to explore the anti-inflammatory effects of physalin E on RAW 264.7 mouse macrophages stimulated by lipopolysaccharide (LPS) and the potential underlying mechanisms. The results showed that physalin E significantly inhibited LPS-induced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) expression and secretion in a dose-dependent manner. Unlike dexamethasone, these effects could not be blocked by miferstone (RU486). Meanwhile, physalin E reduced the degradation of I-kappa B protein in the cytoplasm and downregulated the nuclear factor-κB (NF-κB) p65 protein in the nuclear, which resulted in the inhibition of the NF-κB nuclear translocation. In conclusion, physalin E exerts its anti-inflammatory activities in LPS-induced macrophages. Physalin E can inhibit the production of inflammatory cytokines by targeting the NF-κB signaling pathway.

  4. Ampelopsin attenuates lipopolysaccharide-induced inflammatory response through the inhibition of the NF-κB and JAK2/STAT3 signaling pathways in microglia.

    PubMed

    Weng, Leihua; Zhang, He; Li, Xiaoxi; Zhan, Hui; Chen, Fan; Han, Lijuan; Xu, Yun; Cao, Xiang

    2017-03-01

    Increasing evidence suggests that microglia are a major cellular contributor to neuroinflammation. The present study investigated whether Ampelopsin (Amp), a type of flavanonol derivative from Ampelopsis grossedentata, may exert an anti-inflammatory effect on lipopolysaccharide (LPS)-induced BV2 and primary microglia cells. We found that pre-treatment of microglia cells with Amp before LPS with a non-cytotoxic concentration range decreased the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Amp also suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels. In addition, LPS-induced production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) was obviously reduced by Amp. Our mechanistic study indicated that Amp suppressed LPS-induced activation of the IκB/NF-κB inflammation pathway without affecting changes in the phosphorylation levels of mitogen-activated protein kinases (MAPKs) in BV2 cells. Further studies revealed that Amp markedly reduced the phosphorylation levels of JAK2-STAT3 and STAT3 nuclear translocation. Overall, our data suggest that Amp can suppress the LPS-induced inflammatory response of microglial cells, indicating that Amp has potential for the treatment of inflammation-mediated neurodegenerative diseases.

  5. The Role of M2000 as an Anti-inflammatory Agent in Toll-Like Receptor 2/microRNA-155 Pathway

    PubMed Central

    Pourgholi, Fatemeh; Hajivalili, Mahsa; Razavi, Rasoul; Esmaeili, Shadi; Baradaran, Behzad; Movasaghpour, Ali Akbar; Sadreddini, Sanam; Goodarzynejad, Hamidreza; Mirshafiey, Abbas; Yousefi, Mehdi

    2017-01-01

    Background: M2000 is a newly designed and safe Non-Steroidal Anti-Inflammatory Drug (NSAID). The aim of this study was to assess the effects of M2000 on expression levels of Suppressor of Cytokine Signaling-1 (SOCS-1) and Src Homology-2 domain-containing inositol-5′-phosphatase 1 (SHIP1) proteins via Toll-Like Receptor (TLR) 2/microRNA-155 pathway. Methods: HEK293 TLR2 cell line and Peripheral Blood Mononuclear Cells (PBMCs) were treated by different concentrations of M2000 in MTT assay. RNA was extracted by miRNeasy Mini kit. Then, cDNA was synthesized and the expression levels of SOCS1, SHIP1 and miRNA155 were evaluated by Quantitative Real time PCR. Results: Our results showed that M2000 significantly increased the expression levels of SOCS1 and SHIP-1 in Lipopolysachride (LPS)-treated and non-treated cells. Moreover, M2000 decreased expression level of miR-155 in LPS treated PBMCs. Conclusion: M2000 can be used as NSAID in LPS induced inflammation and decrease inflammatory cytokines production by targeting SOCS1, SHIP1 and miR-155 in auto-immune and inflammatory diseases. PMID:28090274

  6. Brazilin plays an anti-inflammatory role with regulating Toll-like receptor 2 and TLR 2 downstream pathways in Staphylococcus aureus-induced mastitis in mice.

    PubMed

    Gao, Xue-jiao; Wang, Tian-cheng; Zhang, Ze-cai; Cao, Yong-guo; Zhang, Nai-sheng; Guo, Meng-yao

    2015-07-01

    Mastitis, which commonly occurs during the postpartum period, is caused by the infection of the mammary glands. The most common infectious bacterial pathogen of mastitis is Staphylococcus aureus (S. aureus) in both human and animals. Brazilin, a compound isolated from the traditional herbal medicine Caesalpinia sappan L., has been shown to exhibit multiple biological properties. The present study was performed to determine the effect of brazilin on the inflammatory response in the mouse model of S. aureus mastitis and to confirm the mechanism of action involved. Brazilin treatment was applied in both a mouse model and cells. After brazilin treatment of cells, Western blotting and qPCR were performed to detect the protein levels and mRNA levels, respectively. Brazilin treatment significantly attenuated inflammatory cell infiltration and inhibited the expressions of TNF-α, IL-1β and IL-6 in a dose-dependent manner. Administration of brazilin in mice suppressed S. aureus-induced inflammatory injury and the production of proinflammatory mediators. This suppression was achieved by reducing the increased expression of TLR2 and regulating the NF-κB and MAPK signaling pathways in the mammary gland tissues and cells with S. aureus-induced mastitis. These results suggest that brazilin appears to be an effective drug for the treatment of mastitis and may be applied as a clinical therapy.

  7. Gallic Acid-g-Chitosan Modulates Inflammatory Responses in LPS-Stimulated RAW264.7 Cells Via NF-κB, AP-1, and MAPK Pathways.

    PubMed

    Ahn, Chang-Bum; Jung, Won-Kyo; Park, Sun-Joo; Kim, Yong-Tae; Kim, Won-Suk; Je, Jae-Young

    2016-02-01

    Chitosan is a naturally occurring polysaccharide, which has exhibited antioxidant, antimicrobial, and anti-cancer activities among others. Modification of chitosan by grafting phenolic compounds is a good strategy for improvement of bioactivities of chitosan. We investigated the anti-inflammatory action of gallic acid-grafted-chitosan (GAC) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. GAC inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) by inhibiting inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW264.7 macrophages. GAC also suppressed the production and mRNA expression of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). GAC inactivated nuclear factor-κB (NF-κB) via inhibiting the phosphorylation and degradation of the NF-κB inhibitor, IκB. In addition, GAC suppresses the activation of activator protein-1 (AP-1) through the phosphorylation of mitogen-activated protein kinase (MAPK) such as extracellular signal-regulated kinase (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase/stress-activated protein kinase (JNK). These results suggest that GAC has the potential anti-inflammatory action by downregulating transcriptional factors (NF-κB and AP-1) through MAPK signaling pathways.

  8. Suppression of TLR-4-related inflammatory pathway and anti-fibrosis effects of probiotic-fermented purple sweet potato yogurt in hearts of spontaneously hypertensive rats.

    PubMed

    Lin, Pei-Pei; Hsieh, You-Miin; Kuo, Wei-Wen; Lin, Yueh-Min; Yeh, Yu-Lan; Lin, Chien-Chung; Tsai, Fuu-Jen; Tsai, Chang-Hai; Tsai, Cheng-Chih; Huang, Chih-Yang

    2013-06-30

    Inflammation plays an important role in triggering fibrosis of cardiovascular disease and hypertension. Gamma-aminobutyric acid (GABA) has hypotensive effect; GABA concentration could be enhanced in milk fermented with lactic acid bacteria (LAB). This study evaluated the effect of probiotic-fermented purple sweet potato yogurt (PSPY) on the toll-like receptor 4 (TLR-4)-related inflammatory components, and on fibrosis in the heart of spontaneously hypertensive rat (SHR). TLR4-related pathway and fibrosis-associated proteins TGFbeta and FGF2 were significantly increased in SHR hearts, but were highly suppressed in 10% PSPY-fed rats. Microscopic examination with Masson trichrome staining of left ventricle further demonstrated that 10% and 100% PSPY both significantly reduced interstitial fibrosis in SHR hearts. These findings indicated that oral administration of 10% probiotic-fermented PSPY was strong enough to lower cardiac fibrosis in SHR rats through the suppression of TLR-4-related inflammatory pathway. Therefore, PSPY may be included in diets to help prevent cardiac fibrosis in patients with hypertension.

  9. Adipose-derived stem cells ameliorate renal interstitial fibrosis through inhibition of EMT and inflammatory response via TGF-β1 signaling pathway.

    PubMed

    Song, Yan; Peng, Changliang; Lv, Shasha; Cheng, Jing; Liu, Shanshan; Wen, Qing; Guan, Guangju; Liu, Gang

    2017-03-01

    Adipose-derived stem cells (ADSCs) have been successfully used to treat acute kidney injury or acute renal failure. However, the effect of ADSCs on treating renal interstitial fibrosis remains unknown. Here, we assessed the therapeutic efficacy of ADSCs on renal interstitial fibrosis induced by unilateral ureter obstruction (UUO) and explored the potential mechanisms. After 7days of UUO, rats were injected with ADSCs (5×10(6)) or vehicle via tail vein. We found that ADSCs administration significantly ameliorated renal interstitial fibrosis, the occurrence of epithelial-mesenchymal transition (EMT) and inflammatory response. Furthermore, ADSCs administration could inhibit the activation of transforming growth factor-β1 (TGF-β1) signaling pathway, which might play a crucial role in renal interstitial fibrosis of the UUO model rats. These results suggested that ADSCs treatment attenuates renal interstitial fibrosis possibly through inhibition of EMT and inflammatory response via TGF-β1 signaling pathway. Therefore, ADSCs may be an effective therapeutic strategy for the treatment of renal interstitial fibrosis.

  10. Gomisin A inhibits lipopolysaccharide-induced inflammatory responses in N9 microglia via blocking the NF-κB/MAPKs pathway.

    PubMed

    Wang, Xiaoxiao; Hu, Di; Zhang, Lijia; Lian, Guoning; Zhao, Siqi; Wang, Chunming; Yin, Jun; Wu, Chunfu; Yang, Jingyu

    2014-01-01

    Gomisin A, one of the major dibenzocyclooctadiene lignans isolated from Schisandra chinensis Baill., has proved to possess a variety of pharmacological effects. The aim of the present study was to investigate the anti-inflammatory and neuroprotective effects of gomisin A as well as its potential molecular mechanisms. It was found that gomisin A not only inhibited the production of NO and PGE2 in a concentration-dependent manner but also suppressed the expressions of iNOS and COX-2 in LPS-stimulated N9 microglia without observable cytotoxicity. Gomisin A was also able to attenuate the mRNA expression and the production of pro-inflammatory factors TNF-α, IL-1β and IL-6. Moreover, LPS induced reactive oxygen species (ROS) production, NADPH oxidase activation, and gp91phox expression, which were markedly inhibited by gomisin A in microglia. Furthermore, the data showed that gomisin A significantly down-regulated the TLR4 protein expression, and inhibited nuclear transcription factor (NF)-κB and mitogen-activated protein kinases (MAPKs) signaling pathways. Additionally, gomisin A alleviated the cell death of SH-SY5Y neuroblastoma, rat primary cortical and hippocampal neurons induced by the conditioned-media from activated microglia. In summary, gomisin A may exert neuroprotective effects by attenuating the microglia-mediated neuroinflammatory response via inhibiting the TLR4-mediated NF-κB and MAPKs signaling pathways.

  11. Efficacy and safety of monoclonal antibodies targeting interleukin-17 pathway for inflammatory arthritis: a meta-analysis of randomized controlled clinical trials

    PubMed Central

    Wei, Min; Duan, Dongmei

    2016-01-01

    T-helper 17 (Th17) pathway plays an important and distinct role in autoimmunity and inflammation. A growing body of evidence demonstrates that interleukin-17 (IL-17) is also synthesized in inflammatory arthritis tissues and exerts potent proinflammatory and joint-destructive activities. Clinical studies have been performed to evaluate the therapeutic efficacy of antibodies blocking the IL-17 signaling pathway in patients with rheumatoid arthritis (RA). In this study, we performed a meta-analysis to systematically evaluate the clinical effects of IL-17 antibodies in RA patients. By searching PubMed, five randomized, placebo-controlled randomized controlled clinical trials that tested three antibodies against IL-17A (LY2439821 and secukinumab/AIN457) and the IL-17A receptor (brodalumab) were identified. The primary outcomes that were analyzed include American College of Rheumatology (ACR) Improvement Criteria and Disease Activity Score in 28 joints (DAS28). Meanwhile, the safety and adverse effects were also systematically analyzed. The results of the meta-analysis demonstrated that IL-17 antibody is effective in ameliorating the RA symptoms. Specifically, IL-17-blocking antibody significantly reduced ACR20 and ACR50. It also dramatically reduced DAS28, an index that measures tenderness and swelling severity of joints. The side effects of and intolerance to the antibody treatment were higher than those in the placebo control. The analysis result provides evidence-based information for clinical use of these agents in the treatment of inflammatory arthritis. PMID:27672309

  12. Protective effect of brown Brazilian propolis against acute vaginal lesions caused by herpes simplex virus type 2 in mice: involvement of antioxidant and anti-inflammatory mechanisms.

    PubMed

    Sartori, Gláubia; Pesarico, Ana Paula; Pinton, Simone; Dobrachinski, Fernando; Roman, Silvane Souza; Pauletto, Fernanda; Rodrigues, Luiz Carlos; Prigol, Marina

    2012-01-01

    Propolis has been highlighted for its antioxidant, anti-inflammatory and antiviral properties. The purpose of this study was to investigate if brown Brazilian hydroalcoholic propolis extract (HPE) protects against vaginal lesions caused by herpes simplex virus type 2 (HSV-2) in female BALB/c mice. The treatment was divided in 5 days of pre-treatment with HPE [50 mg · kg(-1), once a day, intragastric (i.g.)], HSV-2 infection [10 µl of a solution 1 × 10(2) plaque-forming unit (PFU · ml(-1) HSV-2), intravaginal inoculation at day 6] and post-treatment with HPE (50 mg · kg(-1)) for 5 days more. At day 11, the animals were killed, and the in vivo analysis (score of lesions) and ex vivo analysis [haematological and histological evaluation; superoxide dismutase (SOD), catalase (CAT) and myeloperoxidase (MPO) activities; reactive species (RS), tyrosine nitration levels, non-protein thiols (NPSH) and ascorbic acid (AA) levels] were carried out. HPE treatment reduced extravaginal lesions and the histological damage caused by HSV-2 infection in vaginal tissues of animals. HPE was able to decrease RS, tyrosine nitration, AA levels and MPO activity. Also, it protected against the inhibition of CAT activity in vaginal tissues of mice. HPE promoted protective effect on HSV-2 infected animals by acting on inflammatory and oxidative processes, and this effect probably is caused by its antioxidant and anti-inflammatory properties.

  13. Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: anti-inflammatory effect of cholecystokinin.

    PubMed

    Miyamoto, Satoshi; Shikata, Kenichi; Miyasaka, Kyoko; Okada, Shinichi; Sasaki, Motofumi; Kodera, Ryo; Hirota, Daisho; Kajitani, Nobuo; Takatsuka, Tetsuharu; Kataoka, Hitomi Usui; Nishishita, Shingo; Sato, Chikage; Funakoshi, Akihiro; Nishimori, Hisakazu; Uchida, Haruhito Adam; Ogawa, Daisuke; Makino, Hirofumi

    2012-04-01

    Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.

  14. The Dietary Isoflavone Daidzein Reduces Expression of Pro-Inflammatory Genes through PPARα/γ and JNK Pathways in Adipocyte and Macrophage Co-Cultures

    PubMed Central

    Sakamoto, Yuri; Kanatsu, Junko; Toh, Mariko; Naka, Ayano; Kondo, Kazuo; Iida, Kaoruko

    2016-01-01

    Obesity-induced inflammation caused by adipocyte-macrophage interactions plays a critical role in developing insulin resistance, and peroxisome proliferator-activated receptors (PPARs) regulate inflammatory gene expression in these cells. Recently, the soy isoflavone daidzein was reported to act as a PPAR activator. We examined whether daidzein affected adipocyte-macrophage crosstalk via the regulation of PPARs. Co-cultures of 3T3-L1 adipocytes and RAW264 macrophages, or palmitate-stimulated RAW264 macrophages were treated with daidzein in the presence or absence of specific inhibitors for PPARs: GW6471 (a PPARα antagonist), and GW9662 (a PPARγ antagonist). Inflammatory gene expression was then determined. Daidzein significantly decreased chemokine (C-C motif) ligand 2 (Ccl2, known in humans as monocyte chemo-attractant protein 1 (MCP1)) and interleukin 6 (Il6) mRNA levels induced by co-culture. In 3T3-L1 adipocytes, daidzein inversed the attenuation of adiponectin gene expression by co-culture, and these effects were inhibited by the PPAR-γ specific inhibitor. Daidzein also decreased Ccl2 and Il6 mRNA levels in RAW264 macrophages stimulated with palmitate or conditioned medium (CM) from hypertrophied 3T3-L1 adipocytes. This inhibitory effect on Il6 expression was abrogated by a PPAR-α inhibitor. Additionally, we examined the activation of nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways and found that daidzein significantly inhibited palmitate-induced phosphorylation of JNK. Our data suggest that daidzein regulates pro-inflammatory gene expression by activating PPAR-α and -γ and inhibiting the JNK pathway in adipocyte and macrophage co-cultures. These effects might be favorable in improving adipose inflammation, thus, treatment of daidzein may be a therapeutic strategy for chronic inflammation in obese adipose tissue. PMID:26901838

  15. Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

    PubMed Central

    Langkilde, Ane; Olsen, Lene C.; Sætrom, Pål; Drabløs, Finn; Besenbacher, Søren; Raaby, Line; Johansen, Claus; Iversen, Lars

    2016-01-01

    Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin. PMID:28005985

  16. Anti-Inflammatory Effects of Water Chestnut Extract on Cytokine Responses via Nuclear Factor-κB-signaling Pathway.

    PubMed

    Kim, Bora; Kim, Jin Eun; Choi, Byung-Kook; Kim, Hyun-Soo

    2015-01-01

    Water chestnut (Trapa japonica Flerov.) is an annual aquatic plant. In the present study, we showed that the treatment of water chestnut extracted with boiling water resulted in a significant increase 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity and decrease the intracellular H2O2-induced accumulation of reactive oxygen species. In addition, water chestnut extract (WCE) inhibited lipopolysaccharide (LPS)-induced nitric oxide production and suppressed mRNA and protein expression of the inducible nitric oxide synthase gene. The cytokine array results showed that WCE inhibited inflammatory cytokine secretion. Also, WCE reduced tumor necrosis factor-α-and interleukin-6-induced nuclear factor-αB activity. Furthermore, during sodium lauryl sulfate (SLS)-induced irritation of human skin, WCE reduced SLS-induced skin erythema and improved barrier regeneration. These results indicate that WCE may be a promising topical anti-inflammatory agent.

  17. Parenchymal and Stromal Cells Contribute to Pro-Inflammatory Myocardial Environment at Early Stages of Diabetes: Protective Role of Resveratrol

    PubMed Central

    Savi, Monia; Bocchi, Leonardo; Sala, Roberto; Frati, Caterina; Lagrasta, Costanza; Madeddu, Denise; Falco, Angela; Pollino, Serena; Bresciani, Letizia; Miragoli, Michele; Zaniboni, Massimiliano; Quaini, Federico; Del Rio, Daniele; Stilli, Donatella

    2016-01-01

    Background: Little information is currently available concerning the relative contribution of cardiac parenchymal and stromal cells in the activation of the pro-inflammatory signal cascade, at the initial stages of diabetes. Similarly, the effects of early resveratrol (RSV) treatment on the negative impact of diabetes on the different myocardial cell compartments remain to be defined. Methods: In vitro challenge of neonatal cardiomyocytes and fibroblasts to high glucose and in vivo/ex vivo experiments on a rat model of Streptozotocin-induced diabetes were used to specifically address these issues. Results: In vitro data indicated that, besides cardiomyocytes, neonatal fibroblasts contribute to generating initial changes in the myocardial environment, in terms of pro-inflammatory cytokine expression. These findings were mostly confirmed at the myocardial tissue level in diabetic rats, after three weeks of hyperglycemia. Specifically, monocyte chemoattractant protein-1 and Fractalkine were up-regulated and initial abnormalities in cardiomyocyte contractility occurred. At later stages of diabetes, a selective enhancement of pro-inflammatory macrophage M1 phenotype and a parallel reduction of anti-inflammatory macrophage M2 phenotype were associated with a marked disorganization of cardiomyocyte ultrastructural properties. RSV treatment inhibited pro-inflammatory cytokine production, leading to a recovery of cardiomyocyte contractile efficiency and a reduced inflammatory cell recruitment. Conclusion: Early RSV administration could inhibit the pro-inflammatory diabetic milieu sustained by different cardiac cell types. PMID:27854328

  18. Lyn regulates inflammatory responses in Klebsiella pneumoniae infection via the p38/NF-κB pathway.

    PubMed

    Li, Xuefeng; Zhou, Xikun; Ye, Yan; Li, Yi; Li, Jiaxin; Privratsky, Breanna; Wu, Erxi; Gao, Hongwei; Huang, Canhua; Wu, Min

    2014-03-01

    Klebsiella pneumoniae (Kp) is one of the most common pathogens in nosocomial infections and is becoming increasingly multidrug resistant. However, the underlying molecular pathogenesis of this bacterium remains elusive, limiting the therapeutic options. Understanding the mechanism of its pathogenesis may facilitate the development of anti-bacterial therapeutics. Here, we show that Lyn, a pleiotropic Src tyrosine kinase, is involved in host defense against Kp by regulating phagocytosis process and simultaneously downregulating inflammatory responses. Using acute infection mouse models, we observed that lyn(-/-) mice were more susceptible to Kp with increased mortality and severe lung injury compared with WT mice. Kp infected-lyn(-/-) mice exhibited elevated inflammatory cytokines (IL-6 and TNF-α), and increased superoxide in the lung and other organs. In addition, the phosphorylation of p38 and NF-κB p65 subunit increased markedly in response to Kp infection in lyn(-/-) mice. We also demonstrated that the translocation of p65 from cytoplasm to nuclei increased in cultured murine lung epithelial cells by Lyn siRNA knockdown. Furthermore, lipid rafts clustered with activated Lyn and accumulated in the site of Kp invasion. Taken together, these findings revealed that Lyn may participate in host defense against Kp infection through the negative modulation of inflammatory cytokines.

  19. COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset.

    PubMed

    Larsson, Karin; Kock, Anna; Idborg, Helena; Arsenian Henriksson, Marie; Martinsson, Tommy; Johnsen, John I; Korotkova, Marina; Kogner, Per; Jakobsson, Per-Johan

    2015-06-30

    The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E2 (PGE2) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE2. High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1-expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein α, α smooth muscle actin, and PDGF receptor β. Importantly, inhibition of PGE2 production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE2 is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.

  20. Resveratrol nanoparticle system improves dissolution properties and enhances the hepatoprotective effect of resveratrol through antioxidant and anti-inflammatory pathways.

    PubMed

    Lee, Chiang-Wen; Yen, Feng-Lin; Huang, Haw-Wei; Wu, Tzu-Hui; Ko, Horng-Huey; Tzeng, Wen-Sheng; Lin, Chun-Ching

    2012