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Sample records for 15d-pgj2 stimulates ho-1

  1. Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion

    PubMed Central

    Abbasi, Saed; Kajimoto, Kazuaki; Harashima, Hideyoshi

    2016-01-01

    15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has a dual action of stimulating anti-inflammation and anti-proliferation when exogenously administered at high doses. However, at lower doses, it can be toxic inducing opposite actions, ie, stimulation of both inflammation and cell proliferation. This biphasic phenomenon of 15d-PGJ2 is believed to be due to its multitarget behavior. In this study, we provide a strategy for controlling such biphasic pharmacodynamics by separating its dual actions while retaining the beneficial one by using a nanoemulsion (NE). The 15d-PGJ2 was encapsulated in the NE composed of triolein/distearoyl phosphatidylcholine/Tween 80 at a high encapsulation ratio (>83%). Furthermore, NE enhanced drug retention by slowing down its release rate, which was, unconventionally, inversely dependent on the total surface area of the NE system. Next, focusing on the biphasic effect on cell proliferation, we found that the 15d-PGJ2-loaded slow-release NE showed only a dose-dependent inhibition of the viability of a mouse macrophage cell line, RAW264.7, although a fast-release NE as well as free 15d-PGJ2 exerted a biphasic effect. The observed slow-release kinetics are believed to be responsible for elimination of the biphasic pharmacodynamics of 15d-PGJ2 mainly for two reasons: 1) a high proportion of 15d-PGJ2 that is retained in the NE was delivered to the cytosol, where proapoptotic targets are located and 2) 15d-PGJ2 was able to bypass cell membrane-associated targets that lead to the induction of cellular proliferation. Collectively, our strategy of eliminating the 15d-PGJ2-induced biphasic pharmacodynamics was based on the delivery of 15d-PGJ2 to its desired site of action, excluding undesired sites, on a subcellular level. PMID:27354798

  2. Mitochondrial remodeling following fission inhibition by 15d-PGJ2 involves molecular changes in mitochondrial fusion protein OPA1

    SciTech Connect

    Kar, Rekha; Mishra, Nandita; Singha, Prajjal K.; Venkatachalam, Manjeri A.; Saikumar, Pothana

    2010-09-03

    Research highlights: {yields} Chemical inhibition of fission protein Drp1 leads to mitochondrial fusion. {yields} Increased fusion stimulates molecular changes in mitochondrial fusion protein OPA1. {yields} Proteolysis of larger isoforms, new synthesis and ubiquitination of OPA1 occur. {yields} Loss of mitochondrial tubular rigidity and disorganization of cristae. {yields} Generation of large swollen dysfunctional mitochondria. -- Abstract: We showed earlier that 15 deoxy {Delta}{sup 12,14} prostaglandin J2 (15d-PGJ2) inactivates Drp1 and induces mitochondrial fusion . However, prolonged incubation of cells with 15d-PGJ2 resulted in remodeling of fused mitochondria into large swollen mitochondria with irregular cristae structure. While initial fusion of mitochondria by 15d-PGJ2 required the presence of both outer (Mfn1 and Mfn2) and inner (OPA1) mitochondrial membrane fusion proteins, later mitochondrial changes involved increased degradation of the fusion protein OPA1 and ubiquitination of newly synthesized OPA1 along with decreased expression of Mfn1 and Mfn2, which likely contributed to the loss of tubular rigidity, disorganization of cristae, and formation of large swollen degenerated dysfunctional mitochondria. Similar to inhibition of Drp1 by 15d-PGJ2, decreased expression of fission protein Drp1 by siRNA also resulted in the loss of fusion proteins. Prevention of 15d-PGJ2 induced mitochondrial elongation by thiol antioxidants prevented not only loss of OPA1 isoforms but also its ubiquitination. These findings provide novel insights into unforeseen complexity of molecular events that modulate mitochondrial plasticity.

  3. 15d-PGJ2-Loaded Solid Lipid Nanoparticles: Physicochemical Characterization and Evaluation of Pharmacological Effects on Inflammation.

    PubMed

    de Melo, Nathalie Ferreira Silva; de Macedo, Cristina Gomes; Bonfante, Ricardo; Abdalla, Henrique Ballassini; da Silva, Camila Morais Gonçalves; Pasquoto, Tatiane; de Lima, Renata; Fraceto, Leonardo Fernandes; Clemente-Napimoga, Juliana Trindade; Napimoga, Marcelo Henrique

    2016-01-01

    15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has physiological properties including pronounced anti-inflammatory activity, though it binds strongly to serum albumin. The use of solid lipid nanoparticles (SLN) can improve therapeutic properties increasing drug efficiency and availability. 15d-PGJ2-SLN was therefore developed and investigated in terms of its immunomodulatory potential. 15d-PGJ2-SLN and unloaded SLN were physicochemically characterized and experiments in vivo were performed. Animals were pretreated with 15d-PGJ2-SLN at concentrations of 3, 10 or 30 μg·kg-1 before inflammatory stimulus with carrageenan (Cg), lipopolysaccharide (LPS) or mBSA (immune response). Interleukins (IL-1β, IL-10 and IL-17) levels were also evaluated in exudates. The 15d-PGJ2-SLN system showed good colloidal parameters and encapsulation efficiency of 96%. The results showed that the formulation was stable for up to 120 days with low hemolytic effects. The 15d-PGJ2-SLN formulation was able to reduce neutrophil migration in three inflammation models tested using low concentrations of 15d-PGJ2. Additionally, 15d-PGJ2-SLN increased IL-10 levels and reduced IL-1β as well as IL-17 in peritoneal fluid. The new 15d-PGJ2-SLN formulation highlights perspectives of a potent anti-inflammatory system using low concentrations of 15d-PGJ2. PMID:27575486

  4. 15d-PGJ2-Loaded Solid Lipid Nanoparticles: Physicochemical Characterization and Evaluation of Pharmacological Effects on Inflammation

    PubMed Central

    da Silva, Camila Morais Gonçalves; Pasquoto, Tatiane; de Lima, Renata; Fraceto, Leonardo Fernandes

    2016-01-01

    15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has physiological properties including pronounced anti-inflammatory activity, though it binds strongly to serum albumin. The use of solid lipid nanoparticles (SLN) can improve therapeutic properties increasing drug efficiency and availability. 15d-PGJ2-SLN was therefore developed and investigated in terms of its immunomodulatory potential. 15d-PGJ2-SLN and unloaded SLN were physicochemically characterized and experiments in vivo were performed. Animals were pretreated with 15d-PGJ2-SLN at concentrations of 3, 10 or 30 μg·kg-1 before inflammatory stimulus with carrageenan (Cg), lipopolysaccharide (LPS) or mBSA (immune response). Interleukins (IL-1β, IL-10 and IL-17) levels were also evaluated in exudates. The 15d-PGJ2-SLN system showed good colloidal parameters and encapsulation efficiency of 96%. The results showed that the formulation was stable for up to 120 days with low hemolytic effects. The 15d-PGJ2-SLN formulation was able to reduce neutrophil migration in three inflammation models tested using low concentrations of 15d-PGJ2. Additionally, 15d-PGJ2-SLN increased IL-10 levels and reduced IL-1β as well as IL-17 in peritoneal fluid. The new 15d-PGJ2-SLN formulation highlights perspectives of a potent anti-inflammatory system using low concentrations of 15d-PGJ2. PMID:27575486

  5. The low molecular weight fraction of human serum albumin upregulates production of 15d-PGJ2 in Peripheral Blood Mononuclear Cells.

    PubMed

    Thomas, Gregory W; Rael, Leonard T; Hausburg, Melissa; Frederick, Elizabeth D; Mains, Charles W; Slone, Denetta; Carrick, Matthew M; Bar-Or, David

    2016-05-13

    Activation of the innate immune system involves a series of events designed to counteract the initial insult followed by the clearance of debris and promotion of healing. Aberrant regulation can lead to systemic inflammatory response syndrome, multiple organ failure, and chronic inflammation. A better understanding of the innate immune response may help manage complications while allowing for proper immune progression. In this study, the ability of several classes of anti-inflammatory drugs to affect LPS-induced cytokine and prostaglandin release from peripheral blood mononuclear cells (PBMC) was evaluated. PBMC were cultured in the presence of dexamethasone (DEX), ibuprofen (IBU), and the low molecular weight fraction of 5% albumin (LMWF5A) followed by stimulation with LPS. After 24 h, TNFα, PGE2, and 15d-PGJ2 release was determined by ELISA. Distinct immunomodulation patterns emerged following LPS stimulation of PBMC in the presence of said compounds. DEX, a steroid with strong immunosuppressive properties, reduced TNFα, PGE2, and 15d-PGJ2 release. IBU caused significant reduction in prostaglandin release while TNFα release was unchanged. An emerging biologic with known anti-inflammatory properties, LMWF5A, significantly reduced TNFα release while enhancing PGE2 and 15d-PGJ2 release. Incubating LMWF5A together with IBU negated this observed increased prostaglandin release without affecting the suppression of TNFα release. Additionally, LMWF5A caused an increase in COX-2 transcription and translation. LMWF5A exhibited a unique immune modulation pattern in PBMC, disparate from steroid or NSAID administration. This enhancement of prostaglandin release (specifically 15d-PGJ2), in conjunction with a decrease in TNFα release, suggests a switch that favors resolution and decreased inflammation. PMID:27095392

  6. 15d-PGJ2 inhibits cell growth and induces apoptosis of MCG-803 human gastric cancer cell line

    PubMed Central

    Chen, Yun-Xian; Zhong, Xue-Yun; Qin, Yan-Fang; Bing, Wang; He, Li-Zhen

    2003-01-01

    AIM: To investigate the influence of peroxisome proliferator-activated receptor γ (PPARγ) ligand, 15-deoxy-△12, 14-prostaglandin J2 (15dPGJ2) on the proliferation and apoptosis of MCG-803 human gastric cancer cell lines. METHODS: Cell proliferation was measured by 3H-TdR assay. Apoptosis was determined by ELISA and TUNEL staining. Protein and mRNA level of bcl-2 family and COXs were measured by Western blotting and Northern blotting respectively. PGE2 production was examined by RIA. RESULTS: 15dPGJ2 inhibited cell growth and induced apoptosis of MCG-803 cells. The COX-2 and bcl-2/bax ratios were decreased following 15dPGJ2 treatment. The PGE2 production in supernatants was also decreased. These changes were in a dose-dependent manner. CONCLUSION: 15dPGJ2 may be a useful therapeutic agent for the treatment of gastric cancer. PMID:14562367

  7. Proteome analysis identified the PPARγ ligand 15d-PGJ2 as a novel drug inhibiting melanoma progression and interfering with tumor-stroma interaction.

    PubMed

    Paulitschke, Verena; Gruber, Silke; Hofstätter, Elisabeth; Haudek-Prinz, Verena; Klepeisz, Philipp; Schicher, Nikolaus; Jonak, Constanze; Petzelbauer, Peter; Pehamberger, Hubert; Gerner, Christopher; Kunstfeld, Rainer

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) have been originally thought to be restricted to lipid metabolism or glucose homeostasis. Recently, evidence is growing that PPARγ ligands have inhibitory effects on tumor growth. To shed light on the potential therapeutic effects on melanoma we tested a panel of PPAR agonists on their ability to block tumor proliferation in vitro. Whereas ciglitazone, troglitazone and WY14643 showed moderate effects on proliferation, 15d-PGJ2 displayed profound anti-tumor activity on four different melanoma cell lines tested. Additionally, 15d-PGJ2 inhibited proliferation of tumor-associated fibroblasts and tube formation of endothelial cells. 15d-PGJ2 induced the tumor suppressor gene p21, a G(2)/M arrest and inhibited tumor cell migration. Shot gun proteome analysis in addition to 2D-gel electrophoresis and immunoprecipitation of A375 melanoma cells suggested that 15d-PGJ2 might exert its effects via modification and/or downregulation of Hsp-90 (heat shock protein 90) and several chaperones. Applying the recently established CPL/MUW database with a panel of defined classification signatures, we demonstrated a regulation of proteins involved in metastasis, transport or protein synthesis including paxillin, angio-associated migratory cell protein or matrix metalloproteinase-2 as confirmed by zymography. Our data revealed for the first time a profound effect of the single compound 15d-PGJ2 on melanoma cells in addition to the tumor-associated microenvironment suggesting synergistic therapeutic efficiency. PMID:23049949

  8. Total Synthesis of Prostaglandin 15d-PGJ(2) and Investigation of its Effect on the Secretion of IL-6 and IL-12.

    PubMed

    Egger, Julian; Fischer, Stefan; Bretscher, Peter; Freigang, Stefan; Kopf, Manfred; Carreira, Erick M

    2015-09-01

    An efficient synthesis of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, 1) is reported. The route described allows for diversification of the parent structure to prepare seven analogues of 1 in which the positioning of electrophilic sites is varied. These analogues were tested in SAR studies for their ability to reduce the secretion of proinflammatory cytokines. It was shown that the endocyclic enone is crucial for the bioactivity investigated and that the conjugated ω-side chain serves in a reinforcing manner.

  9. Contrasting effects of peroxisome-proliferator-activated receptor (PPAR)γ agonists on membrane-associated prostaglandin E2 synthase-1 in IL-1β-stimulated rat chondrocytes: evidence for PPARγ-independent inhibition by 15-deoxy-Δ12,14prostaglandin J2

    PubMed Central

    Bianchi, Arnaud; Moulin, David; Sebillaud, Sylvie; Koufany, Meriem; Galteau, Marie-Madeleine; Netter, Patrick; Terlain, Bernard; Jouzeau, Jean-Yves

    2005-01-01

    Microsomal prostaglandin E synthase (mPGES)-1 is a newly identified inducible enzyme of the arachidonic acid cascade with a key function in prostaglandin (PG)E2 synthesis. We investigated the kinetics of inducible cyclo-oxygenase (COX)-2 and mPGES-1 expression with respect to the production of 6-keto-PGF1α and PGE2 in rat chondrocytes stimulated with 10 ng/ml IL-1β, and compared their modulation by peroxisome-proliferator-activated receptor (PPAR)γ agonists. Real-time PCR analysis showed that IL-1β induced COX-2 expression maximally (37-fold) at 12 hours and mPGES-1 expression maximally (68-fold) at 24 hours. Levels of 6-keto-PGF1α and PGE2 peaked 24 hours after stimulation with IL-1β; the induction of PGE2 was greater (11-fold versus 70-fold, respectively). The cyclopentenone 15-deoxy-Δ12,14prostaglandin J2 (15d-PGJ2) decreased prostaglandin synthesis in a dose-dependent manner (0.1 to 10 μM), with more potency on PGE2 level than on 6-keto-PGF1α level (-90% versus -66% at 10 μM). A high dose of 15d-PGJ2 partly decreased COX-2 expression but decreased mPGES-1 expression almost completely at both the mRNA and protein levels. Rosiglitazone was poorly effective on these parameters even at 10 μM. Inhibitory effects of 10 μM 15d-PGJ2 were neither reduced by PPARγ blockade with GW-9662 nor enhanced by PPARγ overexpression, supporting a PPARγ-independent mechanism. EMSA and TransAM® analyses demonstrated that mutated IκBα almost completely suppressed the stimulating effect of IL-1β on mPGES-1 expression and PGE2 production, whereas 15d-PGJ2 inhibited NF-κB transactivation. These data demonstrate the following in IL-1-stimulated rat chondrocytes: first, mPGES-1 is rate limiting for PGE2 synthesis; second, activation of the prostaglandin cascade requires NF-κB activation; third, 15d-PGJ2 strongly inhibits the synthesis of prostaglandins, in contrast with rosiglitazone; fourth, inhibition by 15d-PGJ2 occurs independently of PPARγ through inhibition of

  10. 15d-PGJ{sub 2} stimulates HO-1 expression through p38 MAP kinase and Nrf-2 pathway in rat vascular smooth muscle cells

    SciTech Connect

    Lim, Hyun-Joung; Lee, Kuy-Sook; Lee, Seahyoung; Park, Jin-Hee; Choi, Hye-Eun; Go, Sang Hee; Kwak, Hyun-Jeong; Park, Hyun-Young

    2007-08-15

    15d-PGJ{sub 2}, a potent endogenous ligand for peroxisome proliferators activated receptor-{gamma}, is a cyclopentenone-type prostaglandin produced by many different types of cells. Pertinent to its effect on vascular smooth muscle cell (VSMC), antiproliferative effects have been most frequently reported. In the present study, we investigated the effect of 15d-PGJ{sub 2} on HO-1 expression that has been reported to inhibit VSMC proliferation. According to our data, 15d-PGJ{sub 2} significantly induced ROS/NO production and HO-1 expression in rVSMCs. We also observed 15d-PGJ{sub 2}-induced translocation of Nrf-2. In addition, ROS scavenger pretreatment suppressed 15d-PGJ{sub 2}-induced HO-1 expression while PPAR{gamma} antagonist did not, suggesting nuclear translocation of Nrf-2 and subsequent HO-1 expression was ROS dependent rather than PPAR{gamma} dependent. Furthermore, an inhibitor of p38 MAPK abolished 15d-PGJ{sub 2}-induced HO-1 expression. These data suggest that 15d-PGJ{sub 2}-induced up-regulation of HO-1 is independent of PPAR{gamma} but dependent of ROS and p38 MAPK pathway. The present study reports for the first time that 15d-PGJ{sub 2} induces HO-1 expression possibly using Nrf-2 pathway as a response to ROS in VSMCs.

  11. Anti-inflammatory activity of myricetin from Diospyros lotus through suppression of NF-κB and STAT1 activation and Nrf2-mediated HO-1 induction in lipopolysaccharide-stimulated RAW264.7 macrophages.

    PubMed

    Cho, Byoung Ok; Yin, Hong Hua; Park, Sang Hyun; Byun, Eui Baek; Ha, Hun Yong; Jang, Seon Il

    2016-08-01

    Diospyros lotus is traditionally used for the treatment of diabetes, diarrhea, tumor, and hypertension. The purpose of this study was to investigate the anti-inflammatory effect and underlying molecular mechanisms of myricetin in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Myricetin dose-dependently suppressed the production of pro-inflammatory mediators (NO, iNOS, PGE2, and COX-2) in LPS-stimulated RAW264.7 macrophages. Myricetin administration decreased the production of NO, iNOS, TNF-α, IL-6, and IL-12 in mice. Myricetin decreased NF-κB activation by suppressing the degradation of IκBα, nuclear translocation of p65 subunit of NF-κB, and NF-κB DNA binding activity in LPS-stimulated RAW264.7 macrophages. Moreover, myricetin attenuated the phosphorylation of STAT1 and the production of IFN-β in LPS-stimulated RAW264.7 macrophages. Furthermore, myricetin induced the expression of HO-1 through Nrf2 translocation. In conclusion, these results suggest that myricetin inhibits the production of pro-inflammatory mediators through the suppression of NF-κB and STAT1 activation and induction of Nrf2-mediated HO-1 expression in LPS-stimulated RAW264.7 macrophages. PMID:27068250

  12. Morin downregulates nitric oxide and prostaglandin E2 production in LPS-stimulated BV2 microglial cells by suppressing NF-κB activity and activating HO-1 induction.

    PubMed

    Dilshara, Matharage Gayani; Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Lee, Seungheon; Choi, Yung Hyun; Kim, Gi-Young

    2016-06-01

    Morin possesses anti-inflammatory activity against septic shock and allergic responses, and prevents acute liver damage. However, the biological mechanism of action of morin in neuroinflammation remains largely unknown. Therefore, the present study investigated whether morin has the ability to attenuate expression of proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Morin inhibited the expression of LPS-induced proinflammatory mediators such as NO and PGE2, without any cytotoxic effects. Furthermore, LPS-induced inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were inhibited both at the mRNA and protein levels in response to morin. Morin also attenuated LPS-induced DNA-binding activity of nuclear transcription factor-κB (NF-κB) and its promoter activity. Pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor, downregulated the expression of LPS-induced iNOS and COX-2, which suggests that morin-mediated NF-κB inhibition is the main signaling pathway responsible for the inhibition of iNOS and COX-2 expression. Additionally, morin increased induction of heme oxygenase-1 (HO-1) activity, leading to the suppression of NO and PGE2 production. Our results indicate that morin downregulates the expression of proinflammatory genes, such as iNOS and COX-2, involved in the synthesis of NO and PGE2 in LPS-stimulated BV2 microglial cells by suppressing NF-κB activity and activation of HO-1. Taken together, the findings of the present study suggest that morin may have potential as a therapeutic for the prevention of neuroinflammation.

  13. Induction of heme oxygenase-1 in normal and malignant B lymphocytes by 15-deoxy-Δ12, 14-prostaglandin J2 requires Nrf2

    PubMed Central

    Bancos, Simona; Baglole, Carolyn J.; Rahman, Irfan; Phipps, Richard P.

    2011-01-01

    Heme-oxygenase-1 (HO-1) is induced in response to oxidative stress and is believed to be a cytoprotective and anti-inflammatory enzyme. It is unknown whether normal or malignant human B lineage cells express HO-1. 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) is an interesting electrophilic lipid mediator able to increase oxidative stress in B cells. Here, we tested normal and malignant human B lineage cells for their ability to express HO-1 in response to 15d-PGJ2, as well as the signaling pathways required for HO-1 expression. 15d-PGJ2 potently induced HO-1 protein expression in normal and malignant B cells. Malignant B cells exhibited a greater induction of HO-1 protein compared to normal B lymphocytes. Using siRNA directed against the transcription factor Nrf2 and B cells isolated from Nrf2-deficient mice, we show that HO-1 induction by 15d-PGJ2 is dependent on Nrf2. These results show that, compared to normal B lymphocytes, malignant B cells have a greater capacity to increase their HO-1 protein levels in response to 15d-PGJ2. We speculate that the ability to highly express HO-1 by malignant B cells could confer a survival advantage. PMID:20064636

  14. Induction of heme oxygenase-1 in normal and malignant B lymphocytes by 15-deoxy-Delta(12,14)-prostaglandin J(2) requires Nrf2.

    PubMed

    Bancos, Simona; Baglole, Carolyn J; Rahman, Irfan; Phipps, Richard P

    2010-01-01

    Heme-oxygenase-1 (HO-1) is induced in response to oxidative stress and is believed to be a cytoprotective and anti-inflammatory enzyme. It is unknown whether normal or malignant human B-lineage cells express HO-1. 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an interesting electrophilic lipid mediator able to increase oxidative stress in B cells. Here, we tested normal and malignant human B-lineage cells for their ability to express HO-1 in response to 15d-PGJ(2), as well as the signaling pathways required for HO-1 expression. 15d-PGJ(2) potently induced HO-1 protein expression in normal and malignant B cells. Malignant B cells exhibited a greater induction of HO-1 protein compared to normal B lymphocytes. Using siRNA directed against the transcription factor Nrf2 and B cells isolated from Nrf2-deficient mice, we show that HO-1 induction by 15d-PGJ(2) is dependent on Nrf2. These results show that, compared to normal B lymphocytes, malignant B cells have a greater capacity to increase their HO-1 protein levels in response to 15d-PGJ(2). We speculate that the ability to highly express HO-1 by malignant B cells could confer a survival advantage.

  15. Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement.

    PubMed

    Zeng, Bin; Ren, Xiaofeng; Lin, Guosheng; Zhu, Chengang; Chen, Honglei; Yin, Jiechao; Jiang, Hong; Yang, Bo; Ding, Danhua

    2008-10-01

    The aim has been to determine whether the supernatants of mesenchymal stem cells (MSCs) transfected with adenovirus carrying human heme oxygenase-1 (hHO-1) gene protect cardiomyocytes from ischemic injury. We have found that hHO-1 infected MSCs (hHO-1-MSCs) increased expression of hHO-1 protein. Apoptosis of cultured hHO-1-MSCs exposed to hypoxia was suppressed. Several cytokines, including HGF, bFGF, TGF-beta, VEGF and IL-1beta, were produced by hHO-1-MSCs, some being significantly enhanced under hypoxia stimulation. Meanwhile, those cytokines reduced caspase-3 level and activity in cultured adult rat ventricular cardiomyocytes (ARVCs) exposed to hypoxia. Supernatants obtained from hHO-1-MSCs improved left ventricular function, limited myocardial infarct size, increased microvessel density, and inhibited apoptosis of cardiomyocytes in rat myocardial infarction. It can be concluded hHO-1-modified MSCs prevent myocardial cell injury via secretion of paracrine-acting mediators.

  16. Glial HO-1 expression, iron deposition and oxidative stress in neurodegenerative diseases.

    PubMed

    Schipper, H M

    1999-09-01

    The mechanisms responsible for the pathological deposition of brain iron in Parkinson's disease, Alzheimer's disease and other human neurodegenerative disorders remain poorly understood. In rat primary astrocyte cultures, we demonstrated that dopamine, cysteamine, H(2)O(2) and menadione rapidly induce heme oxygenase-1 (HO-1) expression (mRNA and protein) followed by sequestration of non-transferrin-derived (55)Fe by the mitochondrial compartment. The effects of dopamine on HO-1 expression were inhibited by ascorbate implicating a free radical mechanism of action. Dopamine-induced mitochondrial iron trapping was abrogated by administration of the heme oxygenase inhibitors, tin mesoporphyrin (SnMP) or dexamethasone (DEX) indicating that HO-1 upregulation is necessary for subsequent mitochondrial iron deposition in these cells. Overexpression of the human HO-1 gene in cultured rat astroglia by transient transfection also stimulated mitochondrial (55)Fe deposition, an effect that was again preventible by SnMP or DEX administration. We hypothesize that free ferrous iron and carbon monoxide generated by HO-1-mediated heme degradation promote mitochondrial membrane injury and the deposition of redox-active iron within this organelle. We have shown that the percentages of GFAP-positive astrocytes that co-express HO-1 in Parkinson-affected substantia nigra and Alzheimer-diseased hippocampus are significantly increased relative to age-matched controls. Stress-induced up-regulation of HO-1 in astroglia may be responsible for the abnormal patterns of brain iron deposition and mitochondrial insufficiency documented in various human neurodegenerative disorders. PMID:12835114

  17. Modulation of cGMP by human HO-1 retrovirus gene transfer in pulmonary microvessel endothelial cells.

    PubMed

    Abraham, Nader G; Quan, Shuo; Mieyal, Paul A; Yang, Liming; Burke-Wolin, Theresa; Mingone, Christopher J; Goodman, Alvin I; Nasjletti, Alberto; Wolin, Michael S

    2002-11-01

    Carbon monoxide (CO) stimulates guanylate cyclase (GC) and increases guanosine 3',5'-cyclic monophosphate (cGMP) levels. We transfected rat-lung pulmonary endothelial cells with a retrovirus-mediated human heme oxygenase (hHO)-1 gene. Pulmonary cells that expressed hHO-1 exhibited a fourfold increase in HO activity associated with decreases in the steady-state levels of heme and cGMP without changes in soluble GC (sGC) and endothelial nitric oxide synthase (NOS) proteins or basal nitrite production. Heme elicited significant increases in CO production and intracellular cGMP levels in both pulmonary endothelial and pulmonary hHO-1-expressing cells. N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, significantly decreased cGMP levels in heme-treated pulmonary endothelial cells but not heme-treated hHO-1-expressing cells. In the presence of exogenous heme, CO and cGMP levels in hHO-1-expressing cells exceeded the corresponding levels in pulmonary endothelial cells. Acute exposure of endothelial cells to SnCl2, which is an inducer of HO-1, increased cGMP levels, whereas chronic exposure decreased heme and cGMP levels. These results indicate that prolonged overexpression of HO-1 ultimately decreases sGC activity by limiting the availability of cellular heme. Heme activates sGC and enhances cGMP levels via a mechanism that is largely insensitive to NOS inhibition.

  18. EGR-1 regulates Ho-1 expression induced by cigarette smoke

    SciTech Connect

    Chen, Huaqun; Wang, Lijuan; Gong, Tao; Yu, Yang; Zhu, Chunhua; Li, Fen; Wang, Li; Li, Chaojun

    2010-05-28

    As an anti-oxidant molecule, heme oxygenase-1 (HO-1) has been implicated in the protection of lung injury by cigarette smoke (CS). The mechanisms regulating its expression have not been defined. In this report, the role of early growth response 1 (EGR-1) in the regulation of Ho-1 expression was investigated. In C57BL/6 mice with CS exposure, HO-1 was greatly increased in bronchial epithelial cells and alveolar inflammatory cells. In primary cultured mouse lung fibroblasts and RAW264.7 cells exposed to cigarette smoke water extract (CSE), an increase in HO-1 protein level was detected. In addition, CSE induced HO-1 expression was decreased in Egr-1 deficient mouse embryo fibroblasts (Egr-1{sup -/-} MEFs). Nuclear localization of EGR-1 was examined in mouse lung fibroblasts after exposure to CSE. Luciferase reporter activity assays showed that the enhancer region of the Ho-1 gene containing a proposed EGR-1 binding site was responsible for the induction of HO-1. A higher increase of alveolar mean linear intercept (Lm) was observed in lung tissues, and a larger increase in the number of total cells and monocytes/macrophages from bronchial alveolar lavage fluid was found in CS-exposed mice by loss of function of EGR-1 treatment. In summary, the present data demonstrate that EGR-1 plays a critical role in HO-1 production induced by CS.

  19. Expression and characterization of truncated human heme oxygenase (hHO-1) and a fusion protein of hHO-1 with human cytochrome P450 reductase.

    PubMed

    Wilks, A; Black, S M; Miller, W L; Ortiz de Montellano, P R

    1995-04-01

    A human heme oxygenase (hHO-1) gene without the sequence coding for the last 23 amino acids has been expressed in Escherichia coli behind the pho A promoter. The truncated enzyme is obtained in high yields as a soluble, catalytically-active protein, making it available for the first time for detailed mechanistic studies. The purified, truncated hHO-1/heme complex is spectroscopically indistinguishable from that of the rat enzyme and converts heme to biliverdin when reconstituted with rat liver cytochrome P450 reductase. A self-sufficient heme oxygenase system has been obtained by fusing the truncated hHO-1 gene to the gene for human cytochrome P450 reductase without the sequence coding for the 20 amino acid membrane binding domain. Expression of the fusion protein in pCWori+ yields a protein that only requires NADPH for catalytic turnover. The failure of exogenous cytochrome P450 reductase to stimulate turnover and the insensitivity of the catalytic rate toward changes in ionic strength establish that electrons are transferred intramolecularly between the reductase and heme oxygenase domains of the fusion protein. The Vmax for the fusion protein is 2.5 times higher than that for the reconstituted system. Therefore, either the covalent tether does not interfere with normal docking and electron transfer between the flavin and heme domains or alternative but equally efficient electron transfer pathways are available that do not require specific docking.

  20. 15-deoxy prostaglandin J2, the nonenzymatic metabolite of prostaglandin D2, induces apoptosis in keratinocytes of human hair follicles: a possible explanation for prostaglandin D2-mediated inhibition of hair growth.

    PubMed

    Joo, Hyun Woo; Kang, Yoo Ri; Kwack, Mi Hee; Sung, Young Kwan

    2016-07-01

    Recent studies have shown that prostaglandin D2 (PGD2) and its nonenzymatic metabolite, 15-deoxy-Δ(12,14)-prostaglandin J2 (15-dPGJ2), inhibit in vitro growth of explanted human hair follicles and inhibit hair growth in mice through the GPR44 (DP2). However, the underlying mechanism is still unclear. In this study, we first investigated the expression of DP2 in human hair follicles and in cultured follicular cells. We found that DP2 is strongly expressed in the outer root sheath (ORS) cells and weakly expressed in the dermal papilla (DP) cells. We observed slight growth stimulation when ORS and DP cells were treated with PGD2. We also observed slight growth stimulation when DP and ORS cells were treated with low concentrations (0.5 and 1 μM) of 15-dPGJ2. However, 5 μM 15-dPGJ2 inhibited the viability and caused apoptosis of both cell types. Exposure of cultured human hair follicles to 15-dPGJ2 resulted in significant apoptosis in follicular keratinocytes. Altogether, our data provide an evidence that 15-dPGJ2 promotes apoptosis in follicular keratinocytes and provide rationale for developing remedies for the prevention and treatment of hair loss based on DP2 antagonism.

  1. Regulation of microglial migration, phagocytosis, and neurite outgrowth by HO-1/CO signaling.

    PubMed

    Scheiblich, Hannah; Bicker, Gerd

    2015-08-01

    Clearance of infected and apoptotic neuronal corpses during inflammatory conditions is a fundamental process to create a favorable environment for neuronal recovery. Microglia are the resident immune cells and the predominant phagocytic cells of the CNS, showing a multitude of cellular responses upon activation. Here, we investigated in functional assays how the CO generating enzyme heme oxygenase 1 (HO-1) influences BV-2 microglial migration, clearance of debris, and neurite outgrowth of human NT2 neurons. Stimulation of HO-1 activity attenuated microglial migration in a scratch wound assay, and phagocytosis in a cell culture model of acute inflammation comprising lipopolysaccharide (LPS)-activated microglia and apoptosis-induced neurons. Application of a CO donor prevented the production of NO during LPS stimulation, and reduced microglial migration and engulfment of neuronal debris. LPS-activated microglia inhibited neurite elongation of human neurons without requiring direct cell-cell surface contact. The inhibition of neurite outgrowth was totally reversed by application of exogenous CO or increased internal CO production through supply of the substrate hemin to HO. Our results point towards a vital cytoprotective role of HO-1/CO signaling after microglial activation. In addition, they support a therapeutic potential of CO releasing chemical agents in the treatment of excessive inflammatory conditions in the CNS.

  2. Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.

    PubMed

    Ghosh, Asish K; Bhattacharyya, Swati; Wei, Jun; Kim, Suyeon; Barak, Yaacov; Mori, Yasuji; Varga, John

    2009-09-01

    Ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-beta). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-gamma in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-beta activity by PPAR-gamma ligands involves cellular PPAR-gamma, since 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) failed to block TGF-beta-induced responses in either primary cultures of PPAR-gamma-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-gamma. Next, we examined the molecular basis underlying the abrogation of TGF-beta signaling by PPAR-gamma in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-gamma without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-beta, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-gamma. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-beta-induced stimulation of COL1A2 in the presence of PPAR-gamma ligands. Collectively, these results indicate that PPAR-gamma blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-beta-induced collagen gene expression. Pharmacological activation of PPAR-gamma thus may represent a novel therapeutic approach to target p300-dependent TGF-beta profibrotic responses such as stimulation of collagen gene expression.

  3. Role of Hydroxytyrosol-dependent Regulation of HO-1 Expression in Promoting Wound Healing of Vascular Endothelial Cells via Nrf2 De Novo Synthesis and Stabilization.

    PubMed

    Zrelli, Houda; Kusunoki, Miki; Miyazaki, Hitoshi

    2015-07-01

    Hydroxytyrosol (HT), an olive plant (Olea europaea L.) polyphenol, has proven atheroprotective effects. We previously demonstrated that heme oxygenase-1 (HO-1) is involved in the HT dependent prevention of dysfunction induced by oxidative stress in vascular endothelial cells (VECs). Here, we further investigated the signaling pathway of HT-dependent HO-1 expression in VECs. HT dose- and time-dependently increased HO-1 mRNA and protein levels through the PI3K/Akt and ERK1/2 pathways. Cycloheximide and actinomycin D inhibited both increases, suggesting that HT-triggered HO-1 induction is transcriptionally regulated and that de novo protein synthesis is necessary for this HT effect. HT stimulated nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2). This Nrf2 accumulation was blocked by actinomycin D and cycloheximide whereas HT in combination with the 26S proteasome inhibitor MG132 enhanced the accumulation. HT also extended the half-life of Nrf2 proteins by decelerating its turnover. Moreover, HO-1 inhibitor, ZnppIX and CO scavenger, hemoglobin impaired HT-dependent wound healing while CORM-2, a CO generator, accelerated wound closure. Together, these data demonstrate that HT upregulates HO-1 expression by stimulating the nuclear accumulation and stabilization of Nrf2, leading to the wound repair of VECs crucial in the prevention of atherosclerosis.

  4. NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells

    SciTech Connect

    Pecorelli, Alessandra; Bocci, Velio; Acquaviva, Alessandra; Belmonte, Giuseppe; Gardi, Concetta; Virgili, Fabio; Ciccoli, Lucia; Valacchi, Giuseppe

    2013-02-15

    During the last decade, it has been shown that the activation of NRF2 and the binding to electrophile-responsive element (EpREs), stimulates the expression of a great number of genes responsible for the synthesis of phase I and phase II proteins, including antioxidants enzymes and heme oxygenase-1 (HO-1). This critical cell response occurs in cardiovascular, degenerative and chronic infective diseases aggravated by a chronic oxidative stress. In our previous reports we have shown that ozonated plasma is able to up-regulate HO-1 expression in endothelial cells. In the present work we investigated a candidate mechanism involved in this process. After treatment with increasing doses of ozonated serum (20, 40 and 80 μg/mL O{sub 3} per mL of serum), a clear dose dependent activation of NRF2 and the subsequent induction of HO-1 and NAD(P)H quinone oxidoreductase 1(NQO1) was observed. This effect was also present when cells were treated with serum and hydrogen peroxide (H{sub 2}O{sub 2}) or serum and 4-hydroxynonenal (4HNE). Moreover, the treatment with ozonated serum was associated with a dose-dependent activation of extracellular-signal-regulated kinases (ERK1/2) and p38 MAP kinases (p38), not directly involved in NRF2 activation. These data, provide a new insight on the mechanism responsible for the induction of HO-1 expression by ozonated serum in the endothelium, and have a practical importance as an expedient approach to the treatment of patients with both effective orthodox drugs and ozonated autohemotherapy, targeted to the restoration of redox homeostasis. - Highlights: ► Endothelial HO1 is upregulated by ozonated plasma ► This activation is induced by NRF2 and it is ERK independent. ► 4HNE and H{sub 2}O{sub 2} are the main molecules involved in this process. ► Ozonated plasma induced a hormetic effect ► Combination of orthodox medicine and ozonated plasma can be a useful treatment.

  5. AN ENZYME LINKED IMMUNOSORBENT ASSAY FOR THE HO-1 ISOFORM OF HEME OXYGENASE

    EPA Science Inventory

    AN ENZYME LINKED IMMUNOSORBENT ASSAY FOR THE HO-1 ISOFORM OF HEME OXYGENASE

    Heme oxygenase (HO) occurs in biological tissues as two major isoforms HO-1 and HO-2. HO-1 is inducible by many treatments, particularly oxidative stress-related conditions such as depletion of gl...

  6. Involvement of PKA and HO-1 signaling in anti-inflammatory effects of surfactin in BV-2 microglial cells

    SciTech Connect

    Park, Sun Young; Kim, Ji-Hee; Lee, Sang Joon; Kim, YoungHee

    2013-04-01

    Surfactin, one of the most powerful biosurfactants, is a bacterial cyclic lipopeptide. Here, we investigated the anti-neuroinflammatory properties of surfactin in lipoteichoic acid (LTA)-stimulated BV-2 microglial cells. Surfactin significantly inhibited excessive production of the pro-inflammatory mediators TNF-α, IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), prostaglandin E{sub 2} (PGE{sub 2}), nitric oxide (NO) and reactive oxygen species (ROS), and suppressed the expression of matrix metalloproteinase-9 (MMP-9), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Subsequent mechanistic studies revealed that surfactin inhibited LTA-induced nuclear factor-kappaB (NF-κB) and signal transducer and activator of transcription-1 (STAT-1) activation. However, surfactin increases the phosphorylation of the STAT-3, a component of the homeostatic mechanism causing anti-inflammatory events. We also demonstrated that surfactin induces heme oxygenase-1 (HO-1) expression and nuclear factor-regulated factor-2 (Nrf-2) activation, and that the anti-inflammatory effects of surfactin are abrogated by small interfering RNA-mediated knock-down of HO-1 or Nrf-2. Interestingly, we found that surfactin increased the level of cAMP and induced phosphorylation of cAMP responsive element binding protein (CREB) in microglial cells. Furthermore, treatment with the protein kinase A (PKA) inhibitor, H-89, blocked HO-1 induction by surfactin and abolished surfactin's suppressive effects on ROS and NO production. These results indicate that HO-1 and its upstream effector, PKA, play a pivotal role in the anti-neuroinflammatory response of surfactin in LTA-stimulated microglia. Therefore, surfactin might have therapeutic potential for neuroprotective agents to treat inflammatory and neurodegenerative diseases. - Highlights: ► Surfactin inhibits proinflammatory mediator synthesis in LTA-activated BV-2 cells. ► Surfactin suppresses NF-κB and STAT-1, but potentiates

  7. Non-coding RNA derived from the region adjacent to the human HO-1 E2 enhancer selectively regulates HO-1 gene induction by modulating Pol II binding

    PubMed Central

    Maruyama, Atsushi; Mimura, Junsei; Itoh, Ken

    2014-01-01

    Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation. However, it remains unclear whether eRNAs are involved in the regulation of human heme oxygenase-1 gene (HO-1) induction. Here, we report that multiple nuclear-enriched eRNAs are transcribed from the regions adjacent to two human HO-1 enhancers (i.e. the distal E2 and proximal E1 enhancers), and some of these eRNAs are induced by the oxidative stress-causing reagent diethyl maleate (DEM). We demonstrated that the expression of one forward direction (5′ to 3′) eRNA transcribed from the human HO-1 E2 enhancer region (named human HO-1enhancer RNA E2-3; hereafter called eRNA E2-3) was induced by DEM in an NRF2-dependent manner in HeLa cells. Conversely, knockdown of BACH1, a repressor of HO-1 transcription, further increased DEM-inducible eRNA E2-3 transcription as well as HO-1 expression. In addition, we showed that knockdown of eRNA E2-3 selectively down-regulated DEM-induced HO-1 expression. Furthermore, eRNA E2-3 knockdown attenuated DEM-induced Pol II binding to the promoter and E2 enhancer regions of HO-1 without affecting NRF2 recruitment to the E2 enhancer. These findings indicate that eRNAE2-3 is functional and is required for HO-1 induction. PMID:25404134

  8. HO-1 expression increases mesenchymal stem cell-derived osteoblast but decreases adipocyte lineage

    PubMed Central

    Vanella, Luca; Kim, Dong Hyun; Asprinio, David; Peterson, Stephen J.; Barbagallo, Ignazio; Vanella, Angelo; Goldstein, Dove; Ikehara, Susumu; Abraham, Nader G.

    2009-01-01

    Human bone marrow mesenchymal stem cells (MSC) are pleitrophic cells that differentiate to either adipocytes or osteoblasts as a result of cross-talk by specific signaling pathways including heme oxygenase (HO)-1/-2 expression. We examined the effect of inducers of HO-1 expression and inhibitors of HO activity on MSC differentiation to the osteoblast and adipogenesis lineage. HO-1 expression is increased during osteoblast stem cell development, but remains elevated, at 25 days. The increase in HO-1 levels proceed an increase in alkaline phosphatase (AP) activity and an increase in BMP, osteonectin and RUNX-2 mRNA. Induction of HO-1 by osteogenic growth peptide (OGP) was associated with an increase in BMP-2 and osteonectin. Exposure of MSC to high glucose levels decreased osteocalcin and osteogenic protein expression, which was reversed by upregulation of the OGP-mediated increase in HO-1 expression. The glucose mediated decrease in HO-1 resulted in decreased levels of pAMPK, pAKT and the eNOS signaling pathway and was reversed by OGP. In contrast, MSC-derived adipocytes were increased by glucose. HO-1 siRNA decreased HO-1 expression but increased adipocyte stem cell differentiation and the adipogenesis marker, PPARγ. Thus, upregulation of HO-1 expression shifts the balance of MSC differentiation in favor of the osteoblast lineage. In contrast, a decrease in HO-1 or exposure to glucose drives the MSC towards adipogenesis. Thus targeting HO-1 expression is a portal to increased osteoblast stem cell differentiation and to the attenuation of osteoporosis by the promotion of bone formation. PMID:19853072

  9. [hHO-1 structure prediction and its mutant construct, expression, purification and activity analysis].

    PubMed

    Xia, Zhen Wei; Cui, Wen Jun; Zhou, Wen Pu; Zhang, Xue Hong; Shen, Qing Xiang; Li, Yun Zhu; Yu, Shan Chang

    2004-10-01

    Human Heme Oxygenase-1 (hHO-1) is the rate-limiting enzyme in the catabolism reaction of heme, which directly regulates the concentration of bilirubin in human body. The mutant structure was simulated by Swiss-pdbviewer procedure, which showed that the structure of active pocket was changed distinctly after Ala25 substituted for His25 in active domain, but the mutated enzyme still binded with heme. On the basis of the results, the expression vectors, pBHO-1 and pBHO-1(M), were constructed, induced by IPTG and expressed in E. coli DH5alpha strain. The expression products were purified with 30%-60% saturation (NH4)2SO4 and Q-Sepharose Fast Flow column chromatography. The concentration of hHO-1 in 30%-60% saturation (NH4)2SO4 components and in fractions through twice column chromatography was 3.6-fold and 30-fold higher than that in initial product, respectively. The activity of wild hHO-1 (whHO-1) and mutant hHO-1 (deltahHO-1) showed that the activity of deltahHO-1 was reduced 91.21% compared with that of whHO-1. The study shows that His25 is of importance for the mechanism of hHO-1, and provides the possibility for effectively regulating the activity to exert biological function.

  10. Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth

    PubMed Central

    Adamo, Hanibal; Thysell, Elin; Jernberg, Emma; Stattin, Pär; Widmark, Anders; Wikström, Pernilla; Bergh, Anders

    2016-01-01

    Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer. PMID:27280718

  11. Induction of heme-oxygenase-1 (HO-1) does not enhance adiponectin production in human adipocytes: Evidence against a direct HO-1 - Adiponectin axis.

    PubMed

    Yang, Mengliu; Kimura, Masaki; Ng, Choaping; He, Jingjing; Keshvari, Sahar; Rose, Felicity J; Barclay, Johanna L; Whitehead, Jonathan P

    2015-09-15

    Adiponectin is a salutary adipokine and hypoadiponectinemia is implicated in the aetiology of obesity-related inflammation and cardiometabolic disease making therapeutic strategies to increase adiponectin attractive. Emerging evidence, predominantly from preclinical studies, suggests induction of heme-oxygenase-1 (HO-1) increases adiponectin production and reduces inflammatory tone. Here, we aimed to test whether induction of HO-1 enhanced adiponectin production from mature adipocytes. Treatment of human adipocytes with cobalt protoporphyrin (CoPP) or hemin for 24-48 h increased HO-1 expression and activity without affecting adiponectin expression and secretion. Treatment of adipocytes with TNFα reduced adiponectin secretion and increased expression and secretion of additional pro-inflammatory cytokines, IL-6 and MCP-1, as well as expression of sXBP-1, a marker of ER stress. HO-1 induction failed to reverse these effects. These results demonstrate that induction of HO-1 does not directly enhance adiponectin production or ameliorate the pro-inflammatory effects of TNFα and argue against a direct HO-1 - adiponectin axis.

  12. The Anti-Inflammatory Activity of Eucommia ulmoides Oliv. Bark. Involves NF-κB Suppression and Nrf2-Dependent HO-1 Induction in BV-2 Microglial Cells

    PubMed Central

    Kwon, Seung-Hwan; Ma, Shi-Xun; Hwang, Ji-Young; Ko, Yong-Hyun; Seo, Ji-Yeon; Lee, Bo-Ram; Lee, Seok-Yong; Jang, Choon-Gon

    2016-01-01

    In the present study, we investigated the anti-inflammatory properties of Eucommia ulmoides Oliv. Bark. (EUE) in lipopolysaccharide (LPS)-stimulated microglial BV-2 cells and found that EUE inhibited LPS-mediated up-regulation of pro-inflammatory response factors. In addition, EUE inhibited the elevated production of pro-inflammatory cytokines, mediators, and reactive oxygen species (ROS) in LPS-stimulated BV-2 microglial cells. Subsequent mechanistic studies revealed that EUE suppressed LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs), phosphoinositide-3-kinase (PI3K)/Akt, glycogen synthase kinase-3β (GSK-3β), and their downstream transcription factor, nuclear factor-kappa B (NF-κB). EUE also blocked the nuclear translocation of NF-κB and inhibited its binding to DNA. We next demonstrated that EUE induced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated heme oxygenase-1 (HO-1) expression. We determined that the significant up-regulation of HO-1 expression by EUE was a consequence of Nrf2 nuclear translocation; furthermore, EUE increased the DNA binding of Nrf2. In contrast, zinc protoporphyrin (ZnPP), a specific HO-1 inhibitor, blocked the ability of EUE to inhibit NO and PGE2 production, indicating the vital role of HO-1. Overall, our results indicate that EUE inhibits pro-inflammatory responses by modulating MAPKs, PI3K/Akt, and GSK-3β, consequently suppressing NF-κB activation and inducing Nrf2-dependent HO-1 activation. PMID:27068259

  13. HO-1-mediated macroautophagy: a mechanism for unregulated iron deposition in aging and degenerating neural tissues.

    PubMed

    Zukor, Hillel; Song, Wei; Liberman, Adrienne; Mui, Jeannie; Vali, Hojatollah; Fillebeen, Carine; Pantopoulos, Kostas; Wu, Ting-Di; Guerquin-Kern, Jean-Luc; Schipper, Hyman M

    2009-05-01

    Oxidative stress, deposition of non-transferrin iron, and mitochondrial insufficiency occur in the brains of patients with Alzheimer disease (AD) and Parkinson disease (PD). We previously demonstrated that heme oxygenase-1 (HO-1) is up-regulated in AD and PD brain and promotes the accumulation of non-transferrin iron in astroglial mitochondria. Herein, dynamic secondary ion mass spectrometry (SIMS) and other techniques were employed to ascertain (i) the impact of HO-1 over-expression on astroglial mitochondrial morphology in vitro, (ii) the topography of aberrant iron sequestration in astrocytes over-expressing HO-1, and (iii) the role of iron regulatory proteins (IRP) in HO-1-mediated iron deposition. Astroglial hHO-1 over-expression induced cytoplasmic vacuolation, mitochondrial membrane damage, and macroautophagy. HO-1 promoted trapping of redox-active iron and sulfur within many cytopathological profiles without impacting ferroportin, transferrin receptor, ferritin, and IRP2 protein levels or IRP1 activity. Thus, HO-1 activity promotes mitochondrial macroautophagy and sequestration of redox-active iron in astroglia independently of classical iron mobilization pathways. Glial HO-1 may be a rational therapeutic target in AD, PD, and other human CNS conditions characterized by the unregulated deposition of brain iron.

  14. HO-1 Upregulation Attenuates Adipocyte Dysfunction, Obesity, and Isoprostane Levels in Mice Fed High Fructose Diets

    PubMed Central

    Harsh, Mohit; Sodhi, Komal; Shapiro, Joseph I.; Abraham, Nader G.

    2014-01-01

    Background. Fructose metabolism is an unregulated metabolic pathway and excessive fructose consumption is known to activate ROS. HO-1 is a potent antioxidant gene that plays a key role in decreasing ROS and isoprostanes. We examined whether the fructose-mediated increase in adipocyte dysfunction involves an increase in isoprostanes and that pharmacological induction of HO-1 would decrease both isoprostane levels and adipogenesis. Methods and Results. We examined the effect of fructose, on adipogenesis in human MSCs in the presence and absence of CoPP, an inducer of HO-1. Fructose increased adipogenesis and the number of large lipid droplets while decreasing the number of small lipid droplets (P < 0.05). Levels of heme and isoprostane in fructose treated MSC-derived adipocytes were increased. CoPP reversed these effects and markedly increased HO-1 and the Wnt signaling pathway. The high fructose diet increased heme levels in adipose tissue and increased circulating isoprostane levels (P < 0.05 versus control). Fructose diets decreased HO-1 and adiponectin levels in adipose tissue. Induction of HO-1 by CoPP decreased isoprostane synthesis (P < 0.05 versus fructose). Conclusion. Fructose treatment resulted in increased isoprostane production and adipocyte dysfunction, which was reversed by the increased expression of HO-1. PMID:25295182

  15. The role of HO-1 in protection against lead-induced neurotoxicity.

    PubMed

    Li, Xiaoyi; Ye, Fang; Li, Lili; Chang, Wei; Wu, Xiongwen; Chen, Jun

    2016-01-01

    Lead is a pervasive and persistent environmental pollutant that exerts deleterious effects on all living organisms and continues to threaten public health on a global scale. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme that mediates antioxidative and cytoprotective effects to maintain cellular redox homeostasis and protect cells from oxidative stress. This study was designed to explore the role of HO-1 in protection against lead neurotoxicity and the signaling pathways involved. Lead acetate (PbAc) exposure resulted in increased HO-1 expression in primary rat hippocampal neurons and SH-SY5Y cells. PbAc-induced intracellular reactive oxygen species (ROS) also increased, and cell viability decreased in SH-SY5Y cells. We further demonstrated that HO-1 could be induced by PbAc through the P38, ERK1/2, and PI3K/AKT signaling pathways in a ROS-dependent manner and through the JNK pathway in a ROS-independent manner. Further investigation revealed that HO-1 overexpression significantly restrained cell apoptosis and ROS production induced by PbAc in SH-SY5Y cells. Moreover, HO-1 knockdown aggravated PbAc-induced cell apoptosis and ROS production. Our results indicated that HO-1 was a novel protective factor that could efficiently inhibit PbAc-induced oxidative stress and cell death in the nervous system, thereby providing the potential therapeutic strategies for the prevention and treatment of lead-related diseases.

  16. Downregulation of Heme Oxygenase 1 (HO-1) Activity in Hematopoietic Cells Enhances Their Engraftment After Transplantation.

    PubMed

    Adamiak, Mateusz; Moore, Joseph B; Zhao, John; Abdelbaset-Ismail, Ahmed; Grubczak, Kamil; Rzeszotek, Sylwia; Wysoczynski, Marcin; Ratajczak, Mariusz Z

    2016-01-01

    Heme oxygenase 1 (HO-1) is an inducible stress-response enzyme that not only catalyzes the degradation of heme (e.g., released from erythrocytes) but also has an important function in various physiological and pathophysiological states associated with cellular stress, such as ischemic/reperfusion injury. HO-1 has a well-documented anti-inflammatory potential, and HO-1 has been reported to have a negative effect on adhesion and migration of neutrophils in acute inflammation in a model of peritonitis. This finding is supported by our recent observation that hematopoietic stem progenitor cells (HSPCs) from HO-1 KO mice are easy mobilizers, since they respond better to peripheral blood chemotactic gradients than wild-type littermates. Based on these findings, we hypothesized that transient inhibition of HO-1 by nontoxic small-molecule inhibitors would enhance migration of HSPCs in response to bone marrow chemoattractants and thereby facilitate their homing. To directly address this issue, we generated several human hematopoietic cell lines in which HO-1 was upregulated or downregulated. We also exposed murine and human BM-derived cells to small-molecule activators and inhibitors of HO-1. Our results indicate that HO-1 is an inhibitor of hematopoietic cell migration in response to crucial BM homing chemoattractants such as stromal-derived factor 1 (SDF-1) and sphingosine-1-phosphate (S1P). Most importantly, our in vitro and in vivo animal experiments demonstrate for the first time that transiently inhibiting HO-1 activity in HSPCs by small-molecule inhibitors improves HSPC engraftment. We propose that this simple and inexpensive strategy could be employed in the clinical setting to improve engraftment of HSPCs, particularly in those situations in which the number of HSPCs available for transplant is limited (e.g., when transplanting umbilical cord blood). PMID:27412411

  17. Mechanical Stress Changes the Complex Interplay Between HO-1, Inflammation and Fibrosis, During Excisional Wound Repair.

    PubMed

    Cremers, Niels A J; Suttorp, Maarten; Gerritsen, Marlous M; Wong, Ronald J; van Run-van Breda, Coby; van Dam, Gooitzen M; Brouwer, Katrien M; Kuijpers-Jagtman, Anne Marie; Carels, Carine E L; Lundvig, Ditte M S; Wagener, Frank A D T G

    2015-01-01

    Mechanical stress following surgery or injury can promote pathological wound healing and fibrosis, and lead to functional loss and esthetic problems. Splinted excisional wounds can be used as a model for inducing mechanical stress. The cytoprotective enzyme heme oxygenase-1 (HO-1) is thought to orchestrate the defense against inflammatory and oxidative insults that drive fibrosis. Here, we investigated the activation of the HO-1 system in a splinted and non-splinted full-thickness excisional wound model using HO-1-luc transgenic mice. Effects of splinting on wound closure, HO-1 promoter activity, and markers of inflammation and fibrosis were assessed. After seven days, splinted wounds were more than three times larger than non-splinted wounds, demonstrating a delay in wound closure. HO-1 promoter activity rapidly decreased following removal of the (epi)dermis, but was induced in both splinted and non-splinted wounds during skin repair. Splinting induced more HO-1 gene expression in 7-day wounds; however, HO-1 protein expression remained lower in the epidermis, likely due to lower numbers of keratinocytes in the re-epithelialization tissue. Higher numbers of F4/80-positive macrophages, αSMA-positive myofibroblasts, and increased levels of the inflammatory genes IL-1β, TNF-α, and COX-2 were present in 7-day splinted wounds. Surprisingly, mRNA expression of newly formed collagen (type III) was lower in 7-day wounds after splinting, whereas, VEGF and MMP-9 were increased. In summary, these data demonstrate that splinting delays cutaneous wound closure and HO-1 protein induction. The pro-inflammatory environment following splinting may facilitate higher myofibroblast numbers and increase the risk of fibrosis and scar formation. Therefore, inducing HO-1 activity against mechanical stress-induced inflammation and fibrosis may be an interesting strategy to prevent negative effects of surgery on growth and function in patients with orofacial clefts or in patients with

  18. Over-expression of HO-1 on mesenchymal stem cells promotes angiogenesis and improves myocardial function in infarcted myocardium

    PubMed Central

    2010-01-01

    Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with diverse cytoprotective effects, and reported to have an important role in angiogenesis recently. Here we investigated whether HO-1 transduced by mesenchymal stem cells (MSCs) can induce angiogenic effects in infarcted myocardium. HO-1 was transfected into cultured MSCs using an adenoviral vector. 1 × 106 Ad-HO-1-transfected MSCs (HO-1-MSCs) or Ad-Null-transfected MSCs (Null-MSCs) or PBS was respectively injected into rat hearts intramyocardially at 1 h post-myocardial infarction. The results showed that HO-1-MSCs were able to induce stable expression of HO-1 in vitro and in vivo. The capillary density and expression of angiogenic growth factors, VEGF and FGF2 were significantly enhanced in HO-1-MSCs-treated hearts compared with Null-MSCs-treated and PBS-treated hearts. However, the angiogenic effects of HO-1 were abolished by treating the animals with HO inhibitor, zinc protoporphyrin. The myocardial apoptosis was marked reduced with significantly reduced fibrotic area in HO-1-MSCs-treated hearts; Furthermore, the cardiac function and remodeling were also significantly improved in HO-1-MSCs-treated hearts. Our current findings support the premise that HO-1 transduced by MSCs can induce angiogenic effects and improve heart function after acute myocardial infarction. PMID:20925964

  19. Spirulina non-protein components induce BDNF gene transcription via HO-1 activity in C6 glioma cells.

    PubMed

    Morita, Kyoji; Itoh, Mari; Nishibori, Naoyoshi; Her, Song; Lee, Mi-Sook

    2015-01-01

    Blue-green algae are known to contain biologically active proteins and non-protein substances and considered as useful materials for manufacturing the nutritional supplements. Particularly, Spirulina has been reported to contain a variety of antioxidants, such as flavonoids, carotenoids, and vitamin C, thereby exerting their protective effects against the oxidative damage to the cells. In addition to their antioxidant actions, polyphenolic compounds have been speculated to cause the protection of neuronal cells and the recovery of neurologic function in the brain through the production of brain-derived neurotrophic factor (BDNF) in glial cells. Then, the protein-deprived extract was prepared by removing the most part of protein components from aqueous extract of Spirulina platensis, and the effect of this extract on BDNF gene transcription was examined in C6 glioma cells. Consequently, the protein-deprived extract was shown to cause the elevation of BDNF mRNA levels following the expression of heme oxygenase-1 (HO-1) in the glioma cells. Therefore, the non-protein components of S. platensis are considered to stimulate BDNF gene transcription through the HO-1 induction in glial cells, thus proposing a potential ability of the algae to indirectly modulate the brain function through the glial cell activity. PMID:25349086

  20. The neuroprotection of hypoxic preconditioning on rat brain against traumatic brain injury by up-regulated transcription factor Nrf2 and HO-1 expression.

    PubMed

    Shu, Longfei; Wang, Chunlin; Wang, Jinbiao; Zhang, Yongming; Zhang, Xing; Yang, Yanyan; Zhuo, Jianwei; Liu, Jiachuan

    2016-01-12

    Hypoxic preconditioning (HPC) increases the inherent tolerance of brain tissue suffering from severe hypoxia or ischemia insult by stimulating the protective ability of the brain. However, little is known concerning the effect of HPC on traumatic brain injury (TBI). We designed this study to investigate the effect of HPC on TBI and explore its underlying mechanisms. We found that HPC significantly alleviates neurological dysfunction, lessens brain edema, reduces cell apoptosis, increases neuronal survival, up-regulates the expressions of Nrf2 and HO-1, and decreases the inducer of protein carbonyls, 4-hydroxy-2-nonenal, and 8-hydroxy-2-deoxyguanosine in the brain tissue of rats 24h after brain injury. However, no influence was observed in normal rats after only 3d of hypoxic training. Results further indicated that HPC protects the brain against traumatic damage. This protective effect may be achieved by up-regulating Nrf2 and HO-1 expression and alleviating oxidative stress damage. PMID:26590328

  1. HO-1 up-regulation: a key point in high-risk neuroblastoma resistance to bortezomib.

    PubMed

    Furfaro, Anna Lisa; Piras, Sabrina; Passalacqua, Mario; Domenicotti, Cinzia; Parodi, Alessia; Fenoglio, Daniela; Pronzato, Maria Adelaide; Marinari, Umberto Maria; Moretta, Lorenzo; Traverso, Nicola; Nitti, Mariapaola

    2014-04-01

    High-risk neuroblastoma (NB) is characterized by the development of chemoresistance, and bortezomib (BTZ), a selective inhibitor of proteasome, has been proposed in order to overcome drug resistance. Considering the involvement of the nuclear factor-erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in the antioxidant and detoxifying ability of cancer cells, in this study we have investigated their role in differently aggressive NB cell lines treated with BTZ, focusing on the modulation of HO-1 to improve sensitivity to therapy. We have shown that MYCN amplified HTLA-230 cells were slightly sensitive to BTZ treatment, due to the activation of Nrf2 that led to an impressive up-regulation of HO-1. BTZ-treated HTLA-230 cells down-regulated p53 and up-regulated p21, favoring cell survival. The inhibition of HO-1 activity obtained by Zinc (II) protoprophyrin IX (ZnPPIX) was able to significantly increase the pro-apoptotic effect of BTZ in a p53- and p21-independent way. However, MYCN non-amplified SH-SY5Y cells showed a greater sensitivity to BTZ in relation to their inability to up-regulate HO-1. Therefore, we have shown that HO-1 inhibition improves the sensitivity of aggressive NB to proteasome inhibition-based therapy, suggesting that HO-1 up-regulation can be used as a marker of chemoresistance in NB. These results open up a new scenario in developing a combined therapy to overcome chemoresistance in high-risk neuroblastoma.

  2. HO-1 Protects against Hypoxia/Reoxygenation-Induced Mitochondrial Dysfunction in H9c2 Cardiomyocytes

    PubMed Central

    Chen, Dongling; Jin, Zhe; Zhang, Jingjing; Jiang, Linlin; Chen, Kai; He, Xianghu; Song, Yinwei; Ke, Jianjuan; Wang, Yanlin

    2016-01-01

    Background Mitochondrial dysfunction would ultimately lead to myocardial cell apoptosis and death during ischemia-reperfusion injuries. Autophagy could ameliorate mitochondrial dysfunction by autophagosome forming, which is a catabolic process to preserve the mitochondrial’s structural and functional integrity. HO-1 induction and expression are important protective mechanisms. This study in order to investigate the role of HO-1 during mitochondrial damage and its mechanism. Methods and Results The H9c2 cardiomyocyte cell line were incubated by hypoxic and then reoxygenated for the indicated time (2, 6, 12, 18, and 24 h). Cell viability was tested with CCK-8 kit. The expression of endogenous HO-1(RT-PCR and Western blot) increased with the duration of reoxygenation and reached maximum levels after 2 hours of H/R; thereafter, the expression gradually decreased to a stable level. Mitochondrial dysfunction (Flow cytometry quantified the ROS generation and JC-1 staining) and autophagy (The Confocal microscopy measured the autophagy. RFP-GFP-LC3 double-labeled adenovirus was used for testing.) were induced after 6 hours of H/R. Then, genetic engineering technology was employed to construct an Lv-HO1-H9c2 cell line. When HO-1 was overexpressed, the LC3II levels were significantly increased after reoxygenation, p62 protein expression was significantly decreased, the level of autophagy was unchanged, the mitochondrial membrane potential was significantly increased, and the mitochondrial ROS level was significantly decreased. Furthermore, when the HO-1 inhibitor ZnPP was applied the level of autophagy after reoxygenation was significantly inhibited, and no significant improvement in mitochondrial dysfunction was observed. Conclusions During myocardial hypoxia-reoxygenation injury, HO-1 overexpression induces autophagy to protect the stability of the mitochondrial membrane and reduce the amount of mitochondrial oxidation products, thereby exerting a protective effect. PMID

  3. Lung endothelial HO-1 targeting in vivo using lentiviral miRNA regulates apoptosis and autophagy during oxidant injury

    PubMed Central

    Zhang, Yi; Jiang, Ge; Sauler, Maor; Lee, Patty J.

    2013-01-01

    The lung endothelium is a major target for inflammatory and oxidative stress. Heme oxygenase-1 (HO-1) induction is a crucial defense mechanism during oxidant challenges, such as hyperoxia. The role of lung endothelial HO-1during hyperoxia in vivo is not well defined. We engineered lentiviral vectors with microRNA (miRNA) sequences controlled by vascular endothelium cadherin (VE-cad) to study the specific role of lung endothelial HO-1. Wild-type (WT) murine lung endothelial cells (MLECs) or WT mice were treated with lentivirus and exposed to hyperoxia (95% oxygen). We detected HO-1 knockdown (∼55%) specifically in the lung endothelium. MLECs and lungs showed approximately a 2-fold increase in apoptosis and ROS generation after HO-1 silencing. We also demonstrate for the first time that silencing endothelial HO-1 has the same effect on lung injury and survival as silencing HO-1 in multiple lung cell types and that HO-1 regulates caspase 3 activation and autophagy in endothelium during hyperoxia. These studies demonstrate the utility of endothelial-targeted gene silencing in vivo using lentiviral miRNA constructs to assess gene function and that endothelial HO-1 is an important determinant of survival during hyperoxia.—Zhang, Y., Jiang, G., Sauler, M., Lee, P. J. Lung endothelial HO-1 targeting in vivo using lentiviral miRNA regulates apoptosis and autophagy during oxidant injury. PMID:23771928

  4. Diallyl-disulfide, an organosulfur compound of garlic, attenuates airway inflammation via activation of the Nrf-2/HO-1 pathway and NF-kappaB suppression.

    PubMed

    Shin, In-Sik; Hong, Jumi; Jeon, Chan-Mi; Shin, Na-Rae; Kwon, Ok-Kyoung; Kim, Hui-Seong; Kim, Jong-Choon; Oh, Sei-Ryang; Ahn, Kyung-Seop

    2013-12-01

    Diallyl disulfide (DADS) is a major organosulfur compound found in garlic oil that is widely used as a flavoring agent. In this study, we evaluated the effects of DADS on airway inflammation using an ovalbumin-induced model of allergic asthma and RAW264.7 cells. DADS decreased nitric oxide production with a reduction in the levels of interleukins (IL)-1β and IL-6 in RAW264.7 cells stimulated with LPS. DADS also reduced the expression of proinflammatory proteins including inducible nitric oxide synthase (iNOS), nuclear factor (NF)-κB, and matrix metalloproteinase (MMP)-9, and it enhanced the expression of antioxidant proteins including Nrf-2 and hemeoxygenase (HO)-1. In in vivo experiments, DADS decreased the inflammatory cell count in the bronchoalveolar lavage fluid (BALF) with IL-4, IL-5, IL-13, and immunoglobulin (Ig) E. These results were consistent with the histological analysis. DADS attenuated the airway inflammation and mucus hypersecretion induced by OVA challenge. In addition, DADS induced the activation of Nrf-2 and the expression of HO-1. In contrast, DADS reduced the activation of NF-κB, iNOS and MMP-9. In conclusion, DADS reduced the airway inflammation via regulation of Nrf-2/HO-1 and NF-κB. These results suggest that DADS might represent a useful new oral therapy to treat allergic asthma.

  5. Sea cucumber peptides exert anti-inflammatory activity through suppressing NF-κB and MAPK and inducing HO-1 in RAW264.7 macrophages.

    PubMed

    Song, Jiajia; Li, Tiange; Cheng, Xue; Ji, Xiaomin; Gao, Dongxiao; Du, Min; Jiang, Naiyi; Liu, Xueling; Mao, Xueying

    2016-06-15

    The anti-inflammatory effect of sea cucumber peptides (SCP) in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages was tested. SCP significantly reduced LPS-induced nitric oxide release by inhibiting the inducible nitric oxide synthase mRNA expression without affecting the cell viability. The mRNA expression of LPS-induced inflammatory cytokines including tumour necrosis factor-α, interleukin (IL)-1β and IL-6 was suppressed. SCP inhibited LPS-induced degradation of the inhibitor of κBα (IκBα) and nuclear transposition of NF-κB p65, resulting in decreased NF-κB transactivation. Moreover, SCP suppressed the LPS-induced phosphorylation of JNK, ERK and p38. In addition, the expression of heme oxygenase (HO)-1 in macrophages was up-regulated by SCP in a dose-dependent manner. The inhibition effect of SCP on the mRNA expression of LPS-induced inflammatory cytokines was partially reversed by co-treatment with a HO-1 inhibitor. The SCP with anti-inflammatory activity was made up of low-molecular-weight peptides rich in glycine, glutamic acid and aspartic acid. Collectively, these results demonstrate that SCP exerts anti-inflammatory function through inhibiting NF-κB and MAPK activation and inducing HO-1 expression in macrophages.

  6. Sea cucumber peptides exert anti-inflammatory activity through suppressing NF-κB and MAPK and inducing HO-1 in RAW264.7 macrophages.

    PubMed

    Song, Jiajia; Li, Tiange; Cheng, Xue; Ji, Xiaomin; Gao, Dongxiao; Du, Min; Jiang, Naiyi; Liu, Xueling; Mao, Xueying

    2016-06-15

    The anti-inflammatory effect of sea cucumber peptides (SCP) in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages was tested. SCP significantly reduced LPS-induced nitric oxide release by inhibiting the inducible nitric oxide synthase mRNA expression without affecting the cell viability. The mRNA expression of LPS-induced inflammatory cytokines including tumour necrosis factor-α, interleukin (IL)-1β and IL-6 was suppressed. SCP inhibited LPS-induced degradation of the inhibitor of κBα (IκBα) and nuclear transposition of NF-κB p65, resulting in decreased NF-κB transactivation. Moreover, SCP suppressed the LPS-induced phosphorylation of JNK, ERK and p38. In addition, the expression of heme oxygenase (HO)-1 in macrophages was up-regulated by SCP in a dose-dependent manner. The inhibition effect of SCP on the mRNA expression of LPS-induced inflammatory cytokines was partially reversed by co-treatment with a HO-1 inhibitor. The SCP with anti-inflammatory activity was made up of low-molecular-weight peptides rich in glycine, glutamic acid and aspartic acid. Collectively, these results demonstrate that SCP exerts anti-inflammatory function through inhibiting NF-κB and MAPK activation and inducing HO-1 expression in macrophages. PMID:27220344

  7. Stimulants

    MedlinePlus

    Stimulants are drugs that increase your heart rate, breathing rate, and brain function. Some stimulants affect only a specific organ, such as the heart, lungs, brain, or nervous system. Epinephrine is a stimulant. It ...

  8. The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance

    PubMed Central

    Furfaro, A. L.; Traverso, N.; Domenicotti, C.; Piras, S.; Moretta, L.; Marinari, U. M.; Pronzato, M. A.; Nitti, M.

    2016-01-01

    The transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2), acts as a sensor of oxidative or electrophilic stresses and plays a pivotal role in redox homeostasis. Oxidative or electrophilic agents cause a conformational change in the Nrf2 inhibitory protein Keap1 inducing the nuclear translocation of the transcription factor which, through its binding to the antioxidant/electrophilic response element (ARE/EpRE), regulates the expression of antioxidant and detoxifying genes such as heme oxygenase 1 (HO-1). Nrf2 and HO-1 are frequently upregulated in different types of tumours and correlate with tumour progression, aggressiveness, resistance to therapy, and poor prognosis. This review focuses on the Nrf2/HO-1 stress response mechanism as a promising target for anticancer treatment which is able to overcome resistance to therapies. PMID:26697129

  9. The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance.

    PubMed

    Furfaro, A L; Traverso, N; Domenicotti, C; Piras, S; Moretta, L; Marinari, U M; Pronzato, M A; Nitti, M

    2016-01-01

    The transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2), acts as a sensor of oxidative or electrophilic stresses and plays a pivotal role in redox homeostasis. Oxidative or electrophilic agents cause a conformational change in the Nrf2 inhibitory protein Keap1 inducing the nuclear translocation of the transcription factor which, through its binding to the antioxidant/electrophilic response element (ARE/EpRE), regulates the expression of antioxidant and detoxifying genes such as heme oxygenase 1 (HO-1). Nrf2 and HO-1 are frequently upregulated in different types of tumours and correlate with tumour progression, aggressiveness, resistance to therapy, and poor prognosis. This review focuses on the Nrf2/HO-1 stress response mechanism as a promising target for anticancer treatment which is able to overcome resistance to therapies.

  10. Anti-Inflammatory Effect of Angelica gigas via Heme Oxygenase (HO)-1 Expression

    PubMed Central

    Cho, Joon Hyeong; Kwon, Jung Eun; Cho, Youngmi; Kim, Inhye; Kang, Se Chan

    2015-01-01

    Angelica gigas (AG) is effective against various medical conditions such as bacterial infection, inflammation, and cancer. It contains a number of coumarin compounds and the group of interest is the pyranocoumarin, which comprises decursin and decursinol angelate. This group has an effect on controlling inflammation, which is caused by excessive nitric oxide (NO) production. Heme oxygenases (HOs), particularly HO-1, play a role in regulating the production of NO. Thus, this study aimed to investigate the anti-inflammatory effects of AG by measuring HO-1 expression. Treatments with CH2Cl2 layer and Angelica gigas extract (AGE) showed the highest NO inhibition effects. Decursin, decursinol angelate, and nodakenin were isolated from the CH2Cl2 layer of AGE. Decursin also demonstrated the highest anti-oxidative effect among the coumarins. Although decursin had the best NO inhibition and anti-oxidative effects, the effects of AGE treatment far surpassed that of decursin. This is owing to the combination effect of the coumarins present within AGE, which is a solvent extract of AG. The expression of HO-1 is an effective indicator of the anti-inflammatory effects of AG. Based on the results of the coumarin compounds, HO-1 expression was found to be dose dependent and specific to decursin. PMID:26083119

  11. Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib.

    PubMed

    Furfaro, A L; Piras, S; Domenicotti, C; Fenoglio, D; De Luigi, A; Salmona, M; Moretta, L; Marinari, U M; Pronzato, M A; Traverso, N; Nitti, M

    2016-01-01

    The activation of Nrf2 has been demonstrated to play a crucial role in cancer cell resistance to different anticancer therapies. The inhibition of proteasome activity has been proposed as a chemosensitizing therapy but the activation of Nrf2 could reduce its efficacy. Using the highly chemoresistant neuroblastoma cells HTLA-230, here we show that the strong reduction in proteasome activity, obtained by using low concentration of bortezomib (BTZ, 2.5 nM), fails in reducing cell viability. BTZ treatment favours the binding of Nrf2 to the ARE sequences in the promoter regions of target genes such as heme oxygenase 1 (HO-1), the modulatory subunit of γ-glutamylcysteine ligase (GCLM) and the transporter for cysteine (x-CT), enabling their transcription. GSH level is also increased after BTZ treatment. The up-regulation of Nrf2 target genes is responsible for cell resistance since HO-1 silencing and GSH depletion synergistically decrease BTZ-treated cell viability. Moreover, cell exposure to all-trans-Retinoic acid (ATRA, 3 μM) reduces the binding of Nrf2 to the ARE sequences, decreases HO-1 induction and lowers GSH level increasing the efficacy of bortezomib. These data suggest the role of Nrf2, HO-1 and GSH as molecular targets to improve the efficacy of low doses of bortezomib in the treatment of malignant neuroblastoma.

  12. Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib

    PubMed Central

    Furfaro, A. L.; Piras, S.; Domenicotti, C.; Fenoglio, D.; De Luigi, A.; Salmona, M.; Moretta, L.; Marinari, U. M.; Pronzato, M. A.; Traverso, N.; Nitti, M.

    2016-01-01

    The activation of Nrf2 has been demonstrated to play a crucial role in cancer cell resistance to different anticancer therapies. The inhibition of proteasome activity has been proposed as a chemosensitizing therapy but the activation of Nrf2 could reduce its efficacy. Using the highly chemoresistant neuroblastoma cells HTLA-230, here we show that the strong reduction in proteasome activity, obtained by using low concentration of bortezomib (BTZ, 2.5 nM), fails in reducing cell viability. BTZ treatment favours the binding of Nrf2 to the ARE sequences in the promoter regions of target genes such as heme oxygenase 1 (HO-1), the modulatory subunit of γ-glutamylcysteine ligase (GCLM) and the transporter for cysteine (x-CT), enabling their transcription. GSH level is also increased after BTZ treatment. The up-regulation of Nrf2 target genes is responsible for cell resistance since HO-1 silencing and GSH depletion synergistically decrease BTZ-treated cell viability. Moreover, cell exposure to all-trans-Retinoic acid (ATRA, 3 μM) reduces the binding of Nrf2 to the ARE sequences, decreases HO-1 induction and lowers GSH level increasing the efficacy of bortezomib. These data suggest the role of Nrf2, HO-1 and GSH as molecular targets to improve the efficacy of low doses of bortezomib in the treatment of malignant neuroblastoma. PMID:27023064

  13. Catalase prevents maternal diabetes-induced perinatal programming via the Nrf2-HO-1 defense system.

    PubMed

    Chang, Shiao-Ying; Chen, Yun-Wen; Zhao, Xin-Ping; Chenier, Isabelle; Tran, Stella; Sauvé, Alexandre; Ingelfinger, Julie R; Zhang, Shao-Ling

    2012-10-01

    We investigated whether overexpression of catalase (CAT) in renal proximal tubular cells (RPTCs) could prevent the programming of hypertension and kidney disease in the offspring of dams with maternal diabetes. Male offspring of nondiabetic and diabetic dams from two transgenic (Tg) lines (Hoxb7-green fluorescent protein [GFP]-Tg [controls] and Hoxb7/CAT-GFP-Tg, which overexpress CAT in RPTCs) were studied from the prenatal period into adulthood. Nephrogenesis, systolic blood pressure, renal hyperfiltration, kidney injury, and reactive oxygen species (ROS) generation were assessed. Gene expression of transforming growth factor-β1 (TGF-β1), nuclear factor erythroid 2p45-related factor-2 (Nrf2), and heme oxygenase-1 (HO-1) was tested in both in vitro and in vivo studies. Renal dysmorphogenesis was observed in offspring of Hoxb7-GFP-Tg dams with severe maternal diabetes; the affected male offspring displayed higher renal ROS generation and developed hypertension and renal hyperfiltration as well as renal injury with heightened TGF-β1 expression in adulthood. These changes were ameliorated in male offspring of diabetic Hoxb7/CAT-GFP-Tg dams via the Nrf2-HO-1 defense system. CAT promoted Nrf2 nuclear translocation and HO-1 gene expression, seen in both in vitro and in vivo studies. In conclusion, CAT overexpression in the RPTCs ameliorated maternal diabetes-induced perinatal programming, mediated, at least in part, by triggering the Nrf2-HO-1 defense system.

  14. Anti-Inflammatory Effect of Angelica gigas via Heme Oxygenase (HO)-1 Expression.

    PubMed

    Cho, Joon Hyeong; Kwon, Jung Eun; Cho, Youngmi; Kim, Inhye; Kang, Se Chan

    2015-06-15

    Angelica gigas (AG) is effective against various medical conditions such as bacterial infection, inflammation, and cancer. It contains a number of coumarin compounds and the group of interest is the pyranocoumarin, which comprises decursin and decursinol angelate. This group has an effect on controlling inflammation, which is caused by excessive nitric oxide (NO) production. Heme oxygenases (HOs), particularly HO-1, play a role in regulating the production of NO. Thus, this study aimed to investigate the anti-inflammatory effects of AG by measuring HO-1 expression. Treatments with CH2Cl2 layer and Angelica gigas extract (AGE) showed the highest NO inhibition effects. Decursin, decursinol angelate, and nodakenin were isolated from the CH2Cl2 layer of AGE. Decursin also demonstrated the highest anti-oxidative effect among the coumarins. Although decursin had the best NO inhibition and anti-oxidative effects, the effects of AGE treatment far surpassed that of decursin. This is owing to the combination effect of the coumarins present within AGE, which is a solvent extract of AG. The expression of HO-1 is an effective indicator of the anti-inflammatory effects of AG. Based on the results of the coumarin compounds, HO-1 expression was found to be dose dependent and specific to decursin.

  15. Anti-Inflammatory Effect of Rhapontici Radix Ethanol Extract via Inhibition of NF-κB and MAPK and Induction of HO-1 in Macrophages

    PubMed Central

    Oh, You-Chang; Cho, Won-Kyung; Yim, Nam-Hui

    2016-01-01

    Rhapontici Radix (RR) has been used in traditional medicine in East Asia and has been shown to have various beneficial effects. However, its biological properties or mechanism on inflammation-related diseases is unknown. The goal of this study was to determine the anti-inflammatory activity and underlying molecular mechanisms of Rhapontici Radix ethanol extract (RRE). The inhibitory effect of RRE on the production of NO, cytokines, inflammatory-related proteins, and mRNAs in LPS-stimulated macrophages was determined by the Griess assay, ELISA, Western blot analysis, and real-time RT-PCR, respectively. Our results indicate that treatment with RRE significantly inhibited the secretion of NO and inflammatory cytokines in RAW 264.7 cells and mouse peritoneal macrophages without cytotoxicity. We also found that RRE strongly suppressed the expression of iNOS and COX-2 and induced HO-1 expression. It also prevented nuclear translocation of NF-κB by inhibiting the phosphorylation and degradation of IκBα. Furthermore, the phosphorylation of MAPKs in LPS-stimulated RAW 264.7 cells was significantly inhibited by RRE. These findings suggest that RRE may operate as an effective anti-inflammatory agent by inhibiting the activation of NF-κB and MAPK signaling pathways and inducing HO-1 expression in macrophages. Our results suggest that RRE has potential value as candidate to inflammatory therapeutic phytomedicine. PMID:27524868

  16. 3H-1,2-dithiole-3-thione protects retinal pigment epithelium cells against Ultra-violet radiation via activation of Akt-mTORC1-dependent Nrf2-HO-1 signaling

    PubMed Central

    Li, Ke-ran; Yang, Su-qing; Gong, Yi-qing; Yang, Hong; Li, Xiu-miao; Zhao, Yu-xia; Yao, Jin; Jiang, Qin; Cao, Cong

    2016-01-01

    Excessive UV radiation and reactive oxygen species (ROS) cause retinal pigment epithelium (RPE) cell injuries. Nrf2 regulates transcriptional activation of many anti-oxidant genes. Here, we tested the potential role of 3H-1,2-dithiole-3-thione (D3T) against UV or ROS damages in cultured RPE cells (both primary cells and ARPE-19 line). We showed that D3T significantly inhibited UV-/H2O2-induced RPE cell death and apoptosis. UV-stimulated ROS production was dramatically inhibited by D3T pretreatment. D3T induced Nrf2 phosphorylation in cultured RPE cells, causing Nrf2 disassociation with KEAP1 and its subsequent nuclear accumulation. This led to expression of antioxidant response elements (ARE)-dependent gene heme oxygenase-1 (HO-1). Nrf2-HO-1 activation was required for D3T-mediated cytoprotective effect. Nrf2 shRNA knockdown or S40T dominant negative mutation as well as the HO-1 inhibitor Zinc protoporphyrin (ZnPP) largely inhibited D3T’s RPE cytoprotective effects against UV radiation. Yet, exogenous overexpression Nrf2 enhanced D3T’s activity in RPE cells. Further studies showed that D3T activated Akt/mTORC1 in cultured RPE cells. Akt-mTORC1 inhibitors, or Akt1 knockdown by shRNA, not only inhibited D3T-induced Nrf2-HO-1 activation, but also abolished the RPE cytoprotective effects. In vivo, D3T intravitreal injection protected from light-induced retinal dysfunctions in mice. Thus, D3T protects RPE cells from UV-induced damages via activation of Akt-mTORC1-Nrf2-HO-1 signaling axis. PMID:27151674

  17. Adoptive Transfer of Ex Vivo HO-1 Modified Bone Marrow–derived Macrophages Prevents Liver Ischemia and Reperfusion Injury

    PubMed Central

    Ke, Bibo; Shen, Xiu-Da; Gao, Feng; Ji, Haofeng; Qiao, Bo; Zhai, Yuan; Farmer, Douglas G; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W

    2009-01-01

    Macrophages play a critical role in the pathophysiology of liver ischemia and reperfusion (IR) injury (IRI). However, macrophages that overexpress antioxidant heme oxygenase-1 (HO-1) may exert profound anti-inflammatory functions. This study explores the cytoprotective effects and mechanisms of ex vivo modified HO-1-expressing bone marrow–derived macrophages (BMDMs) in well-defined mouse model of liver warm ischemia followed by reperfusion. Adoptive transfer of Ad-HO-1-transduced macrophages prevented IR-induced hepatocellular damage, as evidenced by depressed serum glutamic-oxaloacetic transaminase (sGOT) levels and preserved liver histology (Suzuki scores), compared to Ad-β-gal controls. This beneficial effect was reversed following concomitant treatment with HO-1 siRNA. Ad-HO-1-transfected macrophages significantly decreased local neutrophil accumulation, TNF-α/IL-1β, IFN-γ/E-selectin, and IP-10/MCP-1 expression, caspase-3 activity, and the frequency of apoptotic cells, as compared with controls. Unlike in controls, Ad-HO-1-transfected macrophages markedly increased hepatic expression of antiapoptotic Bcl-2/Bcl-xl and depressed caspase-3 activity. These results establish the precedent for a novel investigative tool and provide the rationale for a clinically attractive new strategy in which native macrophages can be transfected ex vivo with cytoprotective HO-1 and then infused, if needed, to prospective recipients exposed to hepatic IR–mediated local inflammation, such as during liver transplantation, resection, or trauma. PMID:20029397

  18. Unveiling the Association of STAT3 and HO-1 in Prostate Cancer: Role beyond Heme Degradation1

    PubMed Central

    Elguero, Belen; Gueron, Geraldine; Giudice, Jimena; Toscani, Martin A; De Luca, Paola; Zalazar, Florencia; Coluccio-Leskow, Federico; Meiss, Roberto; Navone, Nora; De Siervi, Adriana; Vazquez, Elba

    2012-01-01

    Activation of the androgen receptor (AR) is a key step in the development of prostate cancer (PCa). Several mechanisms have been identified in AR activation, among them signal transducer and activator of transcription 3 (STAT3) signaling. Disruption of STAT3 activity has been associated to cancer progression. Recent studies suggest that heme oxygenase 1 (HO-1) may play a key role in PCa that may be independent of its catalytic function. We sought to explore whether HO-1 operates on AR transcriptional activity through the STAT3 axis. Our results display that HO-1 induction in PCa cells represses AR activation by decreasing the prostate-specific antigen (PSA) promoter activity and mRNA levels. Strikingly, this is the first report to show by chromatin immunoprecipitation analysis that HO-1 associates to gene promoters, revealing a novel function for HO-1 in the nucleus. Furthermore, HO-1 and STAT3 directly interact as determined by co-immunoprecipitation studies. Forced expression of HO-1 increases STAT3 cytoplasmic retention. When PCa cells were transfected with a constitutively active STAT3 mutant, PSA and STAT3 downstream target genes were abrogated under hemin treatment. Additionally, a significant decrease in pSTAT3 protein levels was detected in the nuclear fraction of these cells. Confocal microscopy images exhibit a decreased rate of AR/STAT3 nuclear co-localization under hemin treatment. In vivo studies confirmed that STAT3 nuclear delimitation was significantly decreased in PC3 tumors overexpressing HO-1 grown as xenografts in nude mice. These results provide a novel function for HO-1 down-modulating AR transcriptional activity in PCa, interfering with STAT3 signaling, evidencing its role beyond heme degradation. PMID:23226098

  19. Tetramethylpyrazine improves the recovery of spinal cord injury via Akt/Nrf2/HO-1 pathway.

    PubMed

    Wang, Chao; Wang, Peng; Zeng, Wen; Li, Weixin

    2016-02-15

    Spinal cord injury (SCI) is one of the most severe traumatic conditions, resulting in postoperative complications. Our results and other reports have shown that tetramethylpyrazine (TMP) is able to exhibit neuro-protective effects after SCI. In the current study, we aimed to examine the possible mechanism underlying the neuro-protective effect of TMP in rat model of SCI. TMP improved locomotor functions and decreased permeability of blood-spinal cord barrier in rats with SCI, as evidenced by increase of Basso-Beattie-Bresnahan scores and decrease of Evans blue leakage. In addition, TMP decreased the expression of several proinflammatory cytokines, including IL-1β, TNFα and IL-18, reduced TUNEL-positive cells and caspase 3 and 9 activities, decreased thiobarbituric acid reactive substances content and increased glutathione level and superoxide dismutase activity in rats. All these effects were inhibited by zinc protoporphyrin IX (ZnPP), an inhibitor of HO-1, and LY294002, an inhibitor of Akt. Moreover, TMP inhibited the decrease of mRNA expression of HO-1 which was suppressed by ZnPP and LY294002. TMP inhibited the decrease of Akt phosphorylation in rats after SCI, which was suppressed by LY294002, but not ZnPP. Furthermore, LY294002, but not ZnPP, significantly inhibited TMP-induced increase of mRNA expression of Nrf2 and DNA binding activity of Nrf2 in HO-1 promoters in rat model of SCI. The data suggested that TMP induced neuro-protective effects against injury of spinal cord through the activation of Akt/Nrf2/HO-1 signaling pathway. These results have appointed a new path toward the understanding of pathogenesis and TMP-related therapy of SCI and associated neurodegenerative diseases. PMID:26786697

  20. Tetramethylpyrazine improves the recovery of spinal cord injury via Akt/Nrf2/HO-1 pathway.

    PubMed

    Wang, Chao; Wang, Peng; Zeng, Wen; Li, Weixin

    2016-02-15

    Spinal cord injury (SCI) is one of the most severe traumatic conditions, resulting in postoperative complications. Our results and other reports have shown that tetramethylpyrazine (TMP) is able to exhibit neuro-protective effects after SCI. In the current study, we aimed to examine the possible mechanism underlying the neuro-protective effect of TMP in rat model of SCI. TMP improved locomotor functions and decreased permeability of blood-spinal cord barrier in rats with SCI, as evidenced by increase of Basso-Beattie-Bresnahan scores and decrease of Evans blue leakage. In addition, TMP decreased the expression of several proinflammatory cytokines, including IL-1β, TNFα and IL-18, reduced TUNEL-positive cells and caspase 3 and 9 activities, decreased thiobarbituric acid reactive substances content and increased glutathione level and superoxide dismutase activity in rats. All these effects were inhibited by zinc protoporphyrin IX (ZnPP), an inhibitor of HO-1, and LY294002, an inhibitor of Akt. Moreover, TMP inhibited the decrease of mRNA expression of HO-1 which was suppressed by ZnPP and LY294002. TMP inhibited the decrease of Akt phosphorylation in rats after SCI, which was suppressed by LY294002, but not ZnPP. Furthermore, LY294002, but not ZnPP, significantly inhibited TMP-induced increase of mRNA expression of Nrf2 and DNA binding activity of Nrf2 in HO-1 promoters in rat model of SCI. The data suggested that TMP induced neuro-protective effects against injury of spinal cord through the activation of Akt/Nrf2/HO-1 signaling pathway. These results have appointed a new path toward the understanding of pathogenesis and TMP-related therapy of SCI and associated neurodegenerative diseases.

  1. Contributions of reactive oxygen species and mitogen-activated protein kinase signaling in arsenite-stimulated hemeoxygenase-1 production

    SciTech Connect

    Cooper, Karen L.; Liu, Ke Jian; Hudson, Laurie G. . E-mail: lhudson@salud.unm.edu

    2007-01-15

    Hemeoxygenase-1 (HO-1) is an oxidative stress responsive gene upregulated by various physiological and exogenous stimuli. HO-1 has cytoprotective activities and arsenite is a potent inducer of HO-1 in many cell types and tissues, including epidermal keratinocytes. We investigated the potential contributions of reactive oxygen species (ROS) generation and mitogen-activated protein kinase (MAPK) activation to arsenite-dependent regulation of HO-1 in HaCaT cells, an immortalized human keratinocyte line. Both epidermal growth factor (EGF) and arsenite stimulated ROS production was detected by dihydroethidium (DHE) staining and fluorescence microscopy. Arsenite induced HO-1 in a time- and concentration-dependent manner, while HO-1 expression in response to EGF was modest and evident at extended time points (48-72 h). Inhibition of EGF receptor, MEK I/II or Src decreased arsenite-stimulated HO-1 expression by 20-30%. In contrast, addition of a superoxide scavenger or inhibition of p38 activity decreased the arsenite-dependent response by 80-90% suggesting that ROS and p38 are required for HO-1 induction. However, ROS generation alone was insufficient for the observed arsenite-dependent response as use of a xanthine/xanthine oxidase system to generate ROS did not produce an equivalent upregulation of HO-1. Cooperation between ERK signaling and ROS generation was demonstrated by synergistic induction of HO-1 in cells co-treated with EGF and xanthine/xanthine oxidase resulting in a response nearly equivalent to that observed with arsenite. These findings suggest that the ERK/MAPK activation is necessary but not sufficient for optimal arsenite-stimulated HO-1 induction. The robust and persistent upregulation of HO-1 may have a role in cellular adaptation to chronic arsenic exposure.

  2. Fatty aldehyde dehydrogenases in Acinetobacter sp. strain HO1-N: role in hexadecane and hexadecanol metabolism

    SciTech Connect

    Singer, M.E.; Finnerty, W.R.

    1985-12-01

    The role of fatty aldehyde dehydrogenases (FALDHs) in hexadecane and hexadecanol metabolism was studied in Acinetobacter sp. strain HO1-N. Two distinct FALDHs were demonstrated in Acinetobacter sp. strain HO1-N: (i) a membrane-bound, NADP-dependent FALDH activity induced 5-, 15-, and 9 fold by growth on hexadecanol, dodecyl aldehyde, and hexadecane, respectively, and (ii) a constitutive, NAD-dependent, membrane-localized FALDH. Dodecyl aldehyde-negative mutants were isolated and grouped into two phenotypic classes based on growth: class 1 mutants were hexadecane and hexadecanol negative and class 2 mutants were hexadecane and hexadecanol positive. Specific activity of NADP-dependent FALDH in Ald21 (class 1 mutant) was 85% lower than that of wild-type FALDH, while the specific activity of Ald24 (class 2 mutant) was 55% greater than that of wild-type FALDH. Ald21R, a dodecyl aldehyde-positive revertant able to grow on hexadecane, hexadecanol, and dodecyl aldehyde, exhibited a 100% increase in the specific activity of the NADP-dependent FALDH. This study provides genetic and physiological evidence for the role of fatty aldehyde as an essential metabolic intermediate and NADP-dependent FALDH as a key enzyme in the dissimilation of hexadecane, hexadecanol, and dodecyl aldehyde in Acinetobacter sp. strain HO1-N.

  3. t-BHQ Provides Protection against Lead Neurotoxicity via Nrf2/HO-1 Pathway.

    PubMed

    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.

  4. 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

  5. Schizophrenia-like features in transgenic mice overexpressing human HO-1 in the astrocytic compartment.

    PubMed

    Song, Wei; Zukor, Hillel; Lin, Shih-Hsiung; Hascalovici, Jacob; Liberman, Adrienne; Tavitian, Ayda; Mui, Jeannie; Vali, Hojatollah; Tong, Xin-Kang; Bhardwaj, Sanjeev K; Srivastava, Lalit K; Hamel, Edith; Schipper, Hyman M

    2012-08-01

    Delineation of key molecules that act epigenetically to transduce diverse stressors into established patterns of disease would facilitate the advent of preventive and disease-modifying therapeutics for a host of neurological disorders. Herein, we demonstrate that selective overexpression of the stress protein heme oxygenase-1 (HO-1) in astrocytes of novel GFAP.HMOX1 transgenic mice results in subcortical oxidative stress and mitochondrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3 with attendant suppression of their targeting miRNAs, 145 and 133b; increased tyrosine hydroxylase and α-synuclein expression with downregulation of the targeting miR-7b of the latter; augmented dopamine and serotonin levels in basal ganglia; reduced D1 receptor binding in nucleus accumbens; axodendritic pathology and altered hippocampal cytoarchitectonics; impaired neurovascular coupling; attenuated prepulse inhibition (males); and hyperkinetic behavior. The GFAP.HMOX1 neurophenotype bears resemblances to human schizophrenia and other neurodevelopmental conditions and implicates glial HO-1 as a prime transducer of inimical (endogenous and environmental) influences on the development of monoaminergic circuitry. Containment of the glial HO-1 response to noxious stimuli at strategic points of the life cycle may afford novel opportunities for the effective management of human neurodevelopmental and neurodegenerative conditions. PMID:22875919

  6. MiR-22 promotes porcine reproductive and respiratory syndrome virus replication by targeting the host factor HO-1.

    PubMed

    Xiao, Shuqi; Du, Taofeng; Wang, Xue; Ni, Huaibao; Yan, Yunhuan; Li, Na; Zhang, Chong; Zhang, Angke; Gao, Jiming; Liu, Hongliang; Pu, Fengxing; Zhang, Gaiping; Zhou, En-Min

    2016-08-30

    Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important viruses affecting the swine industry worldwide. MicroRNAs (miRNAs) play vital roles in virus-host interactions by regulating the expression of viral or host gene at posttranscriptional level. Our previous research showed that PRRSV infection down-regulates the expression of heme oxygenase-1 (HO-1), a pivotal cytoprotective enzyme, and overexpression of HO-1 inhibits PRRSV replication. In this study, we demonstrate that host miRNA miR-22 can downregulate HO-1 expression by directly targeting its 3' untranslated region. Suppression of HO-1 expression by miR-22 facilitates PRRSV replication. This work suggests that PRRSV may utilize cellular miRNA to modify antiviral host factor expression, enabling viral replication, which not only provides new insights into virus-host interactions during PRRSV infection, but also suggests potential therapies for PRRSV infection. PMID:27527787

  7. AmeriFlux US-Ho1 Howland Forest (main tower)

    DOE Data Explorer

    Hollinger, David [USDA Forest Service; Hollinger, David [USDA Forest Service

    2016-01-01

    This is the AmeriFlux version of the carbon flux data for the site US-Ho1 Howland Forest (main tower). Site Description - Closed conifer forest, minimal disturbance. References: Fernandez et al. (1993), Canadian Journal of Soil Science 73 317-328. Hollinger et al. (1999), Global Change Biology 5: 891-902. Savage KE, Davidson EA (2001), Global Biogeochemical Cycles 15 337-350. Scott et al. (2004), Environmental Management, Vol. 33, Supplement 1, pp. S9-S22. Hollinger et al. (2004), Global Change Biology 10: 1689-1706.

  8. Oryeongsan inhibits LPS-induced production of inflammatory mediators via blockade of the NF-kappaB, MAPK pathways and leads to HO-1 induction in macrophage cells

    PubMed Central

    2014-01-01

    Background Oryeongsan (OR) is an herbal medication used in east-Asian traditional medicine to treat dysuresia, such as urinary frequency, hematuria, and dysuria due to renal disease and chronic nephritis. Recent studies showed that protective effect against acute gastric mucosal injury and an inhibitory effect on the renin-angiotensin-aldosterone pathway of OR. However, its effect on inflammation still remains unknown. In this study, to provide insight into the biological effects of OR, we investigated their effects on lipopolysaccharide (LPS)-mediated inflammation in the RAW 264.7 macrophage cells. Methods We investigated the pharmacological and biological effects of OR on the production of pro-inflammatory cytokines, inflammatory mediators, and related products through Enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Also, we examined the activation and suppression of nuclear factor (NF)-kappaB and mitogen-activated protein kinases (MAPKs) pathways in LPS-stimulated macrophages via Western blot analysis in order to explore inhibitory mechanism of OR. Results OR had anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta. In addition, it strongly suppressed cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), NO synthesizing enzymes. It also induced heme oxygenase (HO)-1 expression and inhibited NF-kappaB signaling pathway activation and phosphorylation of MAPKs. Conclusions We further demonstrate the anti-inflammatory effects and inhibitory mechanism of OR in LPS-stimulated macrophages for the first time. OR contains strong anti-inflammatory activity and affects various mechanism pathways including NF-kappaB, MAPKs and HO-1. Our results suggest that OR has potential value to be developed as an inflammatory therapeutic agent from a natural substance. PMID:25023125

  9. Sulforaphane Attenuates Contrast-Induced Nephropathy in Rats via Nrf2/HO-1 Pathway.

    PubMed

    Zhao, Zhihong; Liao, Guixiang; Zhou, Qin; Lv, Daoyuan; Holthfer, Harry; Zou, Hequn

    2016-01-01

    Background. Oxidative stress plays an important role in the pathogenesis of contrast-induced nephropathy (CIN). The aim of this study was to investigate the antioxidant effects of sulforaphane (SFN) in a rat model of CIN and a cell model of oxidative stress in HK2 cells. Methods. Rats were randomized into four groups (n = 6 per group): control group, Ioversol group (Ioversol-induced CIN), Ioversol + SFN group (CIN rats pretreated with SFN), and SFN group (rats treated with SFN). Renal function tests, malondialdehyde (MDA), and reactive oxygen species (ROS) were measured. Western blot, real-time polymerase chain reaction analysis, and immunohistochemical analysis were performed for nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) detection. Results. Serum blood urea nitrogen (BUN), creatinine, and renal tissue MDA were increased after contrast exposure. Serum BUN, creatinine, and renal tissue MDA were decreased in the Ioversol + SFN group as compared with those in the Ioversol group. SFN increased the expression of Nrf2 and HO-1 in CIN rats and in Ioversol-induced injury HK2 cells. SFN increased cell viability and attenuated ROS level in vitro. Conclusions. SFN attenuates experimental CIN in vitro and in vivo. This effect is suggested to activate the Nrf2 antioxidant defenses pathway. PMID:27006750

  10. Activated AMPK boosts the Nrf2/HO-1 signaling axis—A role for the unfolded protein response

    PubMed Central

    Zimmermann, Kristin; Baldinger, Johannes; Mayerhofer, Barbara; Atanasov, Atanas G.; Dirsch, Verena M.; Heiss, Elke H.

    2015-01-01

    In light of the emerging interplay between redox and metabolic signaling pathways we investigated the potential cross talk between nuclear factor E2-related factor 2 (Nrf2) and AMP-activated kinase (AMPK), central regulators of the cellular redox and energy balance, respectively. Making use of xanthohumol (XN) as an activator of both the AMPK and the Nrf2 signaling pathway we show that AMPK exerts a positive influence on Nrf2/heme oxygenase (HO)-1 signaling in mouse embryonic fibroblasts. Genetic ablation and pharmacological inhibition of AMPK blunts Nrf2-dependent HO-1 expression by XN already at the mRNA level. XN leads to AMPK activation via interference with mitochondrial function and activation of liver kinase B1 as upstream AMPK kinase. The subsequent AMPK-mediated enhancement of the Nrf2/HO-1 response does not depend on inhibition of the mammalian target of rapamycin, inhibition of glycogen synthase kinase 3β, or altered abundance of Nrf2 (total and nuclear). However, reduced endoplasmic reticulum stress was identified and elaborated as a step in the AMPK-augmented Nrf2/HO-1 response. Overall, we shed more light on the hitherto incompletely understood cross talk between the LKB1/AMPK and the Nrf2/HO-1 axis revealing for the first time involvement of the unfolded protein response as an additional player and suggesting tight cooperation between signaling pathways controlling cellular redox, energy, or protein homeostasis. PMID:25843659

  11. Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle. Role in cell survival.

    PubMed

    Liu, Xiao-ming; Peyton, Kelly J; Ensenat, Diana; Wang, Hong; Schafer, Andrew I; Alam, Jawed; Durante, William

    2005-01-14

    Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). In the present study, we found that endoplasmic reticulum (ER) stress induced by a variety of experimental agents stimulated a time- and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO-1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.

  12. Modification of Caffeic Acid with Pyrrolidine Enhances Antioxidant Ability by Activating AKT/HO-1 Pathway in Heart

    PubMed Central

    Ku, Hui-Chun; Lee, Shih-Yi; Yang, Kai-Chien; Kuo, Yueh-Hsiung; Su, Ming-Jai

    2016-01-01

    Overproduction of free radicals during ischemia/reperfusion (I/R) injury leads to an interest in using antioxidant therapy. Activating an endogenous antioxidant signaling pathway is more important due to the fact that the free radical scavenging behavior in vitro does not always correlate with a cytoprotection effect in vivo. Caffeic acid (CA), an antioxidant, is a major phenolic constituent in nature. Pyrrolidinyl caffeamide (PLCA), a derivative of CA, was compared with CA for their antioxidant and cytoprotective effects. Our results indicate that CA and PLCA exert the same ability to scavenge DPPH in vitro. In response to myocardial I/R stress, PLCA was shown to attenuate lipid peroxydation and troponin release more than CA. These responses were accompanied with a prominent elevation in AKT and HO-1 expression and a preservation of mnSOD expression and catalase activity. PLCA also improved cell viability and alleviated the intracellular ROS level more than CA in cardiomyocytes exposed to H2O2. When inhibiting the AKT or HO-1 pathways, PLCA lost its ability to recover mnSOD expression and catalase activity to counteract with oxidative stress, suggesting AKT/HO-1 pathway activation by PLCA plays an important role. In addition, inhibition of AKT signaling further abolished HO-1 activity, while inhibition of HO-1 signaling attenuated AKT expression, indicating cross-talk between the AKT and HO-1 pathways. These protective effects may contribute to the cardiac function improvement by PLCA. These findings provide new insight into therapeutic approaches using a modified natural compound against oxidative stress from myocardial injuries. PMID:26845693

  13. Modification of Caffeic Acid with Pyrrolidine Enhances Antioxidant Ability by Activating AKT/HO-1 Pathway in Heart.

    PubMed

    Ku, Hui-Chun; Lee, Shih-Yi; Yang, Kai-Chien; Kuo, Yueh-Hsiung; Su, Ming-Jai

    2016-01-01

    Overproduction of free radicals during ischemia/reperfusion (I/R) injury leads to an interest in using antioxidant therapy. Activating an endogenous antioxidant signaling pathway is more important due to the fact that the free radical scavenging behavior in vitro does not always correlate with a cytoprotection effect in vivo. Caffeic acid (CA), an antioxidant, is a major phenolic constituent in nature. Pyrrolidinyl caffeamide (PLCA), a derivative of CA, was compared with CA for their antioxidant and cytoprotective effects. Our results indicate that CA and PLCA exert the same ability to scavenge DPPH in vitro. In response to myocardial I/R stress, PLCA was shown to attenuate lipid peroxydation and troponin release more than CA. These responses were accompanied with a prominent elevation in AKT and HO-1 expression and a preservation of mnSOD expression and catalase activity. PLCA also improved cell viability and alleviated the intracellular ROS level more than CA in cardiomyocytes exposed to H2O2. When inhibiting the AKT or HO-1 pathways, PLCA lost its ability to recover mnSOD expression and catalase activity to counteract with oxidative stress, suggesting AKT/HO-1 pathway activation by PLCA plays an important role. In addition, inhibition of AKT signaling further abolished HO-1 activity, while inhibition of HO-1 signaling attenuated AKT expression, indicating cross-talk between the AKT and HO-1 pathways. These protective effects may contribute to the cardiac function improvement by PLCA. These findings provide new insight into therapeutic approaches using a modified natural compound against oxidative stress from myocardial injuries. PMID:26845693

  14. Knockout of ho-1 protects the striatum from ferrous iron-induced injury in a male-specific manner in mice

    PubMed Central

    Wang, Li-Fang; Yokoyama, Kazunari K.; Lin, Chih-Lung; Chen, Tzu-Yin; Hsiao, Hsiu-Wen; Chiang, Pei-Chi; Hsu, Chin

    2016-01-01

    Men have worse survival than premenopausal women after intracerebral hemorrhage (ICH). After ICH, overproduction of iron associated with induction of heme oxygenase-1 (HO-1) in brain was observed. Rodent ICH model using ferrous citrate (FC)-infusion into the striatum to simulate iron overload, showed a higher degree of injury severity in males than in females. However, the participation of HO-1 in sex-differences of iron-induced brain injury remains unknown. The present results showed a higher level of HO-1 expression associated with more severe injury in males compared with females after FC-infusion. Estradiol (E2) contributed to lower levels of FC-induced HO-1 expression in females compared with males. Heterozygote ho-1 KO decreased the levels of FC-induced injury severity, histological lesions, behavioral deficits, autophagy and autophagic cell death in the striatum of males but not in females. Moreover, ho-1 deficiency enhanced the neuroprotection by E2 only in males. These results suggested that over induction of HO-1 plays a harmful role in FC-induced brain injury in a male-specific manner. Suppression of HO-1 combined with E2 exhibits a synergistic effect on neuroprotection against FC-induced striatal injury in males. These findings open up the prospect for male-specific neuroprotection targeting HO-1 suppression for patients suffering from striatal iron overload. PMID:27198537

  15. Doping induced modification in polyhedral tilt in hexagonal Ho1-xYxMnO3

    NASA Astrophysics Data System (ADS)

    Kaushik, S. D.; Rayaprol, S.

    2012-06-01

    We have studied the effect of systematic doping of Y at Ho site on the crystal structure of hexagonal HoMnO3 We have carried out room temperature neutron diffraction (ND) study on Ho1-xYxMnO3 (x = 0, 0.25, 0.50, 0.75), and by analyzing this ND data we have determined the cell parameters, Mn-O bond length, O-Mn-O bond angle. The variation in certain M-O bond length and O-Mn-O bond angles has been understood in terms of modifications in tilt of the MnO5 polyhedra due to Ho site Y doping in hexagonal HoMnO3.

  16. Transport and structural properties of the Ho1Ba2Cu3O9 - delta superconductor

    NASA Astrophysics Data System (ADS)

    Lee, Sung-Ik; Golben, John P.; Song, Yi; Lee, Sang Young; Noh, Tae W.; Chen, Xiao-dong; Testa, Joe; Gaines, J. R.; Tettenhorst, Rodney T.

    1987-07-01

    The compound Ho1Ba2Cu3O9-δ has been found to be a high Tc superconductor. The onset of the superconducting transition is 88 K with zero resistance achieved at 87 K. The x-ray diffraction spectrum of this material shows it to be a single-phase perovskite similar to the Y1Ba2Cu3O9-δ compound but different from the K2NiF4 perovskite which is believed to be the superconducting phase for the La2(1-x) Ba2xCuO4-δ system. Possible oxygen deficiencies in several of the unit cell planes are discussed. The room-temperature resistance, the superconducting onset temperature, and the emergence of the single phase all depend upon the sample preparation firing conditions.

  17. Kaposi Sarcoma Herpesvirus Induces HO-1 during De Novo Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms

    PubMed Central

    Botto, Sara; Totonchy, Jennifer E.; Gustin, Jean K.

    2015-01-01

    ABSTRACT Kaposi sarcoma (KS) herpesvirus (KSHV) infection of endothelial cells (EC) is associated with strong induction of heme oxygenase-1 (HO-1), a stress-inducible host gene that encodes the rate-limiting enzyme responsible for heme catabolism. KS is an angioproliferative tumor characterized by the proliferation of KSHV-infected spindle cells, and HO-1 is highly expressed in such cells. HO-1 converts the pro-oxidant, proinflammatory heme molecule into metabolites with antioxidant, anti-inflammatory, and proliferative activities. Previously published work has shown that KSHV-infected EC in vitro proliferate in response to free heme in a HO-1-dependent manner, thus implicating virus-enhanced HO-1 activity in KS tumorigenesis. The present study investigated the molecular mechanisms underlying KSHV induction of HO-1 in lymphatic EC (LEC), which are the likely spindle cell precursors. In a time course analysis of KSHV-infected cells, HO-1 expression displays biphasic kinetics characterized by an early transient induction that is followed by a more sustained upregulation coincident with the establishment of viral latency. A viral microRNA miR-K12-11 deletion mutant of KSHV was found to be defective for induction of HO-1 during latency. A potential mechanism for this phenotype was provided by BACH1, a cellular HO-1 transcriptional repressor targeted by miR-K12-11. In fact, in KSHV-infected LEC, the BACH1 message level is reduced, BACH1 subcellular localization is altered, and miR-K12-11 mediates the inverse regulation of HO-1 and BACH1 during viral latency. Interestingly, the data indicate that neither miR-K12-11 nor de novo KSHV gene expression is required for the burst of HO-1 expression observed at early times postinfection, which suggests that additional virion components promote this phenotype. PMID:26045540

  18. Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway.

    PubMed

    Olszanecki, Rafal; Rezzani, Rita; Omura, Shinji; Stec, David E; Rodella, Luigi; Botros, Fady T; Goodman, Alvin I; Drummond, George; Abraham, Nader G

    2007-01-01

    Apoptosis has been shown to contribute to the development of acute and chronic renal failure. The antiapoptotic action of the heme oxygenase (HO) system may represent an important protective mechanism in kidney pathology. We examined whether the lack of HO-1 would influence apoptosis in clipped kidneys of two-kidney, one-clip (2K1C) rats. Five-day-old Sprague-Dawley rats were injected in the left ventricle with approximately 5 x 10(9) colony-forming units/ml of retrovirus containing rat HO-1 antisense (LSN-RHO-1-AS) or control retrovirus (LXSN). After 3 mo, a 0.25-mm U-shaped silver clip was placed around the left renal artery. Animals were killed 3 wk later. Clipping the renal artery in LSN-RHO-1-AS rats did not result in increased HO-1 expression. In contrast to LXSN animals, 2K1C LSN-RHO-1-AS rats showed increased expression of cyclooxygenase 2 (COX-2) and higher 3-nitrotyrosine (3-NT) content as well as increased expression of the proapoptotic protein Apaf-1 and caspase-3 activity. Clipping the renal artery in LXSN rats resulted in increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xl, while clipping the renal artery in LSN-RHO-1-AS rats did not change Bcl-2 levels and decreased the levels of Bcl-xl. Treatment of LSN-RHO-1-AS rats with cobalt protoporphyrin resulted in induction of renal HO-1, which was accompanied by decreases in blood pressure, COX-2, 3-NT, and caspase-3 activity, and increased expression of anti-apoptotic molecules (Bcl-2, Bcl-xl, Akt and p-Akt) in the clipped kidneys. These findings underscore the prominent role of HO-1 in counteracting apoptosis in this 2K1C renovascular hypertension model. PMID:16940561

  19. NS-398, a selective COX-2 inhibitor, inhibits proliferation of IL-1{beta}-stimulated vascular smooth muscle cells by induction of {eta}{omicron}-1

    SciTech Connect

    Choi, Hyoung Chul; Kim, Hee Sun; Lee, Kwang Youn; Chang, Ki Churl Kang, Young Jin

    2008-11-28

    We investigated whether NS-398, a selective inhibitor of COX-2, induces HO-1 in IL-1{beta}-stimulated vascular smooth muscle cells (VSMC). NS-398 reduced the production of PGE{sub 2} without modulation of expression of COX-2 in IL-1{beta}-stimulated VSMC. NS-398 increased HO-1 mRNA and protein in a dose-dependent manner, but inhibited proliferation of IL-1{beta}-stimulated VSMC. Furthermore, SnPPIX, a HO-1 inhibitor, reversed the effects of NS-398 on PGE{sub 2} production, suggesting that COX-2 activity can be affected by HO-1. Hemin, a HO-1 inducer, also reduced the production of PGE{sub 2} and proliferation of IL-1{beta}-stimulated VSMC. CORM-2, a CO-releasing molecule, but not bilirubin inhibited proliferation of IL-1{beta}-stimulated VSMC. NS-398 inhibited proliferation of IL-1{beta}-stimulated VSMC in a HbO{sub 2}-sensitive manner. In conclusion, NS-398 inhibits proliferation of IL-1{beta}-stimulated VSMC by HO-1-derived CO. Thus, NS-398 may facilitate the healing process of vessels in vascular inflammatory disorders such as atherosclerosis.

  20. Nitric oxide sets off an antioxidant response in adrenal cells: involvement of sGC and Nrf2 in HO-1 induction.

    PubMed

    Astort, F; Mercau, M; Giordanino, E; Degese, M S; Caldareri, L; Coso, O; Cymeryng, C B

    2014-02-15

    Induction of microsomal heme oxygenase 1 (HO-1) activity is considered a cytoprotective mechanism in different cell types. In adrenal cells, HO-1 induction by ACTH exerts a modulatory effect on steroid production as well. As nitric oxide (NO) has been also regarded as an autocrine/paracrine modulator of adrenal steroidogenesis we sought to study the effects of NO on the induction of HO-1 and the mechanism involved. We hereby analyzed the time and dose-dependent effect of a NO-donor (DETA/NO) on HO-1 induction in a murine adrenocortical cell line. We showed that this effect is mainly exerted at a transcriptional level as it is inhibited by actinomycin D and HO-1 mRNA degradation rates were not affected by DETA/NO treatment. HO-1 induction by NO does not appear to involve the generation of oxidative stress as it was not affected by antioxidant treatment. We also demonstrated that NO-treatment results in the nuclear translocation of the nuclear factor-erythroid 2-related factor (Nrf2), an effect that is attenuated by transfecting the cells with a dominant negative isoform of Nrf2. We finally show that the effects of the NO-donor are reproduced by a permeable analog of cGMP and that a soluble guanylate cyclase specific inhibitor blocked both the induction of HO-1 by NO and the nuclear translocation of Nrf2. PMID:24361900

  1. Nitric oxide sets off an antioxidant response in adrenal cells: involvement of sGC and Nrf2 in HO-1 induction.

    PubMed

    Astort, F; Mercau, M; Giordanino, E; Degese, M S; Caldareri, L; Coso, O; Cymeryng, C B

    2014-02-15

    Induction of microsomal heme oxygenase 1 (HO-1) activity is considered a cytoprotective mechanism in different cell types. In adrenal cells, HO-1 induction by ACTH exerts a modulatory effect on steroid production as well. As nitric oxide (NO) has been also regarded as an autocrine/paracrine modulator of adrenal steroidogenesis we sought to study the effects of NO on the induction of HO-1 and the mechanism involved. We hereby analyzed the time and dose-dependent effect of a NO-donor (DETA/NO) on HO-1 induction in a murine adrenocortical cell line. We showed that this effect is mainly exerted at a transcriptional level as it is inhibited by actinomycin D and HO-1 mRNA degradation rates were not affected by DETA/NO treatment. HO-1 induction by NO does not appear to involve the generation of oxidative stress as it was not affected by antioxidant treatment. We also demonstrated that NO-treatment results in the nuclear translocation of the nuclear factor-erythroid 2-related factor (Nrf2), an effect that is attenuated by transfecting the cells with a dominant negative isoform of Nrf2. We finally show that the effects of the NO-donor are reproduced by a permeable analog of cGMP and that a soluble guanylate cyclase specific inhibitor blocked both the induction of HO-1 by NO and the nuclear translocation of Nrf2.

  2. Sulforaphane exerts its anti-inflammatory effect against amyloid-β peptide via STAT-1 dephosphorylation and activation of Nrf2/HO-1 cascade in human THP-1 macrophages.

    PubMed

    An, Ye Won; Jhang, Kyoung A; Woo, So-Youn; Kang, Jihee Lee; Chong, Young Hae

    2016-02-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, accounting for most cases of dementia in elderly individuals, and effective therapies are still lacking. This study was designed to investigate the anti-inflammatory properties of sulforaphane against Aβ1-42 monomers in human THP-1 microglia-like cells. The results showed that sulforaphane preferentially inhibited cathepsin B- and caspase-1-dependent NLRP3 inflammasome activation induced by mostly Aβ1-42 monomers, an effect that potently reduced excessive secretion of the proinflammatory cytokine interleukin-1β (IL-1β). Subsequent mechanistic studies revealed that sulforaphane mitigated the activation of signal transducer and activator of transcription-1 induced by Aβ1-42 monomers. Sulforaphane also increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, which was followed by upregulation of heme-oxygenase 1 (HO-1). The anti-inflammatory effect of sulforaphane on Aβ1-42-induced IL-1β production was diminished by small interfering RNA-mediated knockdown of Nrf2 or HO-1. Moreover, sulforaphane significantly attenuated the levels of microRNA-146a, which is selectively upregulated in the temporal cortex and hippocampus of AD brains. The aforementioned effects of sulforaphane were replicated by the tyrosine kinase inhibitor, herbimycin A, and Nrf2 activator. These results indicate that signal transducer and activator of transcription-1 dephosphorylation, HO-1 and its upstream effector, Nrf2, play a pivotal role in triggering an anti-inflammatory signaling cascade of sulforaphane that results in decreases of IL-1β release and microRNA-146a production in Aβ1-42-stimulated human microglia-like cells. These findings suggest that the phytochemical sulforaphane has a potential application in AD therapeutics.

  3. Downregulation of HO-1 promoted apoptosis induced by decitabine via increasing p15INK4B promoter demethylation in myelodysplastic syndrome.

    PubMed

    Ma, D; Fang, Q; Wang, P; Gao, R; Sun, J; Li, Y; Hu, X Y; Wang, J S

    2015-04-01

    Decitabine, which reverses hypermethylation of the p15(INK4B) gene in vitro, has been used to relieve cytopenias and blast excess in over 50% of patients with high-risk myelodysplastic syndrome (MDS). In this study, heme oxygenase-1 (HO-1) was overexpressed in MDS cell line SKM-1, which was closely related to resistance to decitabine-induced apoptosis. We aimed to further investigate the role of HO-1 in apoptosis induced by low-dose decitabine in SKM-1 cells. Upregulation of HO-1 by transfecting it into SKM-1 cells with lentivirus vector promoted cell proliferation and protected them against apoptosis. In contrast, downregulation of HO-1 enhanced decitabine-induced apoptosis but reduced accumulation of the S phase in cell cycle. To explore the mechanism, the expressions of cell cycle-related proteins were detected after the cells were treated by decitabine in each group. p15(INK4B) and CDK4 were overexpressed in SKM-1 cells in which HO-1 was inhibited, and the expression-depending apoptosis was related to the caspase-3 pathway. Even though HO-1 was silenced, the apoptotic rate never increased as the caspase-3 pathway was blocked. It is well known that p15(INK4B) dominantly regulates the S phase of the cell cycle. p15(INK4B) was herein demethylated more evidently in the group of SKM-1 cells in which HO-1 was downregulated, as well as in the mononuclear cells of patients suffering from MDS. In the case of poor prognosis, the mRNA level of HO-1 was raised. In conclusion, overexpression of HO-1 indicated resistance to demethylation of p15(INK4B) induced by decitabine.

  4. Selenolate complexes of CYP101 and the heme-bound hHO-1/H25A proximal cavity mutant.

    PubMed

    Jiang, Yongying; Ortiz de Montellano, Paul R

    2008-05-01

    Thiolate and selenolate complexes of CYP101 (P450cam) and the H25A proximal cavity mutant of heme-bound human heme oxygenase-1 (hHO-1) have been examined by UV-vis spectroscopy. Both thiolate and selenolate ligands bound to the heme distal side in CYP101 and gave rise to characteristic hyperporphyrin spectra. Thiolate ligands also bound to the proximal side of the heme in the cavity created by the H25A mutation in hHO-1, giving a Soret absorption similar to that of the H25C hHO-1 mutant. Selenolate ligands also bound to this cavity mutant under anaerobic conditions but reduced the heme iron to the ferrous state, as shown by the formation of a ferrous CO complex. Under aerobic conditions, the selenolate ligand but not the thiolate ligand was rapidly oxidized. These results indicate that selenocysteine-coordinated heme proteins will not be stable species in the absence of a redox potential stabilizing effect.

  5. Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages

    SciTech Connect

    Zhou, Zhao-Hua; Kumari, Namita; Nekhai, Sergei; Clouse, Kathleen A.; Wahl, Larry M.; Yamada, Kenneth M.; Dhawan, Subhash

    2013-06-07

    Highlights: •Lipopolysaccharide stimulation of heme oxygenase-1 (HO-1) ameliorated HIV-1 infection of primary human macrophages. •The partial protection by HO-1 against HIV infection was associated with induction of chemokines such as MIP1α and MIP1β. •This mechanism explains lipopolysaccharide-stimulated HO-1-mediated inhibition of HIV-1 infection of macrophages. -- Abstract: We have elucidated a putative mechanism for the host resistance against HIV-1 infection of primary human monocyte-derived macrophages (MDM) stimulated with lipopolysaccharide (LPS). We show that LPS-activated MDM both inhibited HIV-1 entry into the cells and were refractory to post-entry productive viral replication. LPS-treated cells were virtually negative for mature virions as revealed by transmission electron microscopy. LPS activation of MDM markedly enhanced the expression of heme oxygenase-1 (HO-1), a potent inducible cytoprotective enzyme. Increased HO-1 expression was accompanied by elevated production of macrophage inflammatory chemokines (MIP1α and MIP1β) by LPS-activated MDM, significantly decreased surface chemokine receptor-5 (CCR-5) expression, and substantially reduced virus replication. Treatment of cells with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) attenuated the LPS-mediated responses, HIV-1 replication and secretion of MIP1α, MIP1β, and LD78β chemokines with little change in surface CCR-5 expression. These results identify a novel role for HO-1 in the modulation of host immune response against HIV infection of MDM.

  6. 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

  7. Ethanol Extract of Ganoderma lucidum Augments Cellular Anti-oxidant Defense through Activation of Nrf2/HO-1

    PubMed Central

    Lee, Yoo-hwan; Kim, Jung-hee; Song, Choon-ho; Jang, Kyung-jeon; kim, Cheol-hong; Kang, Ji- Sook; Choi, Yung-hyun

    2016-01-01

    Objectives: The mushroom Ganoderma lucidum has been widely used as a traditional herbal medicine for many years. Although several studies have focused on the anti-oxidative activity of this mushroom, the molecular mechanisms underlying its activity have not yet been clearly established. The present study investigated the cytoprotective effect of ethanol extract of Ganoderma lucidum (EGL) against oxidative stress (hydrogen peroxide, H2O2) and elucidated the underlying mechanisms in a C2C12 myoblast cell line. Methods: Oxidative stress markers were determined by using the comet assay to measure reactive oxygen species (ROS) generation and deoxyribonucleic acid (DNA) damage. Cell viability and Western blotting analyses were employed to evaluate the cellular response to EGL and H2O2 in C2C12 cells. Transfection with nuclear factor erythroid 2-related factor 2 (Nrf2)-specific small interfering ribonucleic acid (siRNA) was conducted to understand the relationship between Nrf2 expression and H2O2-induced growth inhibition. Results: The results showed that EGL effectively inhibited H2O2-induced growth and the generation of ROS. EGL markedly suppressed H2O2-induced comet-like DNA formation and phosphorylation of histone H2AX at serine 139 (p-γH2AX), a widely used marker of DNA damage, suggesting that EGL prevented H2O2-induced DNA damage. Furthermore, the EGL treatment effectively induced the expression of Nrf2, as well as heme oxygenase-1 (HO-1), with parallel phosphorylation and nuclear translocation of Nrf2 in the C2C12 myoblasts. However, zinc protoporphyrin IX, a HO-1 inhibitor, significantly abolished the protective effects of EGL against H2O2-induced accumulation of ROS and reduced cell growth. Notably, transient transfection with Nrf2-specific siRNA attenuated the cytoprotective effects and HO-1 induction by EGL, indicating that EGL induced the expression of HO-1 in an Nrf2-dependent manner. Conclusion: Collectively, these results demonstrate that EGL augments the

  8. Berberine Hydrochloride Protects C2C12 Myoblast Cells Against Oxidative Stress-Induced Damage via Induction of Nrf-2-Mediated HO-1 Expression.

    PubMed

    Choi, Yung Hyun

    2016-09-01

    Preclinical Research The aim of the present study was to evaluate the effects of berberine hydrochloride (BBH), an isoquinoline alkaloid that can be isolated from a variety of herbs, on hydrogen peroxide (H2 O2 )-induced oxidative stress in C2C12 myoblasts and to investigate the molecular mechanisms involved in this process, especially the expression of the Nrf2/HO-1 pathway. BBH preconditioning attenuated H2 O2 -induced growth inhibition and DNA damage as well as apoptosis in C2C12 cells via suppression of the accumulation of intracellular reactive oxygen species (ROS). Treatment with BBHride alone effectively upregulated the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and elevated HO-1 activity. However, the protective effects of BBH against H2 O2 -induced ROS generation and cell growth reduction were abolished by an HO-1 inhibitor. Moreover, BBH-mediated induction and activation of HO-1 were reduced by genetic silencing of Nrf2 using small interfering RNA (siRNA). In addition, the effects of BBH against H2 O2 -induced ROS accumulation and growth inhibition were abrogated in C2C12 cells transfected with Nrf2 siRNA. Therefore, the present study demonstrated that BBH could protect C2C12 cells against oxidative stress-induced injury and this effect involved activation of the Nrf2/HO-1 pathway. Drug Dev Res, 2016. © 2016 Wiley Periodicals, Inc. PMID:27535021

  9. Sulforaphane Ameliorates Okadaic Acid-Induced Memory Impairment in Rats by Activating the Nrf2/HO-1 Antioxidant Pathway.

    PubMed

    Dwivedi, Subhash; Rajasekar, N; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

    2016-10-01

    Okadaic acid (OKA) causes memory impairment and attenuates nuclear factor erythroid 2-related factor 2 (Nrf2) along with oxidative stress and neuroinflammation in rats. Sulforaphane (dietary isothiocyanate compound), an activator of Nrf2 signaling, exhibits neuroprotective effects. However, the protective effect of sulforaphane in OKA-induced neurotoxicity remains uninvestigated. Therefore, in the present study, the role of sulforaphane in OKA-induced memory impairment in rats was explored. A significant increased Nrf2 expression in the hippocampus and cerebral cortex was observed in trained (Morris water maze) rats, and a significant decreased Nrf2 expression in memory-impaired (OKA, 200 ng icv) rats indicated its involvement in memory function. Sulforaphane administration (5 and 10 mg/kg, ip, days 1 and 2) ameliorates OKA-induced memory impairment in rats. The treatment also restored Nrf2 and its downstream antioxidant protein expression (GCLC, HO-1) and attenuated oxidative stress (ROS, nitrite, GSH), neuroinflammation (NF-κB, TNF-α, IL-10), and neuronal apoptosis in the cerebral cortex and hippocampus of OKA-treated rats. Further, to determine whether modulation of Nrf2 signaling is responsible for the protective effect of sulforaphane, in vitro, Nrf2 siRNA and its downstream HO-1 inhibition studies were carried out in a rat astrocytoma cell line (C6). The protective effects of sulforaphane were abolished with Nrf2 siRNA and HO-1 inhibition in astrocytes. The results suggest that Nrf2-dependent activation of cellular antioxidant machinery results in sulforaphane-mediated protection against OKA-induced memory impairment in rats. Graphical Abstract ᅟ.

  10. Activation of the Nrf2/HO-1 Antioxidant Pathway Contributes to the Protective Effects of Lycium Barbarum Polysaccharides in the Rodent Retina after Ischemia-Reperfusion-Induced Damage

    PubMed Central

    Chang, Raymond Chuen-Chung; So, Kwok-Fai; Brecha, Nicholas C.; Pu, Mingliang

    2014-01-01

    Lycium barbarum polysaccharides (LBP), extracts from the wolfberries, are protective to retina after ischemia-reperfusion (I/R). The antioxidant response element (ARE)–mediated antioxidant pathway plays an important role in maintaining the redox status of the retina. Heme oxygenase-1 (HO-1), combined with potent AREs in its promoter, is a highly effective therapeutic target for the protection against neurodegenerative diseases, including I/R-induced retinal damage. The aim of our present study was to investigate whether the protective effect of LBP after I/R damage was mediated via activation of the Nrf2/HO-1-antioxidant pathway in the retina. Retinal I/R was induced by an increase in intraocular pressure to 130 mm Hg for 60 minutes. Prior to the induction of ischemia, rats were orally treated with either vehicle (PBS) or LBP (1 mg/kg) once a day for 1 week. For specific experiments, zinc protoporphyrin (ZnPP, 20 mg/kg), an HO-1 inhibitor, was intraperitoneally administered at 24 h prior to ischemia. The protective effects of LBP were evaluated by quantifying ganglion cell and amacrine cell survival, and by measuring cell apoptosis in the retinal layers. In addition, HO-1 expression was examined using Western blotting and immunofluorescence analyses. Cytosolic and nuclear Nrf2 was measured using immunofluorescent staining. LBP treatment significantly increased Nrf2 nuclear accumulation and HO-1 expression in the retina after I/R injury. Increased apoptosis and a decrease in the number of viable cells were observed in the ganglion cell layer (GCL) and inner nuclear layer (INL) in the I/R retina, which were reversed by LBP treatment. The HO-1 inhibitor, ZnPP, diminished the LBP treatment-induced protective effects in the retina after I/R. Taken together, these results suggested that LBP partially exerted its beneficial neuroprotective effects via the activation of Nrf2 and an increase in HO-1 protein expression. PMID:24400114

  11. Pro-inflammatory and pro-oxidant status of pancreatic islet in vitro is controlled by TLR-4 and HO-1 pathways.

    PubMed

    Vivot, Kevin; Langlois, Allan; Bietiger, William; Dal, Stéphanie; Seyfritz, Elodie; Pinget, Michel; Jeandidier, Nathalie; Maillard, Elisa; Gies, Jean-Pierre; Sigrist, Séverine

    2014-01-01

    Since their isolation until implantation, pancreatic islets suffer a major stress leading to the activation of inflammatory reactions. The maintenance of controlled inflammation is essential to preserve survival and function of the graft. Identification and targeting of pathway(s) implicated in post-transplant detrimental inflammatory events, is mandatory to improve islet transplantation success. We sought to characterize the expression of the pro-inflammatory and pro-oxidant mediators during islet culture with a focus on Heme oxygenase (HO-1) and Toll-like receptors-4 signaling pathways. Rat pancreatic islets were isolated and pro-inflammatory and pro-oxidant status were evaluated after 0, 12, 24 and 48 hours of culture through TLR-4, HO-1 and cyclooxygenase-2 (COX-2) expression, CCL-2 and IL-6 secretion, ROS (Reactive Oxygen Species) production (Dihydroethidine staining, DHE) and macrophages migration. To identify the therapeutic target, TLR4 inhibition (CLI-095) and HO-1 activation (cobalt protoporphyrin,CoPP) was performed. Activation of NFκB signaling pathway was also investigated. After isolation and during culture, pancreatic islet exhibited a proinflammatory and prooxidant status (increase levels of TLR-4, COX-2, CCL-2, IL-6, and ROS). Activation of HO-1 or inhibition of TLR-4 decreased inflammatory status and oxidative stress of islets. Moreover, the overexpression of HO-1 induced NFκB phosphorylation while the inhibition of TLR-4 had no effect NFκB activation. Finally, inhibition of pro-inflammatory pathway induced a reduction of macrophages migration. These data demonstrated that the TLR-4 signaling pathway is implicated in early inflammatory events leading to a pro-inflammatory and pro-oxidant status of islets in vitro. Moreover, these results provide the mechanism whereby the benefits of HO-1 target in TLR-4 signaling pathway. HO-1 could be then an interesting target to protect islets before transplantation. PMID:25343247

  12. Mechanism of phytoestrogen puerarin-mediated cytoprotection following oxidative injury: Estrogen receptor-dependent up-regulation of PI3K/Akt and HO-1

    SciTech Connect

    Hwang, Yong Pil; Jeong, Hye Gwang

    2008-12-15

    Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. The phytoestrogen puerarin, the main isoflavone glycoside found in the root of Pueraria lobata, has been used for various medicinal purposes in traditional Chinese medicines for thousands of years. Recent studies have indicated that the estrogen receptor (ER), through interaction with p85, regulates phosphoinositide 3-kinase (PI3K) activity, revealing a physiologic, non-nuclear function of ER that may be relevant in cytoprotection. In this study, we demonstrate that the phytoestrogen puerarin inhibits tert-butyl hydroperoxide (t-BHP)-induced oxidative injury via an ER-dependent G{beta}1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of Hepa1c1c7 and HepG2 cells with puerarin significantly reduced t-BHP-induced caspase-3 activation and subsequent cell death. Also, puerarin up-regulated HO-1 expression and this expression conferred cytoprotection against oxidative injury induced by t-BHP. Moreover, puerarin induced Nrf2 nuclear translocation, which is upstream of puerarin-induced HO-1 expression, and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. Puerarin-induced up-regulation of HO-1 and cytoprotection against t-BHP were abolished by silencing Nrf2 expression with specific siRNA. Also, puerarin-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that puerarin augments cellular antioxidant defense capacity through ER-dependent HO-1 induction via the G{beta}1/PI3K/Akt-Nrf2 signaling pathway, thereby protecting cells from oxidative stress.

  13. N-acetylcysteine protects against liver injure induced by carbon tetrachloride via activation of the Nrf2/HO-1 pathway.

    PubMed

    Cai, Zhaobin; Lou, Qi; Wang, Fugen; Li, Er; Sun, Jingjing; Fang, Hongying; Xi, Jianjun; Ju, Liping

    2015-01-01

    Chronic liver injury is an important clinical problem which eventually leads to cirrhosis, hepatocellular carcinoma and end-stage liver failure. It is well known that cell damage induced by reactive oxygen species (ROS) is an important mechanism of hepatocyte injure. N-acetylcysteine (NAC), a precursor of glutathione (GSH), is well-known role as the antidote to acetaminophen toxicity in clinic. NAC is now being utilized more widely in the clinical setting for non-acetaminophen (APAP) related causes of liver injure. However, the mechanisms underlying its beneficial effects are poorly defined. Thus, Aim of the present study was to investigate potential hepatic protective role of NAC and to delineate its mechanism of action against carbon tetrachloride (CCl4)-induced liver injury in models of rat. Our results showed that the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as malondialdehyde (MDA) contents decreased significantly in CCl4-induced rats with NAC treatment. GSH content and superoxide dismutase (SOD) activities remarkably increased in the NAC groups compared with those in CCl4-induced group. Treatment with NAC had been shown to an increase in nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA levels. In conclusion, these results suggested that NAC upregulated HO-1 through the activation of Nrf2 pathway and protected rat against CCl4-induced liver injure. The results of this study provided pharmacological evidence to support the clinical application of NAC. PMID:26339453

  14. Protective Effect of Decursin Extracted from Angelica gigas in Male Infertility via Nrf2/HO-1 Signaling Pathway

    PubMed Central

    Bae, Woong Jin; Ha, U. Syn; Choi, Jin Bong; Kim, Kang Sup; Kim, Su Jin; Cho, Hyuk Jin; Hong, Sung Hoo; Lee, Ji Youl; Wang, Zhiping; Hwang, Sung Yeoun; Kim, Sae Woong

    2016-01-01

    Higher testicular temperature results in altered spermatogenesis due to heat-related oxidative stress. We examined the effects of decursin extracted from Angelica gigas Nakai on antioxidant activity in vitro and in a cryptorchidism-induced infertility rat model. TM3 Leydig cell viability was measured based on oxidative stress according to treatment. Either distilled water or AG 400 mg/kg of A. gigas extract was administered orally for 4 weeks after unilateral cryptorchidism was induced. After 1, 2, and 4 weeks, six rats from the control group and six rats from treatment group were sacrificed. Testicular weight, semen quality, antioxidant activities, nuclear factor erythroid 2-related factor 2 (Nrf2) protein, and mRNA expression of Nrf2-regulated genes were analyzed. Treatment with A. gigas extract (1) protected TM3 cells against oxidative stress in a dose-dependent manner, (2) improved the mean weight of the cryptorchid testis, (3) maintained sperm counts, motility, and spermatogenic cell density, (4) decreased levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and increased levels of superoxide dismutase (SOD), (5) significantly increased Nrf2 and heme oxygenase-1 (HO-1), and (6) significantly decreased apoptosis. This study suggests that decursin extracted from A. gigas is a supplemental agent that can reduce oxidative stress by Nrf2-mediated upregulation of HO-1 in rat experimentally induced unilateral cryptorchidism and may improve cryptorchidism-induced infertility. PMID:27034737

  15. Uric Acid-Induced Adipocyte Dysfunction Is Attenuated by HO-1 Upregulation: Potential Role of Antioxidant Therapy to Target Obesity

    PubMed Central

    Sodhi, Komal; Hilgefort, Jordan; Banks, George; Gilliam, Chelsea; Stevens, Sarah; Ansinelli, Hayden A.; Getty, Morghan; Abraham, Nader G.; Shapiro, Joseph I.

    2016-01-01

    Increased uric acid levels have been implicated in the pathogenesis of metabolic syndrome. To examine the mechanisms by which this occurs, we hypothesized that an increase in heme oxygenase 1, a potent antioxidant gene, will decrease uric acid levels and adipocyte dysfunction via suppression of ROS and xanthine oxidase (XO) levels. We examined the effect of uric acid on adipogenesis in human mesenchymal stem cells (MSCs) in the presence and absence of cobalt protoporphyrin (CoPP), an HO-1 inducer, and tin mesoporphyrin (SnMP), an HO activity inhibitor. Uric acid increased adipogenesis by increasing NADPH oxidase expression and elevation in the adipogenesis markers C/EBPα, PPARγ, and Mest, while decreasing small lipid droplets and Wnt10b levels. We treated MSCs with fructose, a fuel source that increases uric acid levels. Our results showed that fructose increased XO expression as compared to the control and concomitant treatment with CoPP significantly decreased XO expression and uric acid levels. These beneficial effects of CoPP were reversed by SnMP, supporting a role for HO activity in mediating these effects. These findings demonstrate that increased levels of HO-1 appear crucial in modulating the phenotype of adipocytes exposed to uric acid and in downregulating XO and NADPH oxidase levels. PMID:26681956

  16. Vascular Protective Role of Samul-Tang in HUVECs: Involvement of Nrf2/HO-1 and NO

    PubMed Central

    Choi, Eun Sik; Lee, Yun Jung; Seo, Chang Seob; Yoon, Jung Joo; Han, Byung Hyuk; Park, Min Cheol; Kang, Dae Gill; Lee, Ho Sub

    2016-01-01

    Samul-Tang (Si-Wu-Tang, SMT), composed of four medicinal herbs, is a well-known herbal formula treating hematological disorder or gynecologic disease. However, vascular protective effects of SMT and its molecular mechanisms on the vascular endothelium, known as the central spot of vascular inflammatory process, are not reported. The aim of this study was to investigate vascular protective effects of SMT water extract in human umbilical vein endothelial cells (HUVECs). Water extract of SMT was prepared and identified by HPLC-PDA analysis. Expression of cell adhesion molecules (CAMs) and heme oxygenase-1 (HO-1) and translocation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were determined by western blot. Nuclear localization of NF-κB and Nrf2 was visualized by immunofluorescence and DNA binding activity of NF-κB was measured. ROS production, HL-60 monocyte adhesion, and intracellular nitric oxide (NO) were also measured using a fluorescent indicator. SMT suppressed NF-κB translocation and activation as well as expression of CAMs, monocyte adhesion, and ROS production induced by TNF-α in HUVECs. SMT treated HUVECs showed upregulation of HO-1 and NO which are responsible for vascular protective action. Our study suggests that SMT, a traditionally used herbal formula, protects the vascular endothelium from inflammation and might be used as a promising vascular protective drug. PMID:27366195

  17. Magnetoelectric and magnetic properties of aluminum borates Ho1 - x Nd x Al3(BO3)4

    NASA Astrophysics Data System (ADS)

    Volkov, N. V.; Gudim, I. A.; Demidov, A. A.; Eremin, E. V.

    2015-03-01

    The magnetoelectric and magnetic properties of substituted aluminum borates Ho1 - x Nd x Al3(BO3)4 have been studied experimentally and theoretically. A large magnetoelectric effect exceeding all known values in isostructural compounds except for HoAl3(BO3)4 has been found. The magnetoelectric polarization of Ho0.8Nd0.2Al3(BO3)4 and Ho0.5Nd0.5Al3(BO3)4 at T = 5 K in a field of 9 T is Δ P ab ( B b ) ≈ -2630 and 1380 μC/m2, respectively. A theoretical consideration based on the crystal field model for the rare-earth ion made it possible to interpret all measured properties within the unified approach. The crystal field parameters have been determined. The temperature (3-300 K) and field (up to 9 T) dependences of the magnetization and the temperature (5-100 K) and field (up to 9 T) dependences of the polarization have been described. The studied properties of Ho1 - x Nd x Al3(BO3)4 have been compared with those of HoAl3(BO3)4 demonstrating record-high polarization values.

  18. Nelumbo nucifera leaves protect hydrogen peroxide-induced hepatic damage via antioxidant enzymes and HO-1/Nrf2 activation.

    PubMed

    Je, Jae-Young; Lee, Da-Bin

    2015-06-01

    Naturally occurring phenolic compounds are widely found in plants. Here, the phenolic composition and hepatoprotective effect of the butanolic extract (BE) from Nelumbo nucifera leaves against H2O2-induced hepatic damage in cultured hepatocytes were investigated. BE showed high total phenol and flavonoid contents, and major phenolic compounds are quercetin, catechin, ferulic acid, rutin, and protocatechuic acid by HPLC analysis. BE effectively scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azino-bis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) cation radicals (IC50 values of 5.21 μg mL(-1) for DPPH and 6.22 μg mL(-1) for ABTS(+)) and showed strong reducing power. Pretreatment of BE prior to 650 μM H2O2 exposure markedly increased cell viability and suppressed H2O2-induced intracellular reactive oxygen species generation and AAPH-induced cell membrane lipid peroxidation. In addition, BE up-regulated intracellular glutathione levels under normal and oxidative stress conditions. Notably, the hepatoprotective effect of BE was directly correlated with the increased expression of superoxide dismutase-1 (SOD-1) by 0.62-fold, catalase (CAT) by 0.42-fold, and heme oxygenase-1 (HO-1) by 2.4-fold. Pretreatment of BE also increased the nuclear accumulation of Nrf2 by 8.1-fold indicating that increased SOD-1, CAT, and HO-1 expressions are Nrf2-mediated. PMID:25962859

  19. Isorhamnetin Attenuates Atherosclerosis by Inhibiting Macrophage Apoptosis via PI3K/AKT Activation and HO-1 Induction

    PubMed Central

    Luo, Yun; Sun, Guibo; Dong, Xi; Wang, Min; Qin, Meng; Yu, Yingli; Sun, Xiaobo

    2015-01-01

    Background and Purpose Isorhamnetin (Iso) is a flavonoid compound extracted from the Chinese herb Hippophae rhamnoides L. Previous studies have revealed its anti-cancer, anti-inflammatory, and anti-oxidant activities. This study investigated the ability of Iso to inhibit oxidized low-density lipoprotein (ox-LDL)-induced cell apoptosis in THP-1-derived macrophages. The effects of Iso on atherosclerosis in vivo were also evaluated in apolipoprotein E knockout (ApoE-/-) mice fed a high fat diet. Methods and Results Iso showed significant inhibitory effects on ox-LDL-induced THP-1-derived macrophage injuries via decreasing reactive oxygen species levels, lipid deposition, and caspase-3 activation, restoring mitochondrial membrane potential, reducing the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells, and regulating apoptosis-related proteins. We also determined the protective effects of Iso by PI3K/AKT activation and HO-1 induction. Iso reduced the atherosclerotic plaque size in vivo in ApoE-/- mice as assessed by oil red O, Sudan IV staining, and CD68-positive cells, and reduced macrophage apoptosis as assessed by caspase-3 and TUNEL assays in lesions. Conclusion In conclusion, our results show that Iso inhibited atherosclerotic plaque development in ApoE-/- mice by PI3K/AKT activation and HO-1 induction. PMID:25799286

  20. Production and characterization of soluble human TNFRI-Fc and human HO-1(HMOX1) transgenic pigs by using the F2A peptide.

    PubMed

    Park, Sol Ji; Cho, Bumrae; Koo, Ok Jae; Kim, Hwajung; Kang, Jung Taek; Hurh, Sunghoon; Kim, Su Jin; Yeom, Hye Jung; Moon, Joonho; Lee, Eun Mi; Choi, Ji Yei; Hong, Ju Ho; Jang, Goo; Hwang, Joing-Ik; Yang, Jaeseok; Lee, Byeong Chun; Ahn, Curie

    2014-06-01

    Generation of transgenic pigs for xenotransplantation is one of the most promising technologies for resolving organ shortages. Human heme oxygenase-1 (hHO-1/HMOX1) can protect transplanted organs by its strong anti-oxidative, anti-apoptotic, and anti-inflammatory effects. Soluble human TNFRI-Fc (shTNFRI-Fc) can inhibit the binding of human TNF-α (hTNF-α) to TNF receptors on porcine cells, and thereby, prevent hTNF-α-mediated inflammation and apoptosis. Herein, we successfully generated shTNFRI-Fc-F2A-HA-hHO-1 transgenic (TG) pigs expressing both shTNFRI-Fc and hemagglutinin-tagged-human heme oxygenase-1 (HA-hHO-1) by using an F2A self-cleaving peptide. shTNFRI-Fc and HA-hHO-1 transgenes containing the F2A peptide were constructed under the control of the CAG promoter. Transgene insertion and copy number in the genome of transgenic pigs was confirmed by polymerase chain reaction (PCR) and Southern blot analysis. Expressions of shTNFRI-Fc and HA-hHO-1 in TG pigs were confirmed using PCR, RT-PCR, western blot, ELISA, and immunohistochemistry. shTNFRI-Fc and HA-hHO-1 were expressed in various organs, including the heart, lung, and spleen. ELISA assays detected shTNFRI-Fc in the sera of TG pigs. For functional analysis, fibroblasts isolated from a shTNFRI-Fc-F2A-HA-hHO-1 TG pig (i.e., #14; 1 × 10(5) cells) were cultured with hTNF-α (20 ng/mL) and cycloheximide (10 μg/mL). The viability of shTNFRI-Fc-F2A-HA-hHO-1 TG pig fibroblasts was significantly higher than that of the wild type (wild type vs. shTNFRI-Fc-F2A-HA-hHO-1 TG at 24 h, 31.6 ± 3.2 vs. 60.4 ± 8.3 %, respectively; p < 0.05). Caspase-3/-7 activity of the shTNFRI-Fc-F2A-HA-hHO-1 TG pig fibroblasts was lower than that of the wild type pig fibroblasts (wild type vs. shTNFRI-Fc-F2A-HA-hHO-1 TG at 12 h, 812,452 ± 113,078 RLU vs. 88,240 ± 10,438 RLU, respectively; p < 0.05). These results show that shTNFRI-Fc and HA-hHO-1 TG pigs generated by the F2A self-cleaving peptide express both sh

  1. Posttreatment with 11-Keto-β-Boswellic Acid Ameliorates Cerebral Ischemia-Reperfusion Injury: Nrf2/HO-1 Pathway as a Potential Mechanism.

    PubMed

    Ding, Yi; Chen, MinChun; Wang, MingMing; Li, YuWen; Wen, AiDong

    2015-12-01

    Oxidative stress is well known to play a pivotal role in cerebral ischemia-reperfusion injury. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. 11-Keto-β-boswellic acid (KBA) is a triterpenoid compound from extracts of Boswellia serrata. The aim of the present study was to determine whether KBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was operated on male Sprague-Dawley rats. KBA (25 mg/kg) applied 1 h after reperfusion significantly reduced infarct volumes and apoptotic cells as well as increased neurologic scores at 48 h after reperfusion. Meanwhile, posttreatment with KBA significantly decreased malondialdehyde (MDA) levels, restored the superoxide dismutase (SOD) activity, and increased the protein Nrf2 and HO-1 expression in brain tissues. In primary cultured astrocytes, KBA increased the Nrf2 and HO-1 expression, which provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. But knockdown of Nrf2 or HO-1 attenuated the protective effect of KBA. In conclusion, these findings provide evidence that the neuroprotection of KBA against oxidative stress-induced ischemic injury involves the Nrf2/HO-1 pathway.

  2. Posttreatment with 11-Keto-β-Boswellic Acid Ameliorates Cerebral Ischemia-Reperfusion Injury: Nrf2/HO-1 Pathway as a Potential Mechanism.

    PubMed

    Ding, Yi; Chen, MinChun; Wang, MingMing; Li, YuWen; Wen, AiDong

    2015-12-01

    Oxidative stress is well known to play a pivotal role in cerebral ischemia-reperfusion injury. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. 11-Keto-β-boswellic acid (KBA) is a triterpenoid compound from extracts of Boswellia serrata. The aim of the present study was to determine whether KBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was operated on male Sprague-Dawley rats. KBA (25 mg/kg) applied 1 h after reperfusion significantly reduced infarct volumes and apoptotic cells as well as increased neurologic scores at 48 h after reperfusion. Meanwhile, posttreatment with KBA significantly decreased malondialdehyde (MDA) levels, restored the superoxide dismutase (SOD) activity, and increased the protein Nrf2 and HO-1 expression in brain tissues. In primary cultured astrocytes, KBA increased the Nrf2 and HO-1 expression, which provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. But knockdown of Nrf2 or HO-1 attenuated the protective effect of KBA. In conclusion, these findings provide evidence that the neuroprotection of KBA against oxidative stress-induced ischemic injury involves the Nrf2/HO-1 pathway. PMID:25452227

  3. Neuroprotection by acetyl-11-keto-β-Boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway.

    PubMed

    Ding, Yi; Chen, MinChun; Wang, Min; Wang, MingMing; Zhang, Tiejun; Park, Jongsun; Zhu, YanRong; Guo, Chao; Jia, YanYan; Li, YuWen; Wen, AiDong

    2014-01-01

    Stroke is a complex disease involved oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. Acetyl-11-Keto-β-Boswellic Acid (AKBA) is an active triterpenoid compound from the extract of Boswellia serrate. The present study was to determine whether AKBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. The stroke model was produced in Sprague-Dawley rats via middle cerebral artery occlusion. To model ischemia-like conditions in vitro, primary cultured cortical neurons were exposed to transient oxygen and glucose deprivation (OGD). Treatment of AKBA significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores by elevating the Nrf2 and HO-1 expression in brain tissues in middle cerebral artery occlusion (MCAO) rats at 48 hours post reperfusion. In primary cultured neurons, AKBA increased the Nrf2 and HO-1 expression, which provided protection against OGD-induced oxidative insult. Additionally, AKBA treatment increased Nrf2 binding activity to antioxidant-response elements (ARE). The protective effect of AKBA was attenuated by knockdown of Nrf2 or HO-1. In conclusion, these findings provide evidence that AKBA protects neurons against ischemic injury, and this neuroprotective effect involves the Nrf2/HO-1 pathway. PMID:25384416

  4. Luteolin and luteolin-7-O-glucoside strengthen antioxidative potential through the modulation of Nrf2/MAPK mediated HO-1 signaling cascade in RAW 264.7 cells.

    PubMed

    Song, Young Sun; Park, Chung Mu

    2014-03-01

    It has been understood that glycosidic forms of flavonoids were hydrolyzed by gut bacteria and absorbed as aglycones. However, several reports suggested that glycosides were partly absorbed without hydrolysis and remained biologically active. In this study, we evaluated the antioxidative potential of luteolin and luteolin-7-O-glucoside, glycosidic form of luteolin, against the oxidative damage and compared their antioxidative mechanisms in RAW 264.7 cells. Heme oxygenase-1 (HO-1), one of the phase II enzymes showing an antioxidative activity, was potently induced by luteolin and luteolin-7-O-glucoside treatment, which was in accordance with the translocated nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) into nucleus. Moreover, luteolin and the luteolin-7-O-glucoside activated HO-1 expression by p38 and c-Jun NH2-terminal kinase (JNK) regulation. In order to identify the antioxidation potential by HO-1, tert-butyl hydroperoxide (t-BHP)-induced oxidative damage was applied and ameliorated by luteolin and the luteolin-7-O-glucoside treatment in a dose dependent manner, which was confirmed by HO-1 selective inhibitor and inducer, tin protoporphyrin (SnPP) and cobalt protoporphyrin (CoPP), respectively. Consequently, luteolin and luteolin-7-O-glucoside potently strengthen the HO-1-mediated antioxidative potential through the modulation of the Nrf2/MAPK signaling pathways.

  5. Luteolin and luteolin-7-O-glucoside strengthen antioxidative potential through the modulation of Nrf2/MAPK mediated HO-1 signaling cascade in RAW 264.7 cells.

    PubMed

    Song, Young Sun; Park, Chung Mu

    2014-03-01

    It has been understood that glycosidic forms of flavonoids were hydrolyzed by gut bacteria and absorbed as aglycones. However, several reports suggested that glycosides were partly absorbed without hydrolysis and remained biologically active. In this study, we evaluated the antioxidative potential of luteolin and luteolin-7-O-glucoside, glycosidic form of luteolin, against the oxidative damage and compared their antioxidative mechanisms in RAW 264.7 cells. Heme oxygenase-1 (HO-1), one of the phase II enzymes showing an antioxidative activity, was potently induced by luteolin and luteolin-7-O-glucoside treatment, which was in accordance with the translocated nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) into nucleus. Moreover, luteolin and the luteolin-7-O-glucoside activated HO-1 expression by p38 and c-Jun NH2-terminal kinase (JNK) regulation. In order to identify the antioxidation potential by HO-1, tert-butyl hydroperoxide (t-BHP)-induced oxidative damage was applied and ameliorated by luteolin and the luteolin-7-O-glucoside treatment in a dose dependent manner, which was confirmed by HO-1 selective inhibitor and inducer, tin protoporphyrin (SnPP) and cobalt protoporphyrin (CoPP), respectively. Consequently, luteolin and luteolin-7-O-glucoside potently strengthen the HO-1-mediated antioxidative potential through the modulation of the Nrf2/MAPK signaling pathways. PMID:24361407

  6. S-Propargyl-cysteine Exerts a Novel Protective Effect on Methionine and Choline Deficient Diet-Induced Fatty Liver via Akt/Nrf2/HO-1 Pathway

    PubMed Central

    Li, Wenwen; Ma, Fenfen; Zhang, Laiyin; Huang, Yong; Li, Xinghui; Zhang, Aijie; Hou, Cuilan; Zhu, Yichun; Zhu, YiZhun

    2016-01-01

    This study investigated the antioxidative effect of S-propargyl-cysteine (SPRC) on nonalcoholic fatty liver (NAFLD) by treating mice fed a methionine and choline deficient (MCD) diet with SPRC for four weeks. We found that SPRC significantly reduced hepatic reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels. Moreover, SPRC also increased the superoxide dismutase (SOD) activity. By Western blot, we found that this protective effect of SPRC was importantly attributed to the regulated hepatic antioxidant-related proteins, including protein kinase B (Akt), heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and cystathionine γ-lyase (CSE, an enzyme that synthesizes hydrogen sulfide). Next, we examined the detailed molecular mechanism of the SPRC protective effect using oleic acid- (OA-) induced HepG2 cells. The results showed that SPRC significantly decreased intracellular ROS and MDA levels in OA-induced HepG2 cells by upregulating the phosphorylation of Akt, the expression of HO-1 and CSE, and the translocation of Nrf2. SPRC-induced HO-1 expression and Nrf2 translocation were abolished by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Moreover, the antioxidative effect of SPRC was abolished by CSE inhibitor DL-propargylglycine (PAG) and HO-1 siRNA. Therefore, these results proved that SPRC produced an antioxidative effect on NAFLD through the PI3K/Akt/Nrf2/HO-1 signaling pathway. PMID:27313828

  7. Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

    PubMed Central

    Dai, Chongshan; Tang, Shusheng; Deng, Sijun; Zhang, Shen; Zhou, Yan; Velkov, Tony

    2014-01-01

    Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO

  8. Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway.

    PubMed

    Dai, Chongshan; Tang, Shusheng; Deng, Sijun; Zhang, Shen; Zhou, Yan; Velkov, Tony; Li, Jian; Xiao, Xilong

    2015-01-01

    Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO

  9. Omega-3 polyunsaturated fatty acid has an anti-oxidant effect via the Nrf-2/HO-1 pathway in 3T3-L1 adipocytes

    SciTech Connect

    Kusunoki, Chisato; Yang, Liu; Yoshizaki, Takeshi; Nakagawa, Fumiyuki; Ishikado, Atsushi; Kondo, Motoyuki; Morino, Katsutaro; Sekine, Osamu; Ugi, Satoshi; Nishio, Yoshihiko; Kashiwagi, Atsunori; Maegawa, Hiroshi

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Omega-3 PUFA has a direct anti-oxidant effect in adipocytes. Black-Right-Pointing-Pointer EPA and DHA induce HO-1 expression in 3T3-L1 adipocytes. Black-Right-Pointing-Pointer Omega-3 PUFA and its end-product, 4-HHE, activates the Nrf-2/HO-1 pathway. Black-Right-Pointing-Pointer Omega-3 PUFA protects against oxidative stress-induced cytotoxicity. -- Abstract: Oxidative stress is produced in adipose tissue of obese subjects and has been associated with obesity-related disorders. Recent studies have shown that omega-3 polyunsaturated fatty acid ({omega}3-PUFA) has beneficial effects in preventing atherosclerotic diseases and insulin resistance in adipose tissue. However, the role of {omega}3-PUFA on adipocytes has not been elucidated. In this study, 3T3-L1 adipocytes were treated with {omega}3-PUFA and its metabolites, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or 4-hydroxy hexenal (4-HHE). {omega}3-PUFA and its metabolites dose-dependently increased mRNA and protein levels of the anti-oxidative enzyme, heme oxygenase-1 (HO-1); whereas no changes in the well-known anti-oxidant molecules, superoxide dismutase, catalase, and glutathione peroxidase, were observed. Knockdown of nuclear factor erythroid 2-related factor 2 (Nrf-2) significantly reduced EPA, DHA or 4-HHE-induced HO-1 mRNA and protein expression. Also, pretreatment with {omega}3-PUFA prevented H{sub 2}O{sub 2}-induced cytotoxicity in a HO-1 dependent manner. In conclusion, treatment with EPA and DHA induced HO-1 through the activation of Nrf-2 and prevented oxidative stress in 3T3-L1 adipocytes. This anti-oxidant defense may be of high therapeutic value for clinical conditions associated with systemic oxidative stress.

  10. 15-Deoxy-delta 12,14-prostaglandin J2 biphasically regulates the proliferation of mouse hippocampal neural progenitor cells by modulating the redox state.

    PubMed

    Katura, Takashi; Moriya, Takahiro; Nakahata, Norimichi

    2010-04-01

    The activity of neural progenitor cells (NPCs) is regulated by various humoral factors. Although prostaglandin (PG) D(2) is known to mediate various physiological brain functions such as sleep, its actions on NPCs have not been fully understood. In the process of investigating the effects of PGD(2) on NPCs, we found that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an endogenous metabolite of PGD(2), exhibits a novel regulation of the proliferation of NPCs derived from mouse hippocampus. 15d-PGJ(2) showed biphasic effects on epidermal growth factor-induced proliferation of NPCs; facilitation at low concentrations ( approximately 0.3 muM) and suppression at higher concentrations (0.5-10 microM) in vitro. 2-Chloro-5-nitrobenzanilide (GW9662), an inhibitor of peroxisome proliferator-activated receptor gamma, known to be a molecular target for 15d-PGJ(2), failed to abolish the effects of 15d-PGJ(2). 9,10-dihydro-15d-PGJ(2) (CAY10410), a structural analog of 15d-PGJ(2) lacking the electrophilic carbon in the cyclopentenone ring, did not show 15d-PGJ(2)-like actions. Treatment with 15d-PGJ(2) increased the levels of reactive oxygen species and decreased endogenous GSH levels. Furthermore, supplementation with a membrane-permeable analog of glutathione, GSH ethyl ester (2 mM), diminished the biphasic effects of 15d-PGJ(2). Finally, cell division in the dentate gyrus of postnatal mice was increased by injection of low-dose (1 ng i.c.v.) 15d-PGJ(2) and suppressed by high-dose (30 ng) 15d-PGJ(2). These results suggest that 15d-PGJ(2) regulates the proliferation of NPCs via its electrophilic nature, which enables covalent binding to molecules such as GSH. PMID:20086036

  11. Hawthorn Fruit Extract Elevates Expression of Nrf2/HO-1 and Improves Lipid Profiles in Ovariectomized Rats.

    PubMed

    Yoo, Jeong-Hyun; Liu, Yanan; Kim, Hyun-Sook

    2016-01-01

    The purpose of this study was to investigate the effects of hawthorn (Crataegus pinnatifida Bunge) extract on the lipid profiles and antioxidant properties in ovariectomized (OVX) rats. After ovariectomy, the rats were randomly divided into four groups: the non-OVX control (Sham), the OVX-control (OVX), the OVX + 100 mg/kg b.w. of hawthorn extract (OL), and the OVX + 200 mg/kg b.w. of hawthorn extract (OH). The final body weights of the OVX group were significantly increased, but the increment was significantly decreased in hawthorn groups (p < 0.05). The serum total and low-density lipoprotein (LDL) cholesterol levels were significantly elevated in the OVX group, whereas the hawthorn groups showed a significant decrease in these levels (p < 0.05). The hepatic triglyceride (TG) and malondialdehyde (MDA) levels were significantly reduced in the hawthorn groups compared with the OVX group (p < 0.05). The mRNA expression of nuclear factor erythroid 2-related factor (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase (GPx) were significantly decreased in the OVX group, whereas the hawthorn groups exhibited a significant increase in expression (p < 0.05). The protein expressions of Nrf2, HO-1, and GPx were lower in the OVX group than the Sham group (p < 0.05). The oral administration of hawthorn extract reversed the suppression of protein levels. These results suggest that hawthorn extract could have protective effects in OVX rats by improving lipid profiles, decreasing oxidative stress, and improving the antioxidant defense system. PMID:27187458

  12. Hawthorn Fruit Extract Elevates Expression of Nrf2/HO-1 and Improves Lipid Profiles in Ovariectomized Rats

    PubMed Central

    Yoo, Jeong-Hyun; Liu, Yanan; Kim, Hyun-Sook

    2016-01-01

    The purpose of this study was to investigate the effects of hawthorn (Crataegus pinnatifida Bunge) extract on the lipid profiles and antioxidant properties in ovariectomized (OVX) rats. After ovariectomy, the rats were randomly divided into four groups: the non-OVX control (Sham), the OVX-control (OVX), the OVX + 100 mg/kg b.w. of hawthorn extract (OL), and the OVX + 200 mg/kg b.w. of hawthorn extract (OH). The final body weights of the OVX group were significantly increased, but the increment was significantly decreased in hawthorn groups (p < 0.05). The serum total and low-density lipoprotein (LDL) cholesterol levels were significantly elevated in the OVX group, whereas the hawthorn groups showed a significant decrease in these levels (p < 0.05). The hepatic triglyceride (TG) and malondialdehyde (MDA) levels were significantly reduced in the hawthorn groups compared with the OVX group (p < 0.05). The mRNA expression of nuclear factor erythroid 2–related factor (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase (GPx) were significantly decreased in the OVX group, whereas the hawthorn groups exhibited a significant increase in expression (p < 0.05). The protein expressions of Nrf2, HO-1, and GPx were lower in the OVX group than the Sham group (p < 0.05). The oral administration of hawthorn extract reversed the suppression of protein levels. These results suggest that hawthorn extract could have protective effects in OVX rats by improving lipid profiles, decreasing oxidative stress, and improving the antioxidant defense system. PMID:27187458

  13. α-Dihydroxychalcone-glycoside (α-DHC) isolated from the heartwood of Pterocarpus marsupium inhibits LPS induced MAPK activation and up regulates HO-1 expression in murine RAW 264.7 macrophage.

    PubMed

    Chakraborty, Prarthana; Saraswat, Ghungroo; Kabir, Syed N

    2014-05-15

    Three phenolic glycosides isolated from the heartwood of Pterocarpus marsupium showed significant free radical and superoxide ion scavenging activity and antioxidant potential that were comparable to, or several folds higher than those of standard antioxidants, trolox and ascorbic acid. The effective concentrations of these compounds were far below their cytotoxic levels. Compound 3, which was characterized to be α-dihydroxychalcone-glycoside (α-DHC), was the most potent one. Subsequent studies demonstrated that α-DHC effectively reduced nitric oxide and cytokine production by the LPS stimulated RAW 264.7 mouse macrophage cell line. The compound effectively attenuated the expression of inflammation-mediating enzymes COX-2 and iNOS at the mRNA as well as protein levels in a concentration dependent manner. It prevented phosphorylation of all the three MAPKs (JNK, ERK, p38) and eventually blocked the activation of downstream elements contributing to inflammation. Phosphorylation of IκB-α and subsequent translocation of NF-κB into the nucleus were restricted, while the expression of stress responsive gene HO-1 was up-regulated. α-DHC targeted Keap-1 by modifying its cysteine thiols, dissociating it from Nrf-2 and facilitating nuclear entry of the latter; and this in turn induced HO-1 expression. Thus α-DHC exerts its anti-inflammatory activity in a dual manner: by down regulating MAPKs and restricting nuclear stabilization of NF-κB at one end, and by disrupting Nrf-2-Keap-1 complex on the other. In conclusion, the anti-inflammatory potential together with its high therapeutic index envisages α-DHC as a prospective candidate molecule for the development of therapeutic strategy against inflammatory disorders.

  14. Preconditioning with low concentration NO attenuates subsequent NO-induced apoptosis in vascular smooth muscle cells via HO-1-dependent mitochondrial death pathway

    SciTech Connect

    Kwak, Hyun-Jeong; Park, Kyoung-Mi; Lee, Seahyoung; Lim, Hyun-Joung; Go, Sang-Hee; Eom, Sang-Mi; Park, Hyun-Young . E-mail: hypark65@nih.go.kr

    2006-12-01

    Nitric oxide (NO) signaling pathways are important in both the maintenance of vascular homeostasis and disease progression. Overproduction of NO has been associated with ischemia/reperfusion (I/R) injury. Growing evidences suggest that NO preconditioning has cytoprotective effects against I/R injury. However, the mechanism with which NO mediates these effects remains to be elucidated. The purpose of this study was to examine the mechanism of how NO preconditioning inhibits subsequent NO-induced apoptosis in vascular smooth muscle cells (VSMC), specifically focusing on heme oxygenase-1 (HO-1). According to our data, sodium nitroprusside (SNP) increased HO-1 expression in a concentration dependent manner. Preconditioning with low concentration SNP (0.3 mM) inhibited subsequent high concentration SNP (1.5 mM)-induced apoptosis, and this effect was reversed by the HO-1 inhibitor SnPP. Low concentration SNP-mediated protection involved p38 kinase inactivation and increased Bcl-2 expression. Furthermore, mitochondrial membrane potential was concomitantly increased with decreased expressions of Bax, Apaf-1, and activity of caspase-3, which was reversed by SnPP treatment. Our results show that low concentration SNP preconditioning suppresses subsequent high concentration SNP-induced apoptosis by inhibiting p38 kinase and mitochondrial death pathway via HO-1-dependent mechanisms in VSMC.

  15. Nrf2-mediated HO-1 induction contributes to antioxidant capacity of a Schisandrae Fructus ethanol extract in C2C12 myoblasts.

    PubMed

    Kang, Ji Sook; Han, Min Ho; Kim, Gi-Young; Kim, Cheol Min; Kim, Byung Woo; Hwang, Hye Jin; Hyun, Yung

    2014-12-01

    This study was designed to confirm the protective effect of Schisandrae Fructus, which are the dried fruits of Schisandra chinensis (Turcz.) Baill, against oxidative stress-induced cellular damage and to elucidate the underlying mechanisms in C2C12 myoblasts. Preincubating C2C12 cells with a Schisandrae Fructus ethanol extract (SFEE) significantly attenuated hydrogen peroxide (H2O2)-induced inhibition of growth and induced scavenging activity against intracellular reactive oxygen species (ROS) induced by H2O2. SFEE also inhibited comet tail formation and phospho-histone γH2A.X expression, suggesting that it prevents H2O2-induced cellular DNA damage. Furthermore, treating C2C12 cells with SFEE significantly induced heme oxygenase-1 (HO-1) and phosphorylation of nuclear factor-erythroid 2 related factor 2 (Nrf2). However, zinc protoporphyrin IX, a potent inhibitor of HO-1 activity, significantly reversed the protective effects of SFEE against H2O2-induced growth inhibition and ROS generation in C2C12 cells. Additional experiments revealed that the potential of the SFEE to induce HO-1 expression and protect against H2O2-mediated cellular damage was abrogated by transient transfection with Nrf2-specific small interfering RNA, suggesting that the SFEE protected C2C12 cells against oxidative stress-induced injury through the Nrf2/HO-1 pathway. PMID:25493944

  16. α-Dihydroxychalcone-glycoside (α-DHC) isolated from the heartwood of Pterocarpus marsupium inhibits LPS induced MAPK activation and up regulates HO-1 expression in murine RAW 264.7 macrophage

    SciTech Connect

    Chakraborty, Prarthana; Saraswat, Ghungroo; Kabir, Syed N.

    2014-05-15

    Three phenolic glycosides isolated from the heartwood of Pterocarpus marsupium showed significant free radical and superoxide ion scavenging activity and antioxidant potential that were comparable to, or several folds higher than those of standard antioxidants, trolox and ascorbic acid. The effective concentrations of these compounds were far below their cytotoxic levels. Compound 3, which was characterized to be α-dihydroxychalcone-glycoside (α-DHC), was the most potent one. Subsequent studies demonstrated that α-DHC effectively reduced nitric oxide and cytokine production by the LPS stimulated RAW 264.7 mouse macrophage cell line. The compound effectively attenuated the expression of inflammation-mediating enzymes COX-2 and iNOS at the mRNA as well as protein levels in a concentration dependent manner. It prevented phosphorylation of all the three MAPKs (JNK, ERK, p38) and eventually blocked the activation of downstream elements contributing to inflammation. Phosphorylation of IκB-α and subsequent translocation of NF-κB into the nucleus were restricted, while the expression of stress responsive gene HO-1 was up-regulated. α-DHC targeted Keap-1 by modifying its cysteine thiols, dissociating it from Nrf-2 and facilitating nuclear entry of the latter; and this in turn induced HO-1 expression. Thus α-DHC exerts its anti-inflammatory activity in a dual manner: by down regulating MAPKs and restricting nuclear stabilization of NF-κB at one end, and by disrupting Nrf-2–Keap-1 complex on the other. In conclusion, the anti-inflammatory potential together with its high therapeutic index envisages α-DHC as a prospective candidate molecule for the development of therapeutic strategy against inflammatory disorders. - Highlights: • α-DHC isolated from Pterocarpus marsupium has significant antioxidant potential. • α-DHC inhibits NO, IL-6, IL-1β, TNF-α production in LPS-stimulated RAW 264.7 cells. • α-DHC down-regulates of COX-2, iNOS expression in LPS-stimulated

  17. Inhibition of beta-amyloid-induced neurotoxicity by pinocembrin through Nrf2/HO-1 pathway in SH-SY5Y cells.

    PubMed

    Wang, Yumin; Miao, Yingchun; Mir, Aamina Zia; Cheng, Long; Wang, Lina; Zhao, Linan; Cui, Qifu; Zhao, Weili; Wang, Hongquan

    2016-09-15

    Amyloid beta peptide (Aβ) can cause neurotoxicity in Alzheimer's disease (AD). It evokes a cascade of oxidative damage to neurons. Pinocembrin (PCB), the most abundant flavonoid in propolis, has been proven to have neuroprotective effects in vivo and in vitro. In the present study, we investigated the neuroprotective effects of PCB on Aβ25-35-induced neurotoxicity. Exposure of SH-SY5Y cells to 25μM Aβ25-35 for 24h caused viability loss, apoptotic increase and reactive oxygen species (ROS) increase, pre-treatment with PCB for 4h significantly reduced the viability loss, apoptotic rate and attenuated Aβ-mediated ROS production. PCB strikingly inhibited Aβ25-35-induced mitochondrial dysfunctions, including lowered membrane potential, decreased Bcl-2/Bax ratio. In addition, PCB suppressed the release of cytochrome c and the cleavage of caspase-3. PCB treatment also resulted in an increase in Nrf2 protein levels and subsequent induction of heme oxygenase-1(HO-1) expression in SH-SY5Y cells. RNA interference-mediated knockdown of Nrf2 expression suppressed the PCB-induced HO-1 expression. Notably, we found that the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) markedly diminished the neuroprotective effect of PCB against Aβ-mediated neurotoxicity. Taken together, these results indicated that PCB protects SH-SY5Y cells from Aβ25-35-induced neurotoxicity through activation of Nrf2/HO-1 pathways. Thus, activation of Nrf2/HO-1 pathways and inhibition of mitochondria-dependent apoptosis together may protect cells from Aβ25-35-induceded neurotoxicity. PMID:27538638

  18. Agmatine Reduces Lipopolysaccharide-Mediated Oxidant Response via Activating PI3K/Akt Pathway and Up-Regulating Nrf2 and HO-1 Expression in Macrophages

    PubMed Central

    Chai, Jianshen; Luo, Li; Hou, Fengyan; Fan, Xia; Yu, Jing; Ma, Wei; Tang, Wangqi; Yang, Xue; Zhu, Junyu; Kang, Wenyuan; Yan, Jun; Liang, Huaping

    2016-01-01

    Macrophages are key responders of inflammation and are closely related with oxidative stress. Activated macrophages can enhance oxygen depletion, which causes an overproduction of reactive oxygen species (ROS) and leads to further excessive inflammatory response and tissue damage. Agmatine, an endogenous metabolite of L-arginine, has recently been shown to have neuroprotective effects based on its antioxidant properties. However, the antioxidant effects of agmatine in peripheral tissues and cells, especially macrophages, remain unclear. In this study we explored the role of agmatine in mediating antioxidant effects in RAW 264.7 cells and studied its antioxidant mechanism. Our data demonstrate that agmatine is an activator of Nrf2 signaling that markedly enhances Nrf2 nuclear translocation, increases nuclear Nrf2 protein level, up-regulates the expression of the Nrf2 downstream effector HO-1, and attenuates ROS generation induced by Lipopolysaccharide (LPS). We further demonstrated that the agmatine-induced activation of Nrf2 is likely through the PI3K/Akt pathway. LY294002, a specific PI3K/Akt inhibitor, abolished agmatine-induced HO-1 up-regulation and ROS suppression significantly. Inhibiting HO-1 pathway significantly attenuated the antioxidant effect of agmatine which the products of HO-1 enzymatic activity contributed to. Furthermore, the common membrane receptors of agmatine were evaluated, revealing that α2-adrenoceptor, I1-imidazoline receptor or I2-imidazoline receptor are not required by the antioxidant properties of agmatine. Taken together, our findings revealed that agmatine has antioxidant activity against LPS-induced ROS accumulation in RAW 264.7 cells involving HO-1 expression induced by Nrf2 via PI3K/Akt pathway activation. PMID:27685463

  19. Magnetism of Ho1-xTbxAl₂ alloys: Critical dependence of a first-order transition on Tb concentration

    DOE PAGES

    Khan, Mahmud; Mudryk, Ya.; Gschneidner, K. A.; Pecharsky, V. K.

    2011-12-27

    HoAl₂ exhibits a first-order spin reorientation transition at 20 K, which is manifested as a sharp peak in the heat capacity. When Ho is partially replaced by only 5% of Tb, the sharp heat-capacity peak in Ho1-xTbxAl₂ (x = 0.05) disappears, and then reappears again for x ≥ 0.07. For x = 0.05, the anomaly corresponding to the spin reorientation transition is barely seen in the heat capacity, but as x exceeds 0.07 the weak anomaly transforms to a sharp peak. The spin reorientation transition temperature increases to 29 K for x = 0.05, and as x increases further themore » transition shifts to lower temperature and returns to ~20 K for x = 0.25. The transition is no longer observed when x exceeds 0.60. Temperature-dependent x-ray powder-diffraction data confirm the first-order nature of the spin reorientation transition for the alloy with x = 0.40, and indicate that the compound retains the room-temperature cubic structure within the sensitivity of the technique. Experimental observations are discussed considering the easy magnetization directions of HoAl₂ and TbAl₂.« less

  20. Hysteresis and magnetostriction of TbxDyyHo1-x-yFe1.95 [112] dendritic rods

    NASA Astrophysics Data System (ADS)

    Wun-Fogle, M.; Restorff, J. B.; Clark, A. E.

    1999-04-01

    The magnetization and magnetostriction of a variety of 3/16-in.-diam Laves phase rods of TbxDyyHo1-x-yFe1.95 grown in the form of [112] oriented dendritic compounds were measured as a function of applied magnetic field -3000

  1. Ginkgo biloba Extract Prevents Female Mice from Ischemic Brain Damage and the Mechanism Is Independent of the HO1/Wnt Pathway.

    PubMed

    Tulsulkar, Jatin; Glueck, Bryan; Hinds, Terry D; Shah, Zahoor A

    2016-04-01

    It is well known that gender differences exist in experimental or clinical stroke with respect to brain damage and loss of functional outcome. We have previously reported neuroprotective properties of Ginkgo biloba/EGb 761® (EGb 761) in transient and permanent mouse models of brain ischemia using male mice, and the mechanism of action was attributed to the upregulation of the heme oxygenase 1 (HO1)/Wnt pathway. Here, we sought to investigate whether EGb 761's protective effect in ovariectomized female mice following stroke is also mediated by the HO1/Wnt pathway. Female mice were ovariectomized (OVX) to remove the protective effect of estrogen and were treated with EGb 761 for 7 days prior to inducing permanent middle cerebral artery occlusion (pMCAO) and allowed to survive for an additional 7 days. At day 8, animals were sacrificed, and the brains were harvested for infarct volume analysis, western blots, and immunohistochemistry. The OVX female mice treated with EGb 761 showed significantly lower infarct size as compared to Veh/OVX animals. EGb 761 treatment in female mice inhibited apoptosis by preventing caspase-3 cleavage and blocking the extrinsic apoptotic pathway. EGb 761 pretreatment significantly enhanced neurogenesis in OVX mice as compared to the Veh/OVX group and significantly upregulated androgen receptor expression with no changes in HO1/Wnt signaling. These results suggest that EGb 761 prevented brain damage in OVX female mice by improving grip strength and neurological deficits, and the mechanism of action is not through HO1/Wnt but via blocking the extrinsic apoptotic pathway. PMID:26573919

  2. Transcriptional upregulation centra of HO-1 by EGB via the MAPKs/Nrf2 pathway in mouse C2C12 myoblasts.

    PubMed

    Wang, Jianfeng; Zhang, Li; Zhang, Ying; Luo, Meiling; Wu, Qiong; Yu, Lijun; Chu, Haiying

    2015-03-01

    Long-term abuse of alcohol results in chronic alcoholic myopathy which is associated with increased oxidative stress. Ginkgo biloba extract (EGB) is widely used as a therapeutic agent to treat certain cardiovascular and neurological disorders. Although EGB is known to possess antioxidant functions and potent cytoprotective effects, its protective mechanism on alcohol-induced oxidative damage in C2C12 myoblasts remains unclear. In this study, we investigated the cytoprotective mechanisms of EGB against alcohol-derived oxidative stress in mouse C2C12 myoblasts. Challenge with alcohol (100mM) caused an increase in intracellular reactive oxygen species in mouse C2C12 myoblasts, which was not alleviated by treatment with EGB. These results indicate that EGB does not seem to act as an ROS scavenger in this experimental model. Additionally, EGB produced activation of ERK and JNK [two major mitogen-activated protein kinases (MAPKs)], an increase in the nuclear level of nuclear factor erythroid-2-related factor 2 (Nrf2) and upregulation of heme oxygenase-1 (HO-1, a stress-responsive protein with antioxidant function). Pretreatment with inhibitors of MAPKs PD98059 (a specific inhibitor of ERK), SP600125 (a specific inhibitor of JNK) abolished both EGB-induced Nrf2 nuclear translocation and HO-1 up-regulation. We conclude that EGB confers cytoprotective effects from oxidative stress induced by alcohol in mouse C2C12 myoblasts depend on transcriptional upregulation of HO-1 by EGB via the MAPKs/Nrf2 pathway.

  3. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression.

    PubMed

    Balan, Murugabaskar; Mier y Teran, Eduardo; Waaga-Gasser, Ana Maria; Gasser, Martin; Choueiri, Toni K; Freeman, Gordon; Pal, Soumitro

    2015-03-27

    The receptor tyrosine kinase c-Met is overexpressed in renal cancer cells and can play major role in the growth and survival of tumor. We investigated how the c-Met-mediated signaling through binding to its ligand hepatocyte growth factor (HGF) can modulate the apoptosis and immune escape mechanism(s) of renal cancer cells by the regulations of novel molecules heme oxygenase-1 (HO-1) and programmed death-1 ligand 1 (PD-L1). We found that HGF/c-Met-mediated signaling activated the Ras/Raf pathway and down-regulated cancer cell apoptosis; and it was associated with the overexpression of cytoprotective HO-1 and anti-apoptotic Bcl-2/Bcl-xL. c-Met-induced HO-1 overexpression was regulated at the transcriptional level. Next, we observed that c-Met induction markedly up-regulated the expression of the negative co-stimulatory molecule PD-L1, and this can be prevented following treatment of the cells with pharmacological inhibitors of c-Met. Interestingly, HGF/c-Met-mediated signaling could not induce PD-L1 at the optimum level when either Ras or HO-1 was knocked down. To study the functional significance of c-Met-induced PD-L1 expression, we performed a co-culture assay using mouse splenocytes (expressing PD-L1 receptor PD-1) and murine renal cancer cells (RENCA, expressing high PD-L1). We observed that the splenocyte-mediated apoptosis of cancer cells during co-culture was markedly increased in the presence of either c-Met inhibitor or PD-L1 neutralizing antibody. Finally, we found that both c-Met and PD-L1 are significantly up-regulated and co-localized in human renal cancer tissues. Together, our study suggests a novel mechanism(s) by which c-Met can promote increased survival of renal cancer cells through the regulation of HO-1 and PD-L1.

  4. Proteomic Identification of Protein Targets for 15-Deoxy-Δ12,14-Prostaglandin J2 in Neuronal Plasma Membrane

    PubMed Central

    Yamamoto, Yasuhiro; Takase, Kenkichi; Kishino, Junji; Fujita, Megumi; Okamura, Noboru; Sakaeda, Toshiyuki; Fujimoto, Masafumi; Yagami, Tatsurou

    2011-01-01

    15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is one of factors contributed to the neurotoxicity of amyloid β (Aβ), a causative protein of Alzheimer's disease. Type 2 receptor for prostaglandin D2 (DP2) and peroxysome-proliferator activated receptorγ (PPARγ) are identified as the membrane receptor and the nuclear receptor for 15d-PGJ2, respectively. Previously, we reported that the cytotoxicity of 15d-PGJ2 was independent of DP2 and PPARγ, and suggested that 15d-PGJ2 induced apoptosis through the novel specific binding sites of 15d-PGJ2 different from DP2 and PPARγ. To relate the cytotoxicity of 15d-PGJ2 to amyloidoses, we performed binding assay [3H]15d-PGJ2 and specified targets for 15d-PGJ2 associated with cytotoxicity. In the various cell lines, there was a close correlation between the susceptibilities to 15d-PGJ2 and fibrillar Aβ. Specific binding sites of [3H]15d-PGJ2 were detected in rat cortical neurons and human bronchial smooth muscle cells. When the binding assay was performed in subcellular fractions of neurons, the specific binding sites of [3H]15d-PGJ2 were detected in plasma membrane, nuclear and cytosol, but not in microsome. A proteomic approach was used to identify protein targets for 15d-PGJ2 in the plasma membrane. By using biotinylated 15d-PGJ2, eleven proteins were identified as biotin-positive spots and classified into three different functional proteins: glycolytic enzymes (Enolase2, pyruvate kinase M1 (PKM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH)), molecular chaperones (heat shock protein 8 and T-complex protein 1 subunit α), cytoskeletal proteins (Actin β, F-actin-capping protein, Tubulin β and Internexin α). GAPDH, PKM1 and Tubulin β are Aβ-interacting proteins. Thus, the present study suggested that 15d-PGJ2 plays an important role in amyloidoses not only in the central nervous system but also in the peripheral tissues. PMID:21445266

  5. N-acetyl cysteine inhibits H2O2-mediated reduction in the mineralization of MC3T3-E1 cells by down-regulating Nrf2/HO-1 pathway.

    PubMed

    Lee, Daewoo; Kook, Sung-Ho; Ji, Hyeok; Lee, Seung-Ah; Choi, Ki-Choon; Lee, Kyung-Yeol; Lee, Jeong-Chae

    2015-11-01

    There are controversial findings regarding the roles of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway on bone metabolism under oxidative stress. We investigated how Nrf2/HO-1 pathway affects osteoblast differentiation of MC3T3-E1 cells in response to hydrogen peroxide (H2O2), N-acetyl cysteine (NAC), or both. Exposing the cells to H2O2 decreased the alkaline phosphatase activity, calcium accumulation, and expression of osteoblast markers, such as osteocalcin and runt-related transcription factor-2. In contrast, H2O2 treatment increased the expression of Nrf2 and HO-1 in the cells. Treatment with hemin, a chemical HO-1 inducer, mimicked the inhibitory effect of H2O2 on osteoblast differentiation by increasing the HO-1 expression and decreasing the osteogenic marker genes. Pretreatment with NAC restored all changes induced by H2O2 to near normal levels in the cells. Collectively, our findings suggest that H2O2-mediated activation of Nrf2/HO-1 pathway negatively regulates the osteoblast differentiation, which is inhibited by NAC. PMID:26303969

  6. Crocin Suppresses LPS-Stimulated Expression of Inducible Nitric Oxide Synthase by Upregulation of Heme Oxygenase-1 via Calcium/Calmodulin-Dependent Protein Kinase 4

    PubMed Central

    Kim, Ji-Hee; Park, Ga-Young; Bang, Soo Young; Park, Sun Young; Bae, Soo-Kyung; Kim, YoungHee

    2014-01-01

    Crocin is a water-soluble carotenoid pigment that is primarily used in various cuisines as a seasoning and coloring agent, as well as in traditional medicines for the treatment of edema, fever, and hepatic disorder. In this study, we demonstrated that crocin markedly induces the expression of heme oxygenase-1 (HO-1) which leads to an anti-inflammatory response. Crocin inhibited inducible nitric oxide synthase (iNOS) expression and nitric oxide production via downregulation of nuclear factor kappa B activity in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. These effects were abrogated by blocking of HO-1 expression or activity. Crocin also induced Ca2+ mobilization from intracellular pools and phosphorylation of Ca2+/calmodulin-dependent protein kinase 4 (CAMK4). CAMK4 knockdown and kinase-dead mutant inhibited crocin-mediated HO-1 expression, Nrf2 activation, and phosphorylation of Akt, indicating that HO-1 expression is mediated by CAMK4 and that Akt is a downstream mediator of CAMK4 in crocin signaling. Moreover, crocin-mediated suppression of iNOS expression was blocked by CAMK4 inhibition. Overall, these results suggest that crocin suppresses LPS-stimulated expression of iNOS by inducing HO-1 expression via Ca2+/calmodulin-CAMK4-PI3K/Akt-Nrf2 signaling cascades. Our findings provide a novel molecular mechanism for the inhibitory effects of crocin against endotoxin-mediated inflammation. PMID:24839356

  7. H2 Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain.

    PubMed

    Chen, Yajun; Chen, Hongguang; Xie, Keliang; Liu, Lingling; Li, Yuan; Yu, Yonghao; Wang, Guolin

    2015-10-01

    Neuropathic pain (NP) is characterized by persistent pain, tactile allodynia, or hyperalgesia. Peripheral nerve injury contributes to rapid progress of inflammatory response and simultaneously generates neuropathic pain. Hydrogen (H2) has anti-inflammation, anti-apoptosis, and anti-oxidative stress effects. Therefore, we hypothesized that H2 treatment could alleviate allodynic and hyperalgesic behaviors and the release of inflammatory factors in rats with neuropathic pain. Peripheral neuropathic pain was established by chronic constriction injury of sciatic nerve in rats. H2 was given twice through intraperitoneal injection at a daily dose of 10 mL/kg during days 1-7 after the operation. Hyperalgesia and allodynia were tested, pro-inflammatory factors of dorsal root ganglia (DRG) and the spinal cord were measured by enzyme-linked immunosorbent assay (ELISA) during days 1-14 after the operation, and heme oxygenase (HO)-1 messenger RNA (mRNA) and protein expression and activities were measured at day 14 after sciatic nerve injury in rats. After Sn (IV) protoporphyrin IX dihydrochloride (SnPP)-IX, hemin, and carbon monoxide-releasing molecule (CORM)-2 had been given for chronic constriction injury (CCI) in rats, the above indicators were assessed. We found that H2 clearly inhibited hyperalgesia and allodynia in neuropathic pain and also attenuated the pro-inflammatory cytokines TNF-α, IL-1β, and high-mobility group box (HMGB) 1. H2 improved HO-1 mRNA and protein expression and activities in the process of pain. SnPP-IX reversed the inhibitory effect of H2 on hyperalgesia and allodynia and on pro-inflammatory cytokines in DRG and the spinal cord. The antinociceptive and anti-inflammatory effects of H2 were involved in the activation of HO-1/CO signaling during neuropathic pain in rats. PMID:25820467

  8. Antrodia camphorata Potentiates Neuroprotection against Cerebral Ischemia in Rats via Downregulation of iNOS/HO-1/Bax and Activated Caspase-3 and Inhibition of Hydroxyl Radical Formation.

    PubMed

    Yang, Po-Sheng; Lin, Po-Yen; Chang, Chao-Chien; Yu, Meng-Che; Yen, Ting-Lin; Lan, Chang-Chou; Jayakumar, Thanasekaran; Yang, Chih-Hao

    2015-01-01

    Antrodia camphorata (A. camphorata) is a fungus generally used in Chinese folk medicine for treatment of viral hepatitis and cancer. Our previous study found A. camphorata has neuroprotective properties and could reduce stroke injury in cerebral ischemia animal models. In this study, we sought to investigate the molecular mechanisms of neuroprotective effects of A. camphorata in middle cerebral artery occlusion (MCAO) rats. A selective occlusion of the middle cerebral artery (MCA) with whole blood clots was used to induce ischemic stroke in rats and they were orally treated with A. camphorata (0.25 and 0.75 g/kg/day) alone or combined with aspirin (5 mg/kg/day). To provide insight into the functions of A. camphorata mediated neuroprotection, the expression of Bax, inducible nitric oxide synthase (iNOS), haem oxygenase-1 (HO-1), and activated caspase-3 was determined by Western blot assay. Treatment of aspirin alone significantly reduced the expressions of HO-1 (P < 0.001), iNOS (P < 0.001), and Bax (P < 0.01) in ischemic regions. The reduction of these expressions was more potentiated when rats treated by aspirin combined with A. camphorata (0.75 g/kg/day). Combination treatment also reduced apoptosis as measured by a significant reduction in active caspase-3 expression in the ischemic brain compared to MCAO group (P < 0.01). Moreover, treatment of A. camphorata significantly (P < 0.05) reduced fenton reaction-induced hydroxyl radical (OH(•)) formation at a dose of 40 mg/mL. Taken together, A. camphorata has shown neuroprotective effects in embolic rats, and the molecular mechanisms may correlate with the downregulation of Bax, iNOS, HO-1, and activated caspase-3 and the inhibition of OH(•) signals.

  9. Antrodia camphorata Potentiates Neuroprotection against Cerebral Ischemia in Rats via Downregulation of iNOS/HO-1/Bax and Activated Caspase-3 and Inhibition of Hydroxyl Radical Formation

    PubMed Central

    Yang, Po-Sheng; Lin, Po-Yen; Chang, Chao-Chien; Yu, Meng-Che; Yen, Ting-Lin; Lan, Chang-Chou; Jayakumar, Thanasekaran; Yang, Chih-Hao

    2015-01-01

    Antrodia camphorata (A. camphorata) is a fungus generally used in Chinese folk medicine for treatment of viral hepatitis and cancer. Our previous study found A. camphorata has neuroprotective properties and could reduce stroke injury in cerebral ischemia animal models. In this study, we sought to investigate the molecular mechanisms of neuroprotective effects of A. camphorata in middle cerebral artery occlusion (MCAO) rats. A selective occlusion of the middle cerebral artery (MCA) with whole blood clots was used to induce ischemic stroke in rats and they were orally treated with A. camphorata (0.25 and 0.75 g/kg/day) alone or combined with aspirin (5 mg/kg/day). To provide insight into the functions of A. camphorata mediated neuroprotection, the expression of Bax, inducible nitric oxide synthase (iNOS), haem oxygenase-1 (HO-1), and activated caspase-3 was determined by Western blot assay. Treatment of aspirin alone significantly reduced the expressions of HO-1 (P < 0.001), iNOS (P < 0.001), and Bax (P < 0.01) in ischemic regions. The reduction of these expressions was more potentiated when rats treated by aspirin combined with A. camphorata (0.75 g/kg/day). Combination treatment also reduced apoptosis as measured by a significant reduction in active caspase-3 expression in the ischemic brain compared to MCAO group (P < 0.01). Moreover, treatment of A. camphorata significantly (P < 0.05) reduced fenton reaction-induced hydroxyl radical (OH•) formation at a dose of 40 mg/mL. Taken together, A. camphorata has shown neuroprotective effects in embolic rats, and the molecular mechanisms may correlate with the downregulation of Bax, iNOS, HO-1, and activated caspase-3 and the inhibition of OH• signals. PMID:26379739

  10. Baicalein inhibition of oxidative-stress-induced apoptosis via modulation of ERKs activation and induction of HO-1 gene expression in rat glioma cells C6

    SciTech Connect

    Chen, Y.-C. . E-mail: yc3270@tmu.edu.tw; Chow, J.-M.; Lin, C.-W.; Wu, C.-Y.; Shen, S.-C.

    2006-10-15

    In the present study, we examined the protective mechanism of baicalein (BE) and its glycoside, baicalin (BI), on hydrogen-peroxide (H{sub 2}O{sub 2})-induced cell death in rat glioma C6 cells. Results of the MTT assay, LDH release assay, and morphological observation showed that H{sub 2}O{sub 2} addition reduced the viability of C6 cells, and this was prevented by the addition of BE but not BI. Incubation of C6 cells with BE significantly decreased the intracellular peroxide level induced by H{sub 2}O{sub 2} according to flow cytometric analysis using DCHF-DA as a fluorescent substrate. Suppression of H{sub 2}O{sub 2}-induced apoptotic events including DNA ladders, hypodiploid cells, and activation of caspases 3, 8, and, 9 by BE but not BI was identified in C6 cells. The cytotoxicity and phosphorylation of ERK proteins induced by H{sub 2}O{sub 2} were blocked by the ERK inhibitor PD98059. Catalase addition prevented H{sub 2}O{sub 2}-induced ROS production, ERKs protein phosphorylation, and cell death, and BE dose-dependently inhibited H{sub 2}O{sub 2}-induced ERK protein phosphorylation in C6 cells. These data suggest that ROS-scavenging activity is involved in BE prevention of H{sub 2}O{sub 2}-induced cell death via blocking ERKs activation. Additionally, BE but not BI induced heat shock protein 32 (HSP32; HO-1) protein expression in both time- and dose-dependent manners, but not heme oxygenase 2 (HO-2), heat shock protein 70 (HSP70), or heat shock protein 90 (HSP90) protein expression. In the absence of H{sub 2}O{sub 2}, BE induces ERKs protein phosphorylation, and HO-1 protein expression induced by BE was blocked by the addition of cycloheximide, actinomycin D, and the ERK inhibitor PD98059. The addition of the HO inhibitor ZnPP inhibited the protective effect of BE against H{sub 2}O{sub 2}-induced cytotoxicity in C6 cells according to the MTT assay and apoptotic morphology under microscopic observation, accompanied by blocking the ROS-scavenging activity of BE

  11. Synergistic cardioprotective effects of Danshensu and hydroxysafflor yellow A against myocardial ischemia-reperfusion injury are mediated through the Akt/Nrf2/HO-1 pathway

    PubMed Central

    HU, TIANXIN; WEI, GUO; XI, MIAOMIAO; YAN, JIAJIA; WU, XIAOXIAO; WANG, YANHUA; ZHU, YANRONG; WANG, CHAO; WEN, AIDONG

    2016-01-01

    In clinical practice, the traditional Chinese medicinal herbs, Radix Salvia Miltiorrhiza and Carthamus tinctorius L., are usually prescribed in combination due to their significant cardioprotective effects. However, the mechanisms responsible for these combined effects remain unknown. Thus, in this study, we investigated the mechanisms responsible for the combined effects of Danshensu (DSS) and hydroxysafflor yellow A (HSYA) by establishing a rat model of myocardial ischemia/reperfusion (MI/R), as well as a model of hypoxia/reoxygenation (H/R) using H9c2 cells. The combination index (CI) was calculated using the median-effect method. DSS and HSYA in combination led to a CI value of <1 as regards infarct size in vivo and cell viability in vitro. The rats with MI/R injury that were treated with DSS and/or HSYA were found to have significantly lower levels of creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) and malondialdehyde (MDA), and a lower expressoin of 8-hydroxydeoxyguanosine (8-OHdG), and markedly enhanced superoxide dismutase (SOD) activity. Our in vitro experiments revealed that the cells treated with DSS and/or HSYA had a reduced lactate dehydrogenase (LDH) activity and a decreased percentage of cell apoptosis (increased Bcl-2/Bax ratio, decreased expression of cleaved caspase-3). DSS and HSYA increased the expression of heme oxygenase-1 (HO-1), the phosphorylation of Akt and the trans-location of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, the Akt inhibitor, LY294002, partially hampered the expression of Nrf2 and HO-1. The HO-1 inhibitor, zinc protoporphyrin IX (ZnPP-IX), did not decrease the expression of p-Akt and Nrf2, although it abolished the anti-apoptotic and antioxidant effects of DSS and HSYA. The findings of our study thus demonstrate that DSS and HSYA confer synergistic cardioprotective effects through the Akt/Nrf2/HO-1 signaling pathway, to certain extent, by enhancing the antioxidant defense system and exerting

  12. Edaravone attenuates hippocampal damage in an infant mouse model of pneumococcal meningitis by reducing HMGB1 and iNOS expression via the Nrf2/HO-1 pathway

    PubMed Central

    Li, Zheng; Ma, Qian-qian; Yan, Yan; Xu, Feng-dan; Zhang, Xiao-ying; Zhou, Wei-qin; Feng, Zhi-chun

    2016-01-01

    Aim: Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger that has shown potent antioxidant, anti-inflammatory and neuroprotective effects in variety of disease models. In this study, we investigated whether edaravone produced neuroprotective actions in an infant mouse model of pneumococcal meningitis. Methods: C57BL/6 mice were infected on postnatal d 11 by intracisternal injection of a certain inoculum of Streptococcus pneumoniae. The mice received intracisternal injection of 10 μL of saline containing edaravone (3 mg/kg) once a day for 7 d. The severity of pneumococcal meningitis was assessed with a clinical score. In mice with severe meningitis, the survival rate from the time of infection to d 8 after infection was analyzed using Kaplan-Meier curves. In mice with mild meningitis, the CSF inflammation and cytokine levels in the hippocampus were analyzed d 7 after infection, and the clinical neurological deficit score was evaluated using a neurological scoring system d 14 after infection. The nuclear factor (erythroid-derived 2)-like 2 knockout (Nrf2 KO) mice and heme oxygenase-1 knockout (HO-1 KO) mice were used to confirm the involvement of Nrf2/HO-1 pathway in the neuroprotective actions of edaravone. Results: In mice with severe meningitis, edaravone treatment significantly increased the survival rate (76.4%) compared with the meningitis model group (32.2%). In mice with mild meningitis, edaravone treatment significantly decreased the number of leukocytes and TNF- levels in CSF, as well as the neuronal apoptosis and protein levels of HMGB1 and iNOS in the hippocampus, but did not affect the high levels of IL-10 and IL-6 in the hippocampus. Moreover, edaravone treatment significantly improved the neurological function of mice with mild meningitis. In Nrf2 KO or HO-1 KO mice with the meningitis, edaravone treatment was no longer effective in improving the survival rate of the mice with severe meningitis (20.2% and 53.6%, respectively

  13. Synergistic cardioprotective effects of Danshensu and hydroxysafflor yellow A against myocardial ischemia-reperfusion injury are mediated through the Akt/Nrf2/HO-1 pathway.

    PubMed

    Hu, Tianxin; Wei, Guo; Xi, Miaomiao; Yan, Jiajia; Wu, Xiaoxiao; Wang, Yanhua; Zhu, Yanrong; Wang, Chao; Wen, Aidong

    2016-07-01

    In clinical practice, the traditional Chinese medicinal herbs, Radix Salvia Miltiorrhiza and Carthamus tinctorius L., are usually prescribed in combination due to their significant cardioprotective effects. However, the mechanisms responsible for these combined effects remain unknown. Thus, in this study, we investigated the mechanisms responsible for the combined effects of Danshensu (DSS) and hydroxysafflor yellow A (HSYA) by establishing a rat model of myocardial ischemia/reperfusion (MI/R), as well as a model of hypoxia/reoxygenation (H/R) using H9c2 cells. The combination index (CI) was calculated using the median-effect method. DSS and HSYA in combination led to a CI value of <1 as regards infarct size in vivo and cell viability in vitro. The rats with MI/R injury that were treated with DSS and/or HSYA were found to have significantly lower levels of creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) and malondialdehyde (MDA), and a lower expressoin of 8-hydroxydeoxyguanosine (8-OHdG), and markedly enhanced superoxide dismutase (SOD) activity. Our in vitro experiments revealed that the cells treated with DSS and/or HSYA had a reduced lactate dehydrogenase (LDH) activity and a decreased percentage of cell apoptosis (increased Bcl-2/Bax ratio, decreased expression of cleaved caspase-3). DSS and HSYA increased the expression of heme oxygenase-1 (HO-1), the phosphorylation of Akt and the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, the Akt inhibitor, LY294002, partially hampered the expression of Nrf2 and HO-1. The HO-1 inhibitor, zinc protoporphyrin IX (ZnPP‑IX), did not decrease the expression of p-Akt and Nrf2, although it abolished the anti-apoptotic and antioxidant effects of DSS and HSYA. The findings of our study thus demonstrate that DSS and HSYA confer synergistic cardioprotective effects through the Akt/Nrf2/HO-1 signaling pathway, to certain extent, by enhancing the antioxidant

  14. Attenuation of smoke induced neuronal and physiological changes by bacoside rich extract in Wistar rats via down regulation of HO-1 and iNOS.

    PubMed

    Pandareesh, M D; Anand, T

    2014-01-01

    Bacopa monniera is well known herbal medicine for its neuropharmacological effects. It alleviates variety of disorders including neuronal and physiological changes. Crackers smoke is a potent risk factor that leads to free radical mediated oxidative stress in vivo. The aim of the current study is to evaluate the protective efficacy of B. monniera extract (BME) against crackers smoke induced neuronal and physiological changes via modulating inducible nitric oxide synthase (iNOS) and hemeoxygenase-1 (HO-1) expression in rats. Rats were exposed to smoke for 1h for a period of 3 weeks and consecutively treated with BME at three different dosages (i.e., 10, 20 and 40 mg/kg b.wt.). Our results elucidate that BME treatment ameliorates histopathalogical changes, reactive oxygen species levels, lipid peroxidation, acetylcholine esterase activity and brain neurotransmitter levels to normal. BME supplementation efficiently inhibited HO-1 expression and nitric oxide generation by down-regulating iNOS expression. Smoke induced depletion of antioxidant enzyme status, monoamine oxidase activity was also replenished by BME supplementation. Thus the present study indicates that BME ameliorates various impairments associated with neuronal and physiological changes in rats exposed to crackers smoke by its potent neuromodulatory, antioxidant and adaptogenic propensity.

  15. The cytoprotective effect of isorhamnetin against oxidative stress is mediated by the upregulation of the Nrf2-dependent HO-1 expression in C2C12 myoblasts through scavenging reactive oxygen species and ERK inactivation.

    PubMed

    Choi, Yung Hyun

    2016-04-01

    This study was designed to confirm the protective effects of isorhamnetin against oxidative stress-induced cellular damage. Our results indicated that isorhamnetin inhibited the hydrogen peroxide (H2O2)-induced growth inhibition and exhibited scavenging activity against the intracellular reactive oxygen species (ROS) in mouse-derived C2C12 myoblasts. Isorhamnetin also significantly attenuated H2O2-induced DNA damage and apoptosis, and increased the levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) and its phosphorylation associated with the induction of heme oxygenase-1 (HO-1). However, the protective effects of isorhamnetin on H2O2-induced ROS and growth inhibition were significantly abolished by an HO-1 competitive inhibitor. Moreover, the potential of isorhamnetin to mediate HO-1 induction and protect against H2O2-mediated growth inhibition was abrogated by transient transfection with Nrf2-specific small interfering RNA. Additionally, isorhamnetin induced the activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. However, the specific inhibitor of ERK, but not JNK and p38 MAPK, was able to abolish the HO-1 upregulation and the Nrf2 phosphorylation. Collectively, these results demonstrate that isorhamnetin augments the cellular antioxidant defense capacity by activating the Nrf2/HO-1 pathway involving the activation of the ERK pathway, thus protecting the C2C12 cells from H2O2-induced cytotoxicity. PMID:26830132

  16. Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling

    PubMed Central

    Wang, L-H; Li, Y; Yang, S-N; Wang, F-Y; Hou, Y; Cui, W; Chen, K; Cao, Q; Wang, S; Zhang, T-Y; Wang, Z-Z; Xiao, W; Yang, J-Y; Wu, C-F

    2014-01-01

    Background: Gambogic acid (GA) has been reported to have potent anticancer activity and is authorised to be tested in phase II clinical trials for treatment of non-small-cell lung cancer (NSCLC). The present study aims to investigate whether GA would be synergistic with cisplatin (CDDP) against the NSCLC. Methods: 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI) isobologram, western blot, quantitative PCR, flow cytometry, electrophoretic mobility shift assay, xenograft tumour models and terminal deoxynucleotide transferase-mediated dUTP nick-end labelling analysis were used in this study. Results: The cell viability results showed that sequential CDDP-GA treatment resulted in a strong synergistic action in A549, NCI-H460, and NCI-H1299 cell lines, whereas the reverse sequence and simultaneous treatments led to a slight synergistic or additive action. Increased sub-G1 phase cells and enhanced PARP cleavage demonstrated that the sequence of CDDP-GA treatment markedly increased apoptosis in comparison with other treatments. Furthermore, the sequential combination could enhance the activation of caspase-3, -8, and 9, increase the expression of Fas and Bax, and decrease the expression of Bcl-2, survivin and X-inhibitor of apoptosis protein (X-IAP) in A549 and NCI-H460 cell lines. In addition, increased apoptosis was correlated with enhanced reactive oxygen species generation. Importantly, it was found that, followed by CDDP treatment, GA could inhibit NF-κB and mitogen-activated protein kinase (MAPK)/heme oxygenase-1 (HO-1) signalling pathways, which have been validated to reduce ROS release and confer CDDP resistance. The roles of NF-κB and MAPK pathways were further confirmed by using specific inhibitors, which significantly increased ROS release and apoptosis induced by the sequential combination of CDDP and GA. Moreover, our results indicated that the combination of CDDP and GA exerted increased antitumour effects on A549 xenograft

  17. Lycopene ameliorates atrazine-induced oxidative damage in adrenal cortex of male rats by activation of the Nrf2/HO-1 pathway.

    PubMed

    Abass, Marwa Ahmed; Elkhateeb, Shereen Ahmed; Abd El-Baset, Samia Adel; Kattaia, Asmaa Alhosiny; Mohamed, Eman Mosallam; Atteia, Hebatallah Husseini

    2016-08-01

    Atrazine (ATZ) is one of the most commonly used herbicides contaminating plants, soil and water resources. Several strategies have been used to counteract ATZ toxicity. Here, we tested the hypothesis that lycopene could ameliorate ATZ-induced toxicity in the adrenal cortex. For this purpose, 35 adult male albino rats were randomized into five equal groups: untreated control, vehicle control (received 0.5 mL corn oil/day), lycopene (treated with lycopene dissolved in 0.5 mL corn oil, 10 mg/kg b.w./day), ATZ (received ATZ dissolved in 0.5 mL corn oil 300 mg/kg b.w./day), and ATZ + lycopene (treated with ATZ and lycopene at the same previously mentioned doses). All treatments were given by oral gavage for 4 weeks. We found that ATZ exposure significantly increased relative adrenal weight, plasma ACTH levels, and adrenal oxidative stress as manifested by elevated malondialdehyde levels, decreased reduced glutathione content and depressed antioxidant enzyme activities in adrenal cortex tissues with respect to control groups. Furthermore, the transcription of adrenal cortex nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B, and caspase-3 genes was increased significantly compared with the control groups. This was accompanied with DNA fragmentation and structural and ultrastructural changes in zona glomerulosa and zona fasiculata of the adrenal cortex. Notably, all these changes were partially ameliorated in rats treated concomitantly with ATZ and lycopene. Our results showed that lycopene exerts protective effects against ATZ-induced toxicity in rat adrenal cortex. These effects may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway. PMID:27102619

  18. Mangiferin Mitigates Gastric Ulcer in Ischemia/ Reperfused Rats: Involvement of PPAR-γ, NF-κB and Nrf2/HO-1 Signaling Pathways

    PubMed Central

    Mahmoud-Awny, Magdy; Attia, Ahmed S.; Abd-Ellah, Mohamed F.; El-Abhar, Hanan Salah

    2015-01-01

    Mangiferin (MF), a xanthonoid from Mangifera indica, has been proved to have antisecretory and antioxidant gastroprotective effects against different gastric ulcer models; however, its molecular mechanism has not been previously elucidated. Therefore, the aim of this study was to test its modulatory effect on several signaling pathways using the ischemia/reperfusion model for the first time. Animals were treated with MF, omeprazole (OMP), and the vehicle. The mechanistic studies revealed that MF mediated its gastroprotective effect partly via inducing the expression of Nrf2, HO-1 and PPAR-γ along with downregulating that of NF-κB. Surprisingly, the effect of MF, especially the high dose, exceeded that mediated by OMP except for Nrf2. The molecular results were reflected on the biomarkers measured, where the antioxidant effect of MF was manifested by increasing total antioxidant capacity and glutathione, besides normalizing malondialdehyde level. Additionally, MF decreased the I/R-induced nitric oxide elevation, an effect that was better than that of OMP. In the serum, MF, dose dependently, enhanced endothelial nitric oxide synthase, while reduced the inducible isoform. Regarding the anti-inflammatory effect of MF, it reduced serum level of IL-1β and sE-selectin, effects that were mirrored on the tissue level of myeloperoxidase, the neutrophil infiltration marker. In addition, MF possessed an antiapoptotic character evidenced by elevating Bcl-2 level and reducing that of caspase-3 in a dose related order. As a conclusion, the intimated gastroprotective mechanisms of MF are mediated, partially, by modulation of oxidative stress, inflammation and apoptosis possibly via the Nrf2/HO-1, PPAR-γ/NF-κB signaling pathways. PMID:26196679

  19. Simultaneous Overexpression of Functional Human HO-1, E5NT and ENTPD1 Protects Murine Fibroblasts against TNF-α-Induced Injury In Vitro

    PubMed Central

    Cinti, Alessandro; De Giorgi, Marco; Chisci, Elisa; Arena, Claudia; Galimberti, Gloria; Farina, Laura; Bugarin, Cristina; Rivolta, Ilaria; Gaipa, Giuseppe; Smolenski, Ryszard Tom; Cerrito, Maria Grazia; Lavitrano, Marialuisa; Giovannoni, Roberto

    2015-01-01

    Several biomedical applications, such as xenotransplantation, require multiple genes simultaneously expressed in eukaryotic cells. Advances in genetic engineering technologies have led to the development of efficient polycistronic vectors based on the use of the 2A self-processing oligopeptide. The aim of this work was to evaluate the protective effects of the simultaneous expression of a novel combination of anti-inflammatory human genes, ENTPD1, E5NT and HO-1, in eukaryotic cells. We produced an F2A system-based multicistronic construct to express three human proteins in NIH3T3 cells exposed to an inflammatory stimulus represented by tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine which plays an important role during inflammation, cell proliferation, differentiation and apoptosis and in the inflammatory response during ischemia/reperfusion injury in several organ transplantation settings. The protective effects against TNF-α-induced cytotoxicity and cell death, mediated by HO-1, ENTPD1 and E5NT genes were better observed in cells expressing the combination of genes as compared to cells expressing each single gene and the effect was further improved by administrating enzymatic substrates of the human genes to the cells. Moreover, a gene expression analyses demonstrated that the expression of the three genes has a role in modulating key regulators of TNF-α signalling pathway, namely Nemo and Tnfaip3, that promoted pro-survival phenotype in TNF-α injured cells. These results could provide new insights in the research of protective mechanisms in transplantation settings. PMID:26513260

  20. The Cytoprotective Effects of E-α-(4-Methoxyphenyl)-2',3,4,4'-Tetramethoxychalcone (E-α-p-OMe-C6H4-TMC)--A Novel and Non-Cytotoxic HO-1 Inducer.

    PubMed

    Kaufmann, Kai B; Al-Rifai, Nafisah; Ulbrich, Felix; Schallner, Nils; Rücker, Hannelore; Enzinger, Monika; Petkes, Hermina; Pitzl, Sebastian; Goebel, Ulrich; Amslinger, Sabine

    2015-01-01

    Cell protection against different noxious stimuli like oxidative stress or chemical toxins plays a central role in the treatment of many diseases. The inducible heme oxygenase isoform, heme oxygenase-1 (HO-1), is known to protect cells against a variety of harmful conditions including apoptosis. Because a number of medium strong electrophiles from a series of α-X-substituted 2',3,4,4'-tetramethoxychalcones (α-X-TMCs, X = H, F, Cl, Br, I, CN, Me, p-NO2-C6H4, Ph, p-OMe-C6H4, NO2, CF3, COOEt, COOH) had proven to activate Nrf2 resulting in HO-1 induction and inhibit NF-κB downstream target genes, their protective effect against staurosporine induced apoptosis and reactive oxygen species (ROS) production was investigated. RAW264.7 macrophages treated with 19 different chalcones (15 α-X-TMCs, chalcone, 2'-hydroxychalcone, calythropsin and 2'-hydroxy-3,4,4'-trimethoxychalcone) prior to staurosporine treatment were analyzed for apoptosis and ROS production, as well as HO-1 protein expression and enzyme activity. Additionally, Nrf2 and NF-κB activity was assessed. We found that amongst all tested chalcones only E-α-(4-methoxyphenyl)-2',3,4,4'-tetramethoxychalcone (E-α-p-OMe-C6H4-TMC) demonstrated a distinct, statistically significant antiapoptotic effect in a dose dependent manner, showing no toxic effects, while its double bond isomer Z-α-p-OMe-C6H4-TMC displayed no significant activity. Also, E-α-p-OMe-C6H4-TMC induced HO-1 protein expression and increased HO-1 activity, whilst inhibition of HO-1 by SnPP-IX abolished its antiapoptotic effect. The only weakly electrophilic chalcone E-α-p-OMe-C6H4-TMC reduced the staurosporine triggered formation of ROS, while inducing the translocation of Nrf2 into the nucleus. Furthermore, staurosporine induced NF-κB activity was attenuated following E-α-p-OMe-C6H4-TMC treatment. Overall, E-α-p-OMe-C6H4-TMC demonstrated its effective cytoprotective potential via a non-toxic induction of HO-1 in RAW264.7 macrophages. The

  1. Paeonol and danshensu combination attenuates apoptosis in myocardial infarcted rats by inhibiting oxidative stress: Roles of Nrf2/HO-1 and PI3K/Akt pathway

    PubMed Central

    Li, Hua; Song, Fan; Duan, Lin-Rui; Sheng, Juan-Juan; Xie, Yan-Hua; Yang, Qian; Chen, Ying; Dong, Qian-Qian; Zhang, Bang-Le; Wang, Si-Wang

    2016-01-01

    Paeonol and danshensu is the representative active ingredient of traditional Chinese medicinal herbs Cortex Moutan and Radix Salviae Milthiorrhizae, respectively. Paeonol and danshensu combination (PDSS) has putative cardioprotective effects in treating ischemic heart disease (IHD). However, the evidence for the protective effect is scarce and the pharmacological mechanisms of the combination remain unclear. The present study was designed to investigate the protective effect of PDSS on isoproterenol (ISO)-induced myocardial infarction in rats and to elucidate the potential mechanism. Assays of creatine kinase-MB, cardiac troponin I and T and histopathological analysis revealed PDSS significantly prevented myocardial injury induced by ISO. The ISO-induced profound elevation of oxidative stress was also suppressed by PDSS. TUNEL and caspase-3 activity assay showed that PDSS significantly inhibited apoptosis in myocardia. In exploring the underlying mechanisms of PDSS, we found PDSS enhanced the nuclear translocation of Nrf2 in myocardial injured rats. Furthermore, PDSS increased phosphorylated PI3K and Akt, which may in turn activate antioxidative and antiapoptotic signaling events in rat. These present findings demonstrated that PDSS exerts significant cardioprotective effects against ISO-induced myocardial infarction in rats. The protective effect is, at least partly, via activation of Nrf2/HO-1 signaling and involvement of the PI3K/Akt cell survival signaling pathway. PMID:27021411

  2. Arctigenin Protects against Lipopolysaccharide-Induced Pulmonary Oxidative Stress and Inflammation in a Mouse Model via Suppression of MAPK, HO-1, and iNOS Signaling.

    PubMed

    Zhang, Wen-zhou; Jiang, Zheng-kui; He, Bao-xia; Liu, Xian-ben

    2015-08-01

    Arctigenin, a bioactive component of Arctium lappa (Nubang), has anti-inflammatory activity. Here, we investigated the effects of arctigenin on lipopolysaccharide (LPS)-induced acute lung injury. Mice were divided into four groups: control, LPS, LPS + DMSO, and LPS + Arctigenin. Mice in the LPS + Arctigenin group were injected intraperitoneally with 50 mg/kg of arctigenin 1 h before an intratracheal administration of LPS (5 mg/kg). Lung tissues and bronchoalveolar lavage fluids (BALFs) were collected. Histological changes of the lung were analyzed by hematoxylin and eosin staining. Arctigenin decreased LPS-induced acute lung inflammation, infiltration of inflammatory cells into BALF, and production of pro-inflammatory cytokines. Moreover, arctigenin pretreatment reduced the malondialdehyde level and increased superoxide dismutase and catalase activities and glutathione peroxidase/glutathione disulfide ratio in the lung. Mechanically, arctigenin significantly reduced the production of nitric oxygen and inducible nitric oxygen synthase (iNOS) expression, enhanced the expression of heme oxygenase-1, and decreased the phosphorylation of mitogen-activated protein kinases (MAPKs). Arctigenin has anti-inflammatory and antioxidative effects on LPS-induced acute lung injury, which are associated with modulation of MAPK, HO-1, and iNOS signaling.

  3. Propofol-induced protection of SH-SY5Y cells against hydrogen peroxide is associated with the HO-1 via the ERK pathway.

    PubMed

    Gu, Jing; Chi, Meng; Sun, Xuechao; Wang, Guonian; Li, Mingming; Liu, Li; Li, Xuan

    2013-01-01

    Propofol (2, 6-diisopropylphenol), is an anesthetic and routinely used for the humans sedation during surgery. The potent inducers of phase II detoxifying and antioxidant stress responsive to propofol were investigated. First, a dose of 25-100 µM propofol showed no significant cytotoxicity on SH-SY5Y cells and pre-treatment of SH-SY5Y cells with propofol (25-100 μM) for 8h prevented cell death and maintained cell integrity following exposure to 1 mM hydrogen peroxide by MTT assays. Then, an increase in the generation of ROS following hydrogen peroxide treatment was significantly attenuated by 8 h pre-treatment with propofol. Additionally, the potential roles of ERK, p 38 MAPK and JNK in the regulation of propofol-induced endogenous HO-1 expression in SH-SY5Y cells were estimated by Western blotting assays. Results showed that propofol significantly increased the phosphorylation levels of ERK, p 38 MAPK and JNK and antioxidant stress responsive to propofol was attenuated by the inhibition of ERK signaling biochemical inhibitors. These results suggest that the ERK pathway plays an important role in the regulation of propofol-mediated antioxidant effects in SH-SY5Y cells.

  4. Arctigenin Protects against Lipopolysaccharide-Induced Pulmonary Oxidative Stress and Inflammation in a Mouse Model via Suppression of MAPK, HO-1, and iNOS Signaling.

    PubMed

    Zhang, Wen-zhou; Jiang, Zheng-kui; He, Bao-xia; Liu, Xian-ben

    2015-08-01

    Arctigenin, a bioactive component of Arctium lappa (Nubang), has anti-inflammatory activity. Here, we investigated the effects of arctigenin on lipopolysaccharide (LPS)-induced acute lung injury. Mice were divided into four groups: control, LPS, LPS + DMSO, and LPS + Arctigenin. Mice in the LPS + Arctigenin group were injected intraperitoneally with 50 mg/kg of arctigenin 1 h before an intratracheal administration of LPS (5 mg/kg). Lung tissues and bronchoalveolar lavage fluids (BALFs) were collected. Histological changes of the lung were analyzed by hematoxylin and eosin staining. Arctigenin decreased LPS-induced acute lung inflammation, infiltration of inflammatory cells into BALF, and production of pro-inflammatory cytokines. Moreover, arctigenin pretreatment reduced the malondialdehyde level and increased superoxide dismutase and catalase activities and glutathione peroxidase/glutathione disulfide ratio in the lung. Mechanically, arctigenin significantly reduced the production of nitric oxygen and inducible nitric oxygen synthase (iNOS) expression, enhanced the expression of heme oxygenase-1, and decreased the phosphorylation of mitogen-activated protein kinases (MAPKs). Arctigenin has anti-inflammatory and antioxidative effects on LPS-induced acute lung injury, which are associated with modulation of MAPK, HO-1, and iNOS signaling. PMID:25616905

  5. Grape seed proanthocyanidins protects against cadmium induced oxidative pancreatitis in rats by attenuating oxidative stress, inflammation and apoptosis via Nrf-2/HO-1 signaling.

    PubMed

    Bashir, Nazima; Manoharan, Vaihundam; Miltonprabu, Selvaraj

    2016-06-01

    The present study has been designed and carried out to explore the role of grape seed proanthocyanidins (GSP) in the pancreas of cadmium (Cd)-induced cellular oxidative stress-mediated toxicity in rats. Four groups of healthy rats were given oral doses of Cd (5-mg/kg BW) and to identify the possible mechanism of action of GSP 100-mg/kg BW was selected and was given 90 min before Cd intoxication. The causative molecular and cellular mechanism of Cd was determined using various biochemical assays, histology, western blotting and ELISA. Cd intoxication revealed increased levels of proinflammatory cytokines (TNF-α, IL1β and IFN-γ), reduced levels of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2 and GLUT-4) along with the enhanced levels of signaling molecules of apoptosis (cleaved Caspase-12/9/8/3) in the pancreas of Cd-intoxicated rats. Results suggested that the treatment with GSP reduced blood glucose level, increased plasma insulin and mitigated oxidative stress-related markers. GSP protects pancreatic tissue by attenuated inflammatory responses and inhibited apoptosis. This uniqueness and absence of any detectable adverse effect of GSP proposes the possibility of using it as an effective protector in the oxidative stress-mediated pancreatic dysfunction in rats. PMID:27142746

  6. Propofol-Induced Protection of SH-SY5Y Cells against Hydrogen Peroxide Is Associated with the HO-1 via the ERK Pathway

    PubMed Central

    Gu, Jing; Chi, Meng; Sun, Xuechao; Wang, Guonian; Li, Mingming; Liu, Li; Li, Xuan

    2013-01-01

    Propofol (2, 6-diisopropylphenol), is an anesthetic and routinely used for the humans sedation during surgery. The potent inducers of phase II detoxifying and antioxidant stress responsive to propofol were investigated. First, a dose of 25-100 µM propofol showed no significant cytotoxicity on SH-SY5Y cells and pre-treatment of SH-SY5Y cells with propofol (25-100 μM) for 8h prevented cell death and maintained cell integrity following exposure to 1 mM hydrogen peroxide by MTT assays. Then, an increase in the generation of ROS following hydrogen peroxide treatment was significantly attenuated by 8 h pre-treatment with propofol. Additionally, the potential roles of ERK, p 38 MAPK and JNK in the regulation of propofol-induced endogenous HO-1 expression in SH-SY5Y cells were estimated by Western blotting assays. Results showed that propofol significantly increased the phosphorylation levels of ERK, p 38 MAPK and JNK and antioxidant stress responsive to propofol was attenuated by the inhibition of ERK signaling biochemical inhibitors. These results suggest that the ERK pathway plays an important role in the regulation of propofol-mediated antioxidant effects in SH-SY5Y cells. PMID:23569422

  7. 20C, a bibenzyl compound isolated from Gastrodia elata, protects PC12 cells against rotenone-induced apoptosis via activation of the Nrf2/ARE/HO-1 signaling pathway

    PubMed Central

    Huang, Ju-yang; Yuan, Yu-he; Yan, Jia-qing; Wang, Ya-nan; Chu, Shi-feng; Zhu, Cheng-gen; Guo, Qing-lan; Shi, Jian-gong; Chen, Nai-hong

    2016-01-01

    Aim: Our preliminary study shows that a bibenzyl compound isolated from Gastrodia elata, 2-[4-hydroxy-3-(4-hydroxybenzyl)benzyl]-4-(4-hydroxybenzyl)phenol (designated 20C), protects PC12 cells against H2O2-induced injury. In this study we investigated whether 20C exerted neuroprotective action in a cell model of Parkinson's disease. Methods: A cell model of Parkinson's disease was established in PC12 cells by exposure to rotenone (4 μmol/L) for 48 h. Cell viability and apoptosis were assessed, and intracellular ROS level and the mitochondrial membrane potential (MMP) were detected. The expression of apoptosis-related proteins Bax, Bcl-2, cytochrome c, cleaved caspase-3, and oxidative stress-related proteins Nrf2, HO-1 and NQO1 were examined using Western blotting. The mRNA levels of HO-1 and NQO1 were determined with RT-PCR. The nuclear translocation of Nrf2 was observed with immunofluorescence staining. Results: Treatment with rotenone significantly increased the number of apoptotic cells, accompanied by marked increases in the Bax/Bcl-2 ratio, cytochrome c release and caspase-3 activation. Rotenone also increased ROS accumulation, reduced MMP, and increased the nuclear translocation of Nrf2 as well as the mRNA and protein levels of the Nrf2 downstream target genes HO-1 and NQO1 in PC12 cells. Co-treatment with 20C (0.01–1 μmol/L) dose-dependently attenuated rotenone-induced apoptosis and oxidative stress in PC12 cells. Nrf2 knockdown by siRNA partially reversed the protective effects of 20C in rotenone-treated PC12 cells. Conclusion: The bibenzyl compound 20C protects PC12 cells from rotenone-induced apoptosis, at least in part, via activation of the Nrf2/ARE/HO-1 signaling pathway. PMID:27180985

  8. Beneficial effects of Camellia Oil (Camellia oleifera Abel.) on ketoprofen-induced gastrointestinal mucosal damage through upregulation of HO-1 and VEGF.

    PubMed

    Cheng, Yu-Ting; Wu, Shu-Li; Ho, Cheng-Ying; Huang, Shang-Ming; Cheng, Chun-Lung; Yen, Gow-Chin

    2014-01-22

    Nonsteroidal anti-inflammatory drugs, such as ketoprofen, are generally used to treat pain and inflammation and as pyretic agents in clinical medicine. However, the usage of these drugs may lead to oxidative injury to the gastrointestinal mucosa. Camellia oil ( Camellia oleifera Abel.) is commonly used in Taiwan and China as cooking oil. Traditional remedies containing this oil exert beneficial health effects on the bowel, stomach, liver, and lungs. However, the effects of camellia oil on ketoprofen-induced oxidative gastrointestinal mucosal lesions remain unknown. The objective of this study was to evaluate the effect of camellia oil on ketoprofen-induced acute gastrointestinal ulcers. The results showed that treatment of Int-407 cells with camellia oil (50-75 μg/mL) not only increased the levels of heme oxygenase-1 (HO-1), glutathione peroxidase (GPx), and superoxide dismutase (SOD) mRNA expression but also increased vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2) protein secretion, which served as a mucosal barrier against gastrointestinal oxidative injury. Moreover, Sprague-Dawley (SD) rats treated with camellia oil (2 mL/kg/day) prior to the administration of ketoprofen (50 mg/kg/day) successfully inhibited COX-2 protein expression, inhibited the production of interleukin-6 (IL-6) and nitrite oxide (NO), reversed the impairment of the antioxidant system, and decreased oxidative damage in the gastrointestinal mucosa. More importantly, pretreatment of SD rats with camellia oil strongly inhibited gastrointestinal mucosal injury induced by ketoprofen, which was proved by the histopathological staining of gastrointestinal tissues. Our data suggest that camellia oil exerts potent antiulcer effects against oxidative damage in the stomach and intestine induced by ketoprofen.

  9. The effect of moderate-intensity exercise on the expression of HO-1 mRNA and activity of HO in cardiac and vascular smooth muscle of spontaneously hypertensive rats.

    PubMed

    Ren, Cailing; Qi, Jie; Li, Wanwei; Zhang, Jun

    2016-04-01

    The objective of this study was to observe the effects of moderate-intensity training on the activity of heme oxygenase (HO) and expression of HO-1 mRNA in the aorta and the cardiac muscle of spontaneously hypertensive rats (SHRs). After 9 weeks of swimming exercise, the activity of HO and expression of HO-1 mRNA in the SHRs were measured. The resting blood pressure in the exercise group was increased by 1.7% (P > 0.05), whereas it was significantly elevated by 10.3% (P < 0.01) in the SHR rats. Compared with animals in the control and sedentary groups, the expression level of HO-1 mRNA of aorta and cardiac muscle in the exercise group was significantly enhanced (P < 0.01). The HO activity and the content of plasma carbon monoxide (CO) in the sedentary group were dramatically decreased (P < 0.05 and P < 0.01, respectively) compared with the control group. HO activity and content of plasma CO in the exercise group were significantly higher compared with those in the sedentary group (P < 0.05 and P < 0.01, respectively). The HO/CO metabolic pathway might be involved in the regulation of blood pressure of the SHR models. PMID:26928589

  10. Acute toxicity of a commercial glyphosate formulation on European sea bass juveniles (Dicentrarchus labrax L.): gene expressions of heme oxygenase-1 (ho-1), acetylcholinesterase (AChE) and aromatases (cyp19a and cyp19b).

    PubMed

    Prevot-D'Alvise, N; Richard, S; Coupé, S; Bunet, R; Grillasca, J P

    2013-12-31

    Acute toxicity of Roundup, a commercial glyphosate--based herbicide, was evaluated in a teleost marine fish, the European sea bass, after 96 h of exposure. The LC50 96-h value of Roundup was 529 mg/L. Juveniles (Dicentrarchus labrax L.) were exposed to a sublethal concentration (35% of the LC50, i.e. 193 mg/L) of Roundup for 96-h. The study of heme oxygenase-1 (ho-1) gene expression was performed in four tissues (liver, gills, brain and gonads) and highlighted the disruption of antioxidant defence system. Results showed that ho-1 mRNA levels in liver and gills significantly decreased (p<0.001 and p<0.01 respectively) in fish exposed to 193 mg/L of Roundup, whereas in brain and gonads, ho-1 mRNA level was not altered. The analysis of acetylcholinesterase expression was used to evaluate the overall neurotoxicity of the herbicide and aromatase genes to assess the alteration of the endocrine system. Results showed that AChE and cyp19b gene transcriptions significantly increased (p<0.01) in brain of sea bass, whereas aromatase gene expression (cyp19a) in gonads was not significantly altered. Our results showed complex tissue-specific transcriptional responses after 96 h of exposure to a sublethal concentration. All these disruptions confirmed the deleterious effects of this glyphosate-based herbicide in a marine species.

  11. Rosmarinic Acid Methyl Ester Inhibits LPS-Induced NO Production via Suppression of MyD88- Dependent and -Independent Pathways and Induction of HO-1 in RAW 264.7 Cells.

    PubMed

    So, Yangkang; Lee, Seung Young; Han, Ah-Reum; Kim, Jin-Baek; Jeong, Hye Gwang; Jin, Chang Hyun

    2016-01-01

    In this study, we investigated the anti-inflammatory effect of rosmarinic acid methyl ester (RAME) isolated from a mutant cultivar of Perilla frutescens (L.) Britton. We found that RAME inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production, with an IC50 of 14.25 µM, in RAW 264.7 cells. RAME inhibited the LPS-induced expression of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein-1, interferon-β, and inducible nitric oxide synthase (iNOS). Moreover, RAME suppressed the activation of nuclear factor kappa B. These results suggest that the downregulation of iNOS expression by RAME was due to myeloid differentiation primary response gene 88 (MyD88)-dependent and -independent pathways. Furthermore, RAME induced the expression of heme oxygenase-1 (HO-1) through activation of nuclear factor-erythroid 2-related factor 2. Treatment with tin protoporphyrin, an inhibitor of HO-1, reversed the RAME-induced suppression of NO production. Taken together, RAME isolated from P. frutescens inhibited NO production in LPS-treated RAW 264.7 cells through simultaneous induction of HO-1 and inhibition of MyD88-dependent and -independent pathways. PMID:27548124

  12. Identification of actin as a 15-deoxy-Delta12,14-prostaglandin J2 target in neuroblastoma cells: mass spectrometric, computational, and functional approaches to investigate the effect on cytoskeletal derangement.

    PubMed

    Aldini, Giancarlo; Carini, Marina; Vistoli, Giulio; Shibata, Takahiro; Kusano, Yuri; Gamberoni, Luca; Dalle-Donne, Isabella; Milzani, Aldo; Uchida, Koji

    2007-03-13

    A proteomic approach was used to identify 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) protein targets in human neuroblastoma SH-SY5Y cells. By using biotinylated 15d-PGJ2, beta-actin was found as the major adducted protein; at least 12 proteins were also identified as minor biotin-positive spots, falling in different functional classes, including glycolytic enzymes (enolase and lactate dehydrogenase), redox enzymes (biliverdin reductase), and a eukaryotic regulatory protein (14-3-3gamma). 15d-PGJ2 induced marked morphological changes in the actin filament network and in particular promoted F-actin depolymerization as confirmed by Western blot analysis. By using a mass spectrometric approach, we found that 15d-PGJ2 reacts with isolated G-actin in a 1:1 stoichiometric ratio and selectively binds the Cys374 site through a Michael adduction mechanism. Computational studies showed that the covalent binding of 15d-PGJ2 induces a significant unfolding of actin structure and in particular that 15d-PGJ2 distorts the actin subdomains 2 and 4, which define the nucleotide binding sites impeding the nucleotide exchange. The functional effect of 15d-PGJ2 on G-actin was studied by polymerization measurement: in the presence of 15d-PGJ2, a lower amount of F-actin forms, as followed by the increase in pyrenyl-actin fluorescence intensity, as the major effect of increasing 15d-PGJ2 concentrations occurs on the maximum extent of actin polymerization, whereas it is negligible on the initial rate of reaction. In summary, the results here reported give an insight into the role of 15d-PGJ2 as a cytotoxic compound in neuronal cell dysfunction. Actin is the main protein cellular target of 15d-PGJ2, which specifically binds through a Michael adduction to Cys374, leading to a protein conformational change that can explain the disruption of the actin cytoskeleton, F-actin depolymerization, and impairment of G-actin polymerization. PMID:17297918

  13. Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response.

    PubMed

    Haberzettl, Petra; Hill, Bradford G

    2013-01-01

    Excessive production of unsaturated aldehydes from oxidized lipoproteins and membrane lipids is a characteristic feature of cardiovascular disease. Our previous studies show that unsaturated lipid peroxidation-derived aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) promote autophagy in rat aortic smooth muscle cells (RASMC). In this study, we examined the mechanism by which HNE induces autophagy. Exposure of RASMC to HNE led to the modification of several proteins, most of which were identified by mass spectrometry and confocal microscopy to be localized to the endoplasmic reticulum (ER). HNE stimulated the phosphorylation of PKR-like ER kinase and eukaryotic initiation factor 2α and increased heme oxygenase-1 (HO-1) abundance. HNE treatment also increased LC3-II formation and the phosphorylation of JNK and p38. Pharmacological inhibition of JNK, but not p38, prevented HNE-induced HO-1 expression and LC3-II formation. Inhibition of JNK increased cell death in HNE-treated cells. Pretreatment with the chemical chaperone phenylbutryic acid prevented LC3-II formation as well as JNK phosphorylation and HO-1 induction. Taken together, these data suggest that autophagic responses triggered by unsaturated aldehydes could be attributed, in part, to ER stress, which stimulates autophagy by a JNK-dependent mechanism and promotes cell survival during oxidative stress.

  14. MAP kinase phosphatase-1 expression is regulated by 15-deoxy-Δ12,14-prostaglandin J2 via a HuR-dependent post-transcriptional mechanism.

    PubMed

    Woo, Joo Hong; Lee, Jee Hoon; Kim, Hyunmi; Choi, Yuree; Park, Sang Myun; Joe, Eun-hye; Jou, Ilo

    2015-06-01

    In the present study, we demonstrate a mechanism through which 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) induces MKP-1 expression in rat primary astrocytes, leading to the regulation of inflammatory responses. We show that 15d-PGJ2 enhances the efficiency of MKP-1 pre-mRNA processing (constitutive splicing and 3'-end processing) and increases the stability of the mature mRNA. We further report that this occurs via the RNA-binding protein, Hu antigen R (HuR). Our experiments show that HuR knockdown abrogates the 15d-PGJ2-induced increases in the pre-mRNA processing and mature mRNA stability of MKP-1, whereas HuR overexpression further enhances the 15d-PGJ2-induced increases in these parameters. Using cysteine (Cys)-mutated HuR proteins, we show that the Cys-245 residue of HuR (but not Cys-13 or Cys-284) is critical for the direct binding of HuR with 15d-PGJ2 and the effects downstream of this interaction. Collectively, our data show that HuR is a novel target of 15d-PGJ2 and reveal HuR-mediated pre-mRNA processing and mature mRNA stabilization as important regulatory steps in the 15d-PGJ2-induced expression of MKP-1. The potential to use a small molecule such as 15d-PGJ2 to regulate the induction of MKP-1 at multiple levels of gene expression could be exploited as a novel therapeutic strategy aimed at combating a diverse range of MKP-1-associated pathologies.

  15. Transforming growth factor-beta1 stimulates heme oxygenase-1 expression via the PI3K/Akt and NF-kappaB pathways in human lung epithelial cells.

    PubMed

    Lin, Chen-Chun; Chiang, Ling-Ling; Lin, Chien-Huang; Shih, Chung-Hung; Liao, Yi-Ting; Hsu, Ming-Jen; Chen, Bing-Chang

    2007-04-10

    A previous report showed that transforming growth factor-beta1 (TGF-beta1) can induce heme oxygenase-1 (HO-1) expression, attenuate cellular injury, and maintain tissue homeostasis. In this study, we investigated the involvement of phosphoinositide-3-OH-kinase (PI3K)/Akt and the nuclear factor-kappaB (NF-kappaB) signaling pathway in TGF-beta1-induced HO-1 expression in human lung epithelial cells (A549). Treatment of A549 cells with TGF-beta1 caused HO-1 to be expressed in a concentration- and time-dependent manner. Treatment of A549 cells with LY 294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, a PI3K inhibitor), an Akt inhibitor, and the dominant negative mutant of Akt (Akt DN) inhibited TGF-beta1-induced HO-1 expression and HO-1-luciferase activity. Stimulation of cells with TGF-beta1 caused an increase in Akt phosphorylation in a time-dependent manner, which was inhibited by wortmannin and LY 294002 (PI3K inhibitors). In addition, treatment of A549 cells with Bay 117082 ((E)-3-[4-methylphenylsulfonyl]-2-propenenitrile, an IkappaB phosphorylation inhibitor), pyrrolidine dithiocarbamate (PDTC, an NF-kappaB inhibitor), and the dominant negative mutant of IkappaBalpha (IkappaBalphaM) inhibited TGF-beta1-induced HO-1 expression and HO-1-luciferase activity. Treatment of A549 cells with TGF-beta1-induced IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 Ser536 phosphorylation, and kappaB-luciferase activity. The TGF-beta1-mediated increases in IKKalpha/beta phosphorylation, p65 Ser536 phosphorylation, and kappaB-luciferase activity were inhibited by LY 294002, an Akt inhibitor, and Akt DN. Taken together, these results suggest that the PI3K/Akt dependent IKKalpha/beta/NF-kappaB signaling pathway plays an important role in TGF-beta1-induced HO-1 expression in A549 cells.

  16. Resveratrol pretreatment attenuates injury and promotes proliferation of neural stem cells following oxygen-glucose deprivation/reoxygenation by upregulating the expression of Nrf2, HO-1 and NQO1 in vitro

    PubMed Central

    Shen, Changbo; Cheng, Wei; Yu, Pingping; Wang, Li; Zhou, Lulin; Zeng, Li; Yang, Qin

    2016-01-01

    There is considerable interest in the use of drugs and other methods for protecting implanted neural stem cells (NSCs) from the adverse environment of injured tissue for successful cell therapy. Resveratrol can modify cardiac stem cells to enhance their survival and differentiation, however, its effect and the mechanism underlying its neuroprotective effect on NSCs following stroke remain to be fully elucidated. Nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling is important in antioxidative stress, and the role of Nrf-2 signaling in the enhanced neuroprotection of NSCs by resveratrol following stroke also remains to be elucidated. In the present study, NSCs were pretreated with resveratrol prior to oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. The survival, apoptosis and proliferation of the NSCs were assessed using an MTT assay, Hoechst 33258 staining of nuclei and flow cytometry, respectively. In addition, the activity of superoxide dismutase (SOD), level of malondiadehyde (MDA) and content of glutathione (GSH) were determined. The protein expressions levels of Nrf-2, NAD(P)H:quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) were detected using western blot analysis. It was found that resveratrol markedly enhanced NSC survival and proliferation, decreased apoptosis and the levels of MDA, and increased the activity of SOD and content of GSH in a concentration-dependent manner following OGD/R injury in vitro. In addition, the protein expression levels of Nrf2, HO-1 and NQO1 were significantly upregulated. These findings suggested that resveratrol attenuated injury and promoted proliferation of the NSCs, at least in part, by upregulating the expression of Nrf2, HO-1 and NQO1 following OGD/R injury in vitro. PMID:27573874

  17. Lipoic acid and pentoxifylline mitigate nandrolone decanoate-induced neurobehavioral perturbations in rats via re-balance of brain neurotransmitters, up-regulation of Nrf2/HO-1 pathway, and down-regulation of TNFR1 expression.

    PubMed

    Ahmed, Maha A E; El-Awdan, Sally A

    2015-07-01

    Behavioral perturbations associated with nandrolone decanoate abuse by athletes and adolescents may be attributed to oxidative stress and inflammation. However, the underlying mechanisms are not yet fully explored. On the other hand, the natural antioxidant lipoic acid can pass the blood brain barrier and enhance Nrf2/HO-1 (nuclear factor erythroid-2 related factor 2/heme oxygenase-1) pathway. In addition, the phosphodiesterase-IV inhibitor xanthine derivative pentoxifylline has a remarkable inhibitory effect on tumor necrosis factor-alpha (TNF-α). Therefore, this study aimed at investigation of the possible protective effects of lipoic acid and/or pentoxifylline against nandrolone-induced neurobehavioral alterations in rats. Accordingly, male albino rats were randomly distributed into seven groups and treated with either vehicle, nandrolone (15mg/kg, every third day, s.c.), lipoic acid (100mg/kg/day, p.o.), pentoxifylline (200mg/kg/day, i.p.), or nandrolone with lipoic acid and/or pentoxifylline. Rats were challenged in the open field, rewarded T-maze, Morris water maze, and resident-intruder aggression behavioral tests. The present findings showed that nandrolone induced hyperlocomotion, anxiety, memory impairment, and aggression in rats. These behavioral abnormalities were accompanied by several biochemical changes, including altered levels of brain monoamines, GABA, and acetylcholine, enhanced levels of malondialdehyde and TNF-α, elevated activity of acetylcholinesterase, and up-regulated expression of TNF-α receptor-1 (TNFR1). In addition, inhibited catalase activity, down-regulated Nrf2/HO-1 pathway, and suppressed acetylcholine receptor expression were observed. Lipoic acid and pentoxifylline combination significantly mitigated all the previously mentioned deleterious effects mainly via up-regulation of Nrf2/HO-1 pathway, inhibition of TNF-α and down-regulation of TNFR1 expression. In conclusion, the biochemical and histopathological findings of this

  18. The protective role of vitamin D3 in a murine model of asthma via the suppression of TGF-β/Smad signaling and activation of the Nrf2/HO-1 pathway

    PubMed Central

    Wang, Zhihui; Zhang, Haitao; Sun, Xiaohan; Ren, Lihong

    2016-01-01

    Asthma is a common worldwide health burden, the prevalence of which is increasing. Recently, the biologically active form of vitamin D3, 1,25-dihydroxyvitamin D3, has been reported to have a protective role in murine asthma; however, the molecular mechanisms by which vitamin D3 attenuates asthma-associated airway injury remain elusive. In the present study, BALB/c mice were sensitized to ovalbumin (OVA) and were administered 100 ng 1,25-dihydroxyvitamin D3 (intraperitoneal injection) 30 min prior to each airway challenge. The inflammatory responses were measured by ELISA, airway damage was analyzed by hematoxylin and eosin staining, airway remodeling was analyzed by Masson staining and periodic acid-Schiff staining, markers of oxidative stress were measured by commercial kits, and the expression levels of α-smooth muscle actin (α-SMA) and the activity of the NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and the transforming growth factor-β (TGF-β)/Smad signaling pathways were measured by immunohistochemistry and western blotting. The results demonstrated that OVA-induced airway inflammation and immunoglobulin E overexpression were significantly reduced by vitamin D3 treatment. In addition, treatment with vitamin D3 decreased α-SMA expression, collagen deposition and goblet cell hyperplasia, and inhibited TGF-β/Smad signaling in the asthmatic airway. The upregulated levels of malondialdehyde, and the reduced activities of superoxide dismutase and glutathione in OVA-challenged mice were also markedly restored following vitamin D3 treatment. Furthermore, treatment with vitamin D3 enhanced activation of the Nrf2/HO-1 pathway in the airways of asthmatic mice. In conclusion, these findings suggest that vitamin D3 may protect airways from asthmatic damage via the suppression of TGF-β/Smad signaling and activation of the Nrf2/HO-1 pathway; however, these protective effects were shown to be accompanied by hypercalcemia. PMID:27484042

  19. An IκBα phosphorylation inhibitor induces heme oxygenase-1(HO-1) expression through the activation of reactive oxygen species (ROS)-Nrf2-ARE signaling and ROS-PI3K/Akt signaling in an NF-κB-independent mechanism.

    PubMed

    Min, Kyoung-jin; Lee, Jung Tae; Joe, Eun-hye; Kwon, Taeg Kyu

    2011-09-01

    Reactive oxygen species (ROS) are important signaling molecules in cells. Excessive ROS induce expression of inflammatory mediators, such as iNOS and COX2. Antioxidant enzymes, such as, heme oxygenase-1 (HO-1), tightly regulate ROS levels within cells. Here, we show that Bay 11-7082 (Bay) increased HO-1 mRNA and protein expression in human colon cancer HT29 cells. Bay induced translocation of NF-E2-related factor 2 (Nrf2) into nuclei and increased the binding activity of the antioxidant response element (ARE). In addition, PI3K/Akt inhibitor (LY294002) blocked Bay-induced HO-1 expression. Pretreatment with anti-oxidants (N-acetylcysteine (NAC) or glutathione) significantly reduced Bay-induced HO-1 mRNA/protein expression, nuclear translocation of Nrf2 and phosphorylation of Akt. However, PI3K/Akt signaling was independent of Bay-induced Nrf2 translocation and ARE binding activity. Furthermore, other NF-κB inhibitors, such as pyrrolidine dithiocarbamate (PDTC) and MG132, also increased HO-1 mRNA and protein expression. However, although overexpression of dominant negative inhibitory κB (IκB) reduced NF-κB-driven transcriptional activity, IκB overexpression did not increase HO-1 expression. Taken together, our results suggest that in human colon cancer HT29 cells, Bay induces HO-1 expression by increasing ROS production in an Nrf2-ARE and PI3K dependent manner, but Bay acts independently of NF-κB.

  20. Anti-neuro-inflammatory effects of Nardostachys chinensis in lipopolysaccharide-and lipoteichoic acid-stimulated microglial cells.

    PubMed

    Park, Sun Young; Kim, Young Hun; Park, Geuntae

    2016-05-01

    Excessive microglial cell activation is related to the progression of chronic neuro-inflammatory disorders. Heme oxygenase-1 (HO-1) expression mediated by the NFE2-related factor (Nrf-2) pathway is a key regulator of neuro-inflammation. Nardostachys chinensis is used as an anti-malarial, anti-nociceptive, and neurotrophic treatment in traditional Asian medicines. In the present study, we examined the effects of an ethyl acetate extract of N. chinensis (EN) on the anti-neuro-inflammatory effects mediated by HO-1 up-regulation in Salmonella lipopolysaccharide (LPS)- or Staphylococcus aureus lipoteichoic acid (LTA)-stimulated BV2 microglial cells. Our results indicated that EN suppressed pro-inflammatory cytokine production and induced HO-1 transcription and translation through Nrf-2/antioxidant response element (ARE) signaling. EN markedly inhibited LPS- and LTA-induced activation of nuclear factor-kappa B (NF-κB) as well as phosphorylation of mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT). Furthermore, EN protected hippocampal HT22 cells from indirect neuronal toxicity mediated by LPS- and LTA-treated microglial cells. These results suggested that EN impairs LPS- and LTA-induced neuro-inflammatory responses in microglial cells and confers protection against indirect neuronal damage to HT22 cells. In conclusion, our findings indicate that EN could be used as a natural anti-neuro-inflammatory and neuroprotective agent. PMID:27478097

  1. Extract of Ziziphus jujuba Fruit (Jujube) Stimulates Expression of Enzymes Responsible for Heme Recycle via Anti-oxidant Response Element in Cultured Murine Macrophages.

    PubMed

    Chen, Jianping; Lam, Candy T W; Li, Zhonggui; Yao, Ping; Lin, Huangquan; Dong, Tina T X; Tsim, Karl W K

    2016-02-01

    Jujube, the fruit of Ziziphus jujuba Mill., is a functional food and commonly used as a health supplement worldwide. To study the beneficial role of jujube in heme iron recycling during erythrophagocytosis, the expression of heme oxygenase-1 (HO-1), biliverdin reductase A and B, and ferroportin were determined in jujube-treated cultured RAW 264.7 macrophages. Application of a chemically standardized jujube water extract in cultured RAW 264.7 cells for 24 h stimulated the expressions of HO-1, biliverdin reductase A, biliverdin reductase B, and ferroportin in a concentration-dependent manner, having the maximal responses from twofolds to threefolds. A plasmid containing anti-oxidant response element, a regulator for HO-1 transcription, was transfected into RAW 264.7 cells. Application of jujube water extract onto the transfected macrophages stimulated the anti-oxidant response element-mediated transcriptional activity by twofolds. These results supported the potential capacity of jujube by regulating expressions of heme iron recycling genes in cultured macrophages.

  2. Quercetin protects mouse liver against nickel-induced DNA methylation and inflammation associated with the Nrf2/HO-1 and p38/STAT1/NF-κB pathway.

    PubMed

    Liu, Chan-Min; Ma, Jie-Qiong; Xie, Wan-Ru; Liu, Si-Si; Feng, Zhao-Jun; Zheng, Gui-Hong; Wang, Ai-Min

    2015-08-01

    Quercetin (QE), a natural flavonoid, has been reported to have many benefits and medicinal properties. However, its protective effects against nickel (Ni) induced injury in liver have not been clarified. The aim of the present study was to investigate the effects of quercetin on hepatic DNA methylation and inflammation in mice exposed to nickel. ICR mice were exposed to nickel sulfate with or without quercetin co-administration for 20 days. Our results showed that quercetin administration significantly inhibited nickel-induced liver injury, which was indicated by diagnostic indicators. In exploring the underlying mechanisms of quercetin action, we found that quercetin decreased total DNA methyltransferases (DNMTs) activity and DNA methylation level of the NF-E2 related factor 2 (Nrf2) DNA in livers of nickel-treated mice. Quercetin also induced Nrf2 nuclear translocation and heme oxygenase-1 (HO-1) activity. Moreover, quercetin decreased production of pro-inflammatory markers including TNF-α, IL-1β and iNOS. Quercetin significantly inhibited the p38 and signal transducer and activator of transcription 1 (STAT1) activation, which in turn inactivated NF-κB and the inflammatory cytokines in livers of the nickel-treated mice. In conclusion, these results suggested that the inhibition of nickel-induced inflammation by quercetin is associated with its ability to modulate Nrf2/HO-1 and p38/STAT1/NF-κB signaling pathway.

  3. Garcinone D, a natural xanthone promotes C17.2 neural stem cell proliferation: Possible involvement of STAT3/Cyclin D1 pathway and Nrf2/HO-1 pathway.

    PubMed

    Yang, Xiaohong; Wang, Shengnan; Ouyang, Ying; Tu, Yaling; Liu, Anmin; Tian, Yinghong; He, Mingliang; Pi, Rongbiao

    2016-07-28

    Garcinia mangostana L. (Mangosteen) has been used to treat various pathological conditions, including inflammation and urinary tract infections. Here, we observed that garcinone D, a natural xanthone from mangosteen, promoted the proliferation of C17.2 neural progenitor cells and also resulted in a larger percentage of cells in S phase compared with the control group. Moreover, garcinone D increased the protein levels of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and Cyclin D1 in concentration- and time- dependent manners. Garcinone D also increased the protein levels of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) in concentration- and time- dependent manners, and inhibiting Nrf2 activation by brusatol could partly reverse garcinone D-induced C17.2 cell proliferation. Taken together, it is the first time to show that garcinone D promotes the proliferation of C17.2 neural stem cells, which may involve the STAT3/Cyclin D1 pathway and Nrf2/HO-1 pathway. It would provide new inspiration to develop garcinone D as a lead compound to promote the proliferation of endogenous neural stem cells (NSCs). PMID:27177723

  4. Berberis aristata Ameliorates Adjuvant-Induced Arthritis by Inhibition of NF-κB and Activating Nuclear Factor-E2-related Factor 2/hem Oxygenase (HO)-1 Signaling Pathway.

    PubMed

    Kumar, Rohit; Nair, Vinod; Gupta, Yogendra Kumar; Singh, Surender; Arunraja, S

    2016-08-01

    The present study was carried out to investigate the anti-arthritic activity of Berberis aristata hydroalcoholic extract (BAHE) in formaldehyde-induced arthritis and adjuvant-induced arthritis (AIA) model. Arthritis was induced by administration of either formaldehyde (2% v/v) or CFA into the subplantar surface of the hind paw of the animal. In formaldehyde-induced arthritis and AIA, treatment of BAHE at doses 50, 100 and 200 mg/kg orally significantly decreased joint inflammation as evidenced by decrease in joint diameter and reduced inflammatory cell infiltration in histopathological examination. BAHE treatment demonstrated dose-dependent improvement in the redox status of synovium (decrease in GSH, MDA, and NO levels and increase in SOD and CAT activities). The beneficial effect of BAHE was substantiated with decreased expression of inflammatory markers such as IL-1β, IL-6, TNF-R1, and VEGF by immunohistochemistry analysis in AIA model. BAHE increased HO-1/Nrf-2 and suppressed NF-κB mRNA and protein expression in adjuvant immunized joint. Additionally, BAHE abrogated degrading enzymes, as there was decreased protein expression of MMP-3 and -9 in AIA. In conclusion, we demonstrated the anti-arthritic activity of Berberis aristata hydroalcoholic extract via the mechanism of inhibition of NF-κB and activation of Nrf-2/HO-1.

  5. 15-Deoxy-Δ12,14-prostaglandin J2 inhibits macrophage colonization by Salmonella enterica serovar Typhimurium.

    PubMed

    Buckner, Michelle M C; Antunes, L Caetano M; Gill, Navkiran; Russell, Shannon L; Shames, Stephanie R; Finlay, B Brett

    2013-01-01

    15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d-PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-γ. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified role for this

  6. Zinc protoporphyrin inhibition of lipopolysaccharide-, lipoteichoic acid-, and peptidoglycan-induced nitric oxide production through stimulating iNOS protein ubiquitination

    SciTech Connect

    Chow, J.-M.; Lin, H.-Y.; Shen, S.-C.; Wu, M.-S.; Lin, C.-W.; Chiu, W.-T.; Lin, C.-H. Chen, Y.-C.

    2009-06-15

    In the present study, zinc protoporphyrin (ZnPP), but not ferric protoporphyrin (FePP), tin protoporphyrin (SnPP), or zinc chloride (ZnCl{sub 2}), at the doses of 0.5, 1, and 2 {mu}M, dose-dependently inhibited lipopolysaccharide- (LPS), lipoteichoic acid (LTA), and peptidoglycan (PGN)-induced inducible nitric oxide (iNOS) and nitric oxide (NO) production with an increase in heme oxygenase 1 (HO-1) protein in RAW264.7 macrophages in a serum-free condition. NO inhibition and HO-1 induction by ZnPP were blocked by the separate addition of fetal bovine serum (FBS) and bovine serum albumin (BSA). A decrease in the iNOS/NO ratio and an increase in HO-1 protein by ZnPP were identified in three different conditions including ZnPP pretreatment, ZnPP co-treatment, and ZnPP post-treatment with LPS and LTA. Activation of c-Jun N-terminal kinases (JNKs) and extracellular regulated kinases (ERKs) were detected in LPS-, LTA-, and PGN-treated RAW264.7 cells, and iNOS/NO production was blocked by adding the JNK inhibitor, SP600125, but not the ERK inhibitor, PD98059. However, ZnPP addition potentiated ERK and JNK protein phosphorylation stimulated by LPS, LTA, and PGN. Increases in total protein ubiquitination and ubiquitinated iNOS proteins were detected in ZnPP-treated macrophages elicited by LPS according to Western and immunoprecipitation/Western blotting assays, respectively. The decrease in LPS-induced iNOS protein by ZnPP was reversed by adding the proteasome inhibitors MG132 and lactacystin. The reduction in HO-1 protein induced by ZnPP via transfection of HO-1 small interfering RNA did not affect the inhibitory effect of ZnPP against LPS-induced iNOS/NO production and protein ubiquitination induced by ZnPP in macrophages. Data of the present study provide the first evidence to support ZnPP effectively inhibiting inflammatory iNOS/NO production through activation of protein ubiquitination in a HO-1-independent manner in macrophages.

  7. Identification of a prostaglandin D2 metabolite as a neuritogenesis enhancer targeting the TRPV1 ion channel

    PubMed Central

    Shibata, Takahiro; Takahashi, Katsuhiro; Matsubara, Yui; Inuzuka, Emi; Nakashima, Fumie; Takahashi, Nobuaki; Kozai, Daisuke; Mori, Yasuo; Uchida, Koji

    2016-01-01

    Mast cells play important roles in allergic inflammation by secreting various mediators. In the present study, based on the finding that the medium conditioned by activated RBL-2H3 mast cells enhanced the nerve growth factor (NGF)-induced neuritogenesis of PC12 cells, we attempted to isolate an active compound from the mast cell conditioned culture medium. Our experiment identified 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), one of the PGD2 metabolites, as a potential enhancer of neuritogenesis. 15d-PGJ2 strongly enhanced the neuritogenesis elicited by a low-concentration of NGF that alone was insufficient to induce the neuronal differentiation. This 15d-PGJ2 effect was exerted in a Ca2+-dependent manner, but independently of the NGF receptor TrkA. Importantly, 15d-PGJ2 activated the transient receptor potential vanilloid-type 1 (TRPV1), a non-selective cation channel, leading to the Ca2+ influx. In addition, we observed that (i) NGF promoted the insertion of TRPV1 into the cell surface membrane and (ii) 15d-PGJ2 covalently bound to TRPV1. These findings suggest that the NGF/15d-PGJ2-induced neuritogenesis may be regulated by two sets of mechanisms, one for the translocation of TRPV1 into the cell surface by NGF and one for the activation of TRPV1 by 15d-PGJ2. Thus, there is most likely a link between allergic inflammation and activation of the neuronal differentiation. PMID:26879669

  8. Z-ligustilide ameliorated ultraviolet B-induced oxidative stress and inflammatory cytokine production in human keratinocytes through upregulation of Nrf2/HO-1 and suppression of NF-κB pathway.

    PubMed

    Wu, Zhouwei; Uchi, Hiroshi; Morino-Koga, Saori; Shi, Weimin; Furue, Masutaka

    2015-09-01

    Ultraviolet B (UVB), a harmful environmental factor, is responsible for a variety of skin disorders including skin inflammation through reactive oxygen species (ROS) and inflammatory mediator production. Here, we investigated the effect of Z-ligustilide (Z-lig), an active ingredient isolated from the medicinal plants Cnidium officinale and Angelica acutiloba, on UVB-induced ROS generation and inflammatory mediator production in normal human epidermal keratinocytes (NHEKs) as well as its underlying mechanisms. Z-lig significantly rescued UVB-induced NHEKs damage in a dosage-dependent manner. Pretreatment of NHEKs with Z-lig inhibited UVB-induced ROS production in NHEKs. Both silencing the nuclear factor E2-related factor 2 (Nrf2) and the supplement of tin protoporphyrin IX (SnPP), a haeme oxygenase-1 (HO-1) inhibitor, cancelled the inhibitory effect of Z-lig on UVB-induced ROS upregulation in NHEKs. Moreover, pretreatment of NHEKs with Z-lig reduced UVB-induced nuclear factor kappa B (NF-κB)-dependent inflammatory mediators (IL-6, IL-8 and MCP-1) production at both mRNA and protein level. In the presence of Z-lig, UVB-induced NF-κB subunit p65 nuclear translocation was abolished, and the IκBα degradation was suppressed. Taken together, these findings suggest that Z-lig can suppress UVB-induced ROS generation through Nrf2/HO-1 upregulation and inflammation by suppressing the NF-κB pathway, suggesting that Z-lig may be beneficial in protecting skin from UVB exposure.

  9. Effects of β-Glucan on the Release of Nitric Oxide by Macrophages Stimulated with Lipopolysaccharide

    PubMed Central

    Choi, E. Y.; Lee, S. S.; Hyeon, J. Y.; Choe, S. H.; Keum, B. R.; Lim, J. M.; Park, D. C.; Choi, I. S.; Cho, K. K.

    2016-01-01

    This research analyzed the effect of β-glucan that is expected to alleviate the production of the inflammatory mediator in macrophagocytes, which are processed by the lipopolysaccharide (LPS) of Escherichia. The incubated layer was used for a nitric oxide (NO) analysis. The DNA-binding activation of the small unit of nuclear factor-κB was measured using the enzyme-linked immunosorbent assay-based kit. In the RAW264.7 cells that were vitalized by Escherichia coli (E. coli) LPS, the β-glucan inhibited both the combatant and rendering phases of the inducible NO synthase (iNOS)-derived NO. β-Glucan increased the expression of the heme oxygenase-1 (HO-1) in the cells that were stimulated by E. coli LPS, and the HO-1 activation was inhibited by the tin protoporphyrin IX (SnPP). This shows that the NO production induced by LPS is related to the inhibition effect of β-glucan. The phosphorylation of c-Jun N-terminal kinases (JNK) and the p38 induced by the LPS were not influenced by the β-glucan, and the inhibitory κB-α (IκB-α) decomposition was not influenced either. Instead, β-glucan remarkably inhibited the phosphorylation of the signal transducer and activator of transcription-1 (STAT1) that was induced by the E. coli LPS. Overall, the β-glucan inhibited the production of NO in macrophagocytes that was vitalized by the E .coli LPS through the HO-1 induction and the STAT1 pathways inhibition in this research. As the host immune response control by β-glucan weakens the progress of the inflammatory disease, β-glucan can be used as an effective immunomodulator. PMID:27488844

  10. Protective effect of Xuebijing injection on D-galactosamine- and lipopolysaccharide-induced acute liver injury in rats through the regulation of p38 MAPK, MMP-9 and HO-1 expression by increasing TIPE2 expression

    PubMed Central

    Liu, Ming-Wei; Liu, Rong; Wu, Hai-Yin; Zhang, Wei; Xia, Jing; Dong, Min-Na; Yu, Wen; Wang, Qiang; Xie, Feng-Mei; Wang, Rui; Huang, Yun-Qiao; Qian, Chuan-Yun

    2016-01-01

    Xuebijing injection (XBJ) has long been used to treat infectious diseases in China. The therapeutic effect of XBJ is probably associated with anti-inflammatory effects. However, the precise mechanisms responsible for the effects of XBJ remain unknown. The present study was conducted in order to evaluate the protective effects of XBJ in a rat model of D-galactosamine (D-Gal)- and lipopolysaccharide (LPS)-induced acute liver injury. In the present study, the rats were injected with D-Gal and LPS intraperitoneally to induce acute liver injury. Two hours prior to D-Gal and LPS administration, the treatment group was administered XBJ by intravenous infusion. The effects of XBJ on D-Gal- and LPS-induced expression of tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2), nuclear factor-κB (NF-κB), matrix metalloproteinase-9 (MMP-9) and heme oxygenase-1 (HO-1) as well as mitogen-activated protein kinase (MAPK) signaling was examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot analysis, immunofluorescence, as well as by analysing the serum levels of pro-inflammatory cytokines and the transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD) levels in the rat liver tissues were also measured. For histological analysis, hematoxylin and eosin (H&E)-stained liver samples were evaluated. The results showed that XBJ upregulated TIPE2 and HO-1 expression, reduced the expression of NF-κB65 and MMP-9, inhibited the LPS-induced gene expression of c-jun N-terminal kinase (JNK) and p38 MAPK, decreased the generation of pro-inflammatory cytokines [interleukin (IL)-6, IL-13 and TNF-α], inhibited ALT and AST activity, and ameliorated D-Gal- and LPS-induced liver injury. The histological results also demonstrated that XBJ attenuated D-Gal- and LPS-induced liver inflammation. It was found that XBJ may prevent LPS-induced pro

  11. Cytotoxic and anti-inflammatory effects of onion peel extract on lipopolysaccharide stimulated human colon carcinoma cells.

    PubMed

    Kim, Jungmi; Kim, Ji-Sang; Park, Eunju

    2013-12-01

    The present study investigated the cytotoxic activity of ethanol extract of onion peel (OPE) in HT-29 human colon carcinoma cells. High-performance liquid chromatography (HPLC) analysis was performed to determine the amounts of phenolic acids and flavonoids in OPE. In addition, the influence of OPE on antioxidant- and inflammation-associated gene expression was also determined in a model of lipopolysaccharide (LPS)-stimulated HT-29 cells. HPLC analysis showed that OPE contained well-known antioxidant compounds, including p-coumaric acid, vanillic acid, epicatechin, and morin. After incubation with OPE, HT-29 cells showed either a loss of normal nuclear architecture or detachability from each other. The cytotoxic effects of OPE on HT-29 cells were confirmed by MTT and LDH release assays. LPS-induced oxidative conditions effectively downregulated TNF-α mRNA expression in OPE pretreated HT-29 cells compared with cells only stimulated with LPS. In addition, the expression of heme oxygenase-1 (HO-1) and glutathione S-transferase (GSTs) detoxification genes (i.e., GSTM1, GSTT1, and GSTP1) was upregulated after treatment with LPS at sublethal concentrations. However, the LPS-induced mRNA expression of HO-1 and GSTs was significantly attenuated by treatment with OPE. Therefore, onion peel extract is a promising component of future nutraceuticals and value-added products.

  12. Cytotoxic and anti-inflammatory effects of onion peel extract on lipopolysaccharide stimulated human colon carcinoma cells.

    PubMed

    Kim, Jungmi; Kim, Ji-Sang; Park, Eunju

    2013-12-01

    The present study investigated the cytotoxic activity of ethanol extract of onion peel (OPE) in HT-29 human colon carcinoma cells. High-performance liquid chromatography (HPLC) analysis was performed to determine the amounts of phenolic acids and flavonoids in OPE. In addition, the influence of OPE on antioxidant- and inflammation-associated gene expression was also determined in a model of lipopolysaccharide (LPS)-stimulated HT-29 cells. HPLC analysis showed that OPE contained well-known antioxidant compounds, including p-coumaric acid, vanillic acid, epicatechin, and morin. After incubation with OPE, HT-29 cells showed either a loss of normal nuclear architecture or detachability from each other. The cytotoxic effects of OPE on HT-29 cells were confirmed by MTT and LDH release assays. LPS-induced oxidative conditions effectively downregulated TNF-α mRNA expression in OPE pretreated HT-29 cells compared with cells only stimulated with LPS. In addition, the expression of heme oxygenase-1 (HO-1) and glutathione S-transferase (GSTs) detoxification genes (i.e., GSTM1, GSTT1, and GSTP1) was upregulated after treatment with LPS at sublethal concentrations. However, the LPS-induced mRNA expression of HO-1 and GSTs was significantly attenuated by treatment with OPE. Therefore, onion peel extract is a promising component of future nutraceuticals and value-added products. PMID:24001438

  13. The combination of the active principles of Podophyllum hexandrum supports early recovery of the gastrointestinal system via activation of Nrf2-HO-1 signaling and the hematopoietic system, leading to effective whole-body survival in lethally irradiated mice.

    PubMed

    Dutta, A; Gupta, M L; Kalita, B

    2015-03-01

    This study is aimed at the development of a safe radioprotective formulation to minimize human sufferings during accidental nuclear exposures. In the current study, a combination of three active principles, namely podophyllotoxin, podophyllotoxin beta-D-glucoside, and rutin (G-002M), isolated from Podophyllum hexandrum rhizomes, has been evaluated for its radioprotective potential and mode of action. Total body protection studies have demonstrated that a single prophylactic dose of G-002M delivered more than 85% survival in mice exposed to a lethal (9 Gy) dose of gamma radiation, and significantly protected the radiosensitive hematopoietic and gastrointestinal organs. Studies have also revealed a reduction in free radical generation, lipid peroxidation, protein carbonylation, and cell death in mouse intestine after G-002M treatment, while GSH was observed to be enhanced in the same tissue. Redox-sensitive transcription factor (Nrf2) activation and subsequent upregulation of heme oxygenase-1 (HO-1) and SOD-1 revealed the cytoprotective role of G-002M. A histological examination of the jejunum pretreated with the formulation also demonstrated less damage to the villi, crypts, and the mucosal layers. These observations reiterated that the reduction in the ROS levels, protection of cellular macromolecules, and activation of the antioxidant signaling pathway may have been the principle factors involved in G-002M- mediated protection against radiation-induced tissue impairment. The potentially safe and effective radioprotective characteristics of this new combination are encouraging for further studies for human application.

  14. Lithospermic acid B protects beta-cells from cytokine-induced apoptosis by alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2-HO-1 and Sirt1

    SciTech Connect

    Lee, Byung-Wan; Chun, Sung Wan; Kim, Soo Hyun; Lee, Yongho; Kang, Eun Seok; Cha, Bong-Soo; Lee, Hyun Chul

    2011-04-01

    Lithospermic acid B (LAB) has been reported to protect OLETF rats, an established type 2 diabetic animal model, from the development of diabetes-related vascular complications. We investigated whether magnesium lithospermate B (LAB) has a protective role under cytokine-induced apoptosis in INS-1 cells in vitro and whether it slows the development of diabetes in OLETF rats in vivo. Pretreatment with 50 {mu}M LAB significantly reduced the 1000 U/mL INF-{gamma} and 100 U/mL IL-1{beta}-induced INS-1 cell death. LAB significantly alleviated cytokine-induced phosphorylations of p38 and JNK in accordance with a decrease in cleaved caspase-3 activity in beta-cells. LAB also protected against the cytokine-induced caspase-3 apoptotic pathway via significant activation of Nrf2-HO (heme-oxigenase)-1 and Sirt1 expression. OLETF rats treated with 40 mg/kg/day LAB showed a significant improvement in glucose tolerance compared to untreated OLETF control rats in vivo. Our results suggest that the cytoprotective effects of LAB on pancreatic {beta}-cells are related with both alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2-HO-1 and Sirt1.

  15. Tomato powder impedes the development of azoxymethane-induced colorectal cancer in rats through suppression of COX-2 expression via NF-κB and regulating Nrf2/HO-1 pathway.

    PubMed

    Tuzcu, Mehmet; Aslan, Abdullah; Tuzcu, Zeynep; Yabas, Mehmet; Bahcecioglu, Ibrahim Halil; Ozercan, Ibrahim Hanifi; Kucuk, Omer; Sahin, Kazim

    2012-09-01

    Cancer is one of the leading causes of death worldwide. Since dietary factors have been connected to a reduced risk of a diversity of human cancers, in this study we investigated the effects of tomato powder (TP) on the development of azoxymethane (AOM)-induced colorectal cancer in Wistar rats, and possible mechanism(s) by which TP shows its chemopreventive activity. Here we show that TP added to feed at 5% rate decreases the rate of aberrant crypt foci (ACF) and reduces the development of adenocarcinoma and growth of AOM-induced colorectal cancer in rats. In addition, we demonstrate that TP supplementation shows its chemopreventive activities through inhibition of cyclooxygenase-2 (COX-2) expression via NF-κB pathway and promotion of apoptosis, as well as regulating Nrf2/HO-1 signaling pathway in colorectal tissue of AOM-treated rats. Our findings identify an intimate connection between dietary supplementation of TP and the decreased risk of colorectal cancer in rats, and suggest that consumption of TP would be a natural candidate for the prevention of colorectal cancer in men. PMID:22859375

  16. Effect of 15-Deoxy-△(12,14)-prostaglandin J2 on Expression of Macrophage Migration Inhibitory Factor in Mouse Monocyte/macrophage Cell Line J774A.1.

    PubMed

    Wei-Yang, L I; Yu-Meng, Shi; Xin, Liu; Lin, Yang; Li-Ying, L I

    2016-06-10

    Objective To investigate the effect of 15-Deoxy-△(12,14)-prostaglandin J2 (15 d-PGJ2) on the expression of macrophage migration inhibitory factor (MIF) and its underlying mechanism in J774A.1. Methods The murine monocyte/macrophage cell line J774A.1 were divided into six groups:lipopolysaccharide (LPS) group,incubated with 1 μg/ml LPS for 1 h;normal control group,incubated with PBS for 1 h;negative control group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h;15 d-PGJ2 group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h followed by 1 μg/ml LPS for 1 h;GW9662 group,incubated with 5 μmol/L 15 d-PGJ2 for 1 h following GW9662 10 μmol/L for 1 h,and then incubated with 1 μg/ml LPS for 1 h;and Vehicle group,control of GW9662,GW9662 was replaced by its solvent DMSO. The expression of MIF was detected via immunofluorescence and agarose gel electrophoresis. RT-qPCR and Western blotting were used to test whether 15 d-PGJ2 could regulate mRNA and protein expression of MIF in J774A.1 upon LPS challenge. The effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist GW9662 on the regulation of MIF by 15 d-PGJ2 was observed. The effects of 15 d-PGJ2 on the nuclear translocation of PPAR-γ upon LPS challenge were detected via high content screening analysis. Results MIF DNA and protein expressions were detected in J774A.1. MIF mRNA expression was up-regulated (1.75±0.09,P=0.037) when challenged with LPS and 15 d-PGJ2 inhibited its upregulation (0.84±0.08,P=0.026) in J774A.1. The protein level was consistent with the mRNA level. PPAR-γ antagonist GW9662 reversed the effect of 15 d-PGJ2 (mRNA,1.48±0.06,P=0.016;protein,1.28). Furthermore,nuclear translocation of PPAR-γ was regulated by 15 d-PGJ2 in J774A.1 upon LPS challenge(1.39±0.02 vs. 1.01±0.03,P=0.003). Conclusion 15 d-PGJ2 may down-regulate the MIF expression in J774A.1 in a PPAR-γ-dependent manner. PMID:27544994

  17. Albumin-Binding and Tumor Vasculature Determine the Antitumor Effect of 15-Deoxy-Δ12,14-Prostaglandin-J2 in vivo1

    PubMed Central

    Prakash, Jai; Bansal, Ruchi; Post, Eduard; de Jager-Krikken, Alie; Lub-de Hooge, Marjolijn N; Poelstra, Klaas

    2009-01-01

    15-Deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, induces cell death in tumor cells in vitro; however, no study showed its in vivo effect on tumors. Here, we report that 15d-PGJ2 shows antitumor effects in vivo in mice. However, its effects correlate with tumor uptake of albumin, to which it reversibly binds. 15d-PGJ2 induces cell death in B16F10 melanoma and C26 colon carcinoma cells in vitro. These effects were not elicited through PPARγ-dependent pathways because an irreversible PPARγ antagonist GW9662 did not inhibit these effects. Caspase- and nuclear factor κB- (NF-κB) dependent pathways were found to be involved as determined with caspase-3/7 fluorescent assay and NF-κB containing plasmid transfection assay, respectively. Noticeably, 15d-PGJ2 had significantly stronger effects in C26 cells compared with B16 cells in all assays. However, in vivo, there was no effect on C26 tumors, yet it significantly inhibited the B16 tumor growth in mice by 75%. We found that 15d-PGJ2 rapidly bound to albumin and in vivo albumin greatly distributed to B16 tumors compared with C26 tumors, shown with γ-camera imaging and immunohistochemical staining. Albumin accumulation can be attributed to the large blood vessel diameter in B16 tumors and an enhanced permeability and retention effect. These findings suggest that 15d-PGJ2 can be an effective therapeutic agent for cancer, although its effects seem to be limited to the tumors allowing albumin penetration. PMID:20019843

  18. Synergistic anti-inflammatory effects of nobiletin and sulforaphane in lipopolysaccharide-stimulated RAW 264.7 cells.

    PubMed

    Guo, Shanshan; Qiu, Peiju; Xu, Guang; Wu, Xian; Dong, Ping; Yang, Guanpin; Zheng, Jinkai; McClements, David Julian; Xiao, Hang

    2012-03-01

    Inflammation plays important roles in the initiation and progress of many diseases including cancers in multiple organ sites. Herein, we investigated the anti-inflammatory effects of two dietary compounds, nobiletin (NBN) and sulforaphane (SFN), in combination. Noncytotoxic concentrations of NBN, SFN, and their combinations were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The results showed that combined NBN and SFN treatments produced much stronger inhibitory effects on the production of nitric oxide (NO) than NBN or SFN alone at higher concentrations. These enhanced inhibitory effects were synergistic based on the isobologram analysis. Western blot analysis showed that combined NBN and SFN treatments synergistically decreased iNOS and COX-2 protein expression levels and induced heme oxygenase-1 (HO-1) protein expression. Real-time polymerase chain reaction analysis indicated that low doses of NBN and SFN in combination significantly suppressed LPS-induced upregulation of IL-1 mRNA levels and synergistically increased HO-1 mRNA levels. Overall, our results demonstrated that NBN and SFN in combination produced synergistic effects in inhibiting LPS-induced inflammation in RAW 264.7 cells.

  19. Optical Stimulation of Neurons

    PubMed Central

    Thompson, Alexander C.; Stoddart, Paul R.; Jansen, E. Duco

    2014-01-01

    Our capacity to interface with the nervous system remains overwhelmingly reliant on electrical stimulation devices, such as electrode arrays and cuff electrodes that can stimulate both central and peripheral nervous systems. However, electrical stimulation has to deal with multiple challenges, including selectivity, spatial resolution, mechanical stability, implant-induced injury and the subsequent inflammatory response. Optical stimulation techniques may avoid some of these challenges by providing more selective stimulation, higher spatial resolution and reduced invasiveness of the device, while also avoiding the electrical artefacts that complicate recordings of electrically stimulated neuronal activity. This review explores the current status of optical stimulation techniques, including optogenetic methods, photoactive molecule approaches and infrared neural stimulation, together with emerging techniques such as hybrid optical-electrical stimulation, nanoparticle enhanced stimulation and optoelectric methods. Infrared neural stimulation is particularly emphasised, due to the potential for direct activation of neural tissue by infrared light, as opposed to techniques that rely on the introduction of exogenous light responsive materials. However, infrared neural stimulation remains imperfectly understood, and techniques for accurately delivering light are still under development. While the various techniques reviewed here confirm the overall feasibility of optical stimulation, a number of challenges remain to be overcome before they can deliver their full potential. PMID:26322269

  20. Inhibitory effects of benzaldehyde derivatives from the marine fungus Eurotium sp. SF-5989 on inflammatory mediators via the induction of heme oxygenase-1 in lipopolysaccharide-stimulated RAW264.7 macrophages.

    PubMed

    Kim, Kyoung-Su; Cui, Xiang; Lee, Dong-Sung; Ko, Wonmin; Sohn, Jae Hak; Yim, Joung Han; An, Ren-Bo; Kim, Youn-Chul; Oh, Hyuncheol

    2014-12-19

    Two benzaldehyde derivatives, flavoglaucin (1) and isotetrahydro-auroglaucin (2), were isolated from the marine fungus Eurotium sp. SF-5989 through bioassay- and 1H NMR-guided investigation. In this study, we evaluated the anti-inflammatory effects of these compounds in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We demonstrated that compounds 1 and 2 markedly inhibited LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production by suppressing inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression without affecting cell viability. We also demonstrated that the compounds reduced the secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Furthermore, compounds 1 and 2 inhibited LPS-induced nuclear factor-κB (NF-κB) activation by suppressing phosphorylation of IkappaB (IκB). These results indicated that the anti-inflammatory effects of these benzaldehyde derivatives in LPS-stimulated RAW264.7 macrophages were due to the inactivation of the NF-κB pathway. In addition, compounds 1 and 2 induced heme oxygenase-1 (HO-1) expression through the nuclear transcription factor-E2-related factor 2 (Nrf2) translocation. The inhibitory effects of compounds 1 and 2 on the production of pro-inflammatory mediators and on NF-κB binding activity were reversed by HO-1 inhibitor tin protoporphyrin (SnPP). Thus, the anti-inflammatory effects of compounds 1 and 2 also correlated with their ability of inducing HO-1 expression.

  1. Phorbaketal A, Isolated from the Marine Sponge Phorbas sp., Exerts Its Anti-Inflammatory Effects via NF-κB Inhibition and Heme Oxygenase-1 Activation in Lipopolysaccharide-Stimulated Macrophages

    PubMed Central

    Seo, Yun-Ji; Lee, Kyung-Tae; Rho, Jung-Rae; Choi, Jung-Hye

    2015-01-01

    Marine sponges harbor a range of biologically active compounds. Phorbaketal A is a tricyclic sesterterpenoid isolated from the marine sponge Phorbas sp.; however, little is known about its biological activities and associated molecular mechanisms. In this study, we examined the anti-inflammatory effects and underlying molecular mechanism of phorbaketal A in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E2, in RAW 264.7 cells. Further, phorbaketal A suppressed the expression of inducible NO synthase at both the mRNA and protein levels. In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1. Treatment with phorbaketal A inhibited the transcriptional activity of nuclear factor-kappaB (NF-κB), a crucial signaling molecule in inflammation. Moreover, phorbaketal A up-regulated the expression of heme oxygenase-1 (HO-1) in LPS-stimulated RAW 264.7 cells. These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-κB pathway and up-regulation of the HO-1 pathway. PMID:26610528

  2. Phorbaketal A, Isolated from the Marine Sponge Phorbas sp., Exerts Its Anti-Inflammatory Effects via NF-κB Inhibition and Heme Oxygenase-1 Activation in Lipopolysaccharide-Stimulated Macrophages.

    PubMed

    Seo, Yun-Ji; Lee, Kyung-Tae; Rho, Jung-Rae; Choi, Jung-Hye

    2015-11-01

    Marine sponges harbor a range of biologically active compounds. Phorbaketal A is a tricyclic sesterterpenoid isolated from the marine sponge Phorbas sp.; however, little is known about its biological activities and associated molecular mechanisms. In this study, we examined the anti-inflammatory effects and underlying molecular mechanism of phorbaketal A in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E₂, in RAW 264.7 cells. Further, phorbaketal A suppressed the expression of inducible NO synthase at both the mRNA and protein levels. In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1. Treatment with phorbaketal A inhibited the transcriptional activity of nuclear factor-kappaB (NF-κB), a crucial signaling molecule in inflammation. Moreover, phorbaketal A up-regulated the expression of heme oxygenase-1 (HO-1) in LPS-stimulated RAW 264.7 cells. These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-κB pathway and up-regulation of the HO-1 pathway. PMID:26610528

  3. Peripheral nerve stimulation: definition.

    PubMed

    Abejón, David; Pérez-Cajaraville, Juan

    2011-01-01

    Recently, there has been a tremendous evolution in the field of neurostimulation, both from the technological point of view and from development of the new and different indications. In some areas, such as peripheral nerve stimulation, there has been a boom in recent years due to the variations in the surgical technique and the improved results documented by in multiple published papers. All this makes imperative the need to classify and define the different types of stimulation that are used today. The confusion arises when attempting to describe peripheral nerve stimulation and subcutaneous stimulation. Peripheral nerve stimulation, in its pure definition, involves implanting a lead on a nerve, with the aim to produce paresthesia along the entire trajectory of the stimulated nerve.

  4. Stimulant Use Disorders.

    PubMed

    Park, Taryn M; Haning, William F

    2016-07-01

    Compared with other illicit substances, stimulants are not commonly used by adolescents; however, they represent a serious concern regarding substance use among youths. This article uses methamphetamine as a model for stimulant use in adolescents; cocaine and prescription stimulants are also mentioned. Methamphetamine use among adolescents and young adults is a serious health concern with potentially long-term physical, cognitive, and psychiatric consequences. Brain development and the effects of misusing stimulants align such that usage in adolescents can more dangerous than during adulthood. It seems helpful to keep in mind the differences between adolescents and young adults when implementing interventions. PMID:27338967

  5. Robust hydrolysis of prostaglandin glycerol esters by human monoacylglycerol lipase (MAGL).

    PubMed

    Savinainen, Juha R; Kansanen, Emilia; Pantsar, Tatu; Navia-Paldanius, Dina; Parkkari, Teija; Lehtonen, Marko; Laitinen, Tuomo; Nevalainen, Tapio; Poso, Antti; Levonen, Anna-Liisa; Laitinen, Jarmo T

    2014-11-01

    The primary route of inactivation of the endocannabinoid 2-arachidonoylglycerol in the central nervous system is through enzymatic hydrolysis, mainly carried out by monoacylglycerol lipase (MAGL), along with a small contribution by the α/β-hydrolase domain (ABHD) proteins ABHD6 and ABHD12. Recent methodological progress allowing kinetic monitoring of glycerol liberation has facilitated substrate profiling of the human endocannabinoid hydrolases, and these studies have revealed that the three enzymes have distinct monoacylglycerol substrate and isomer preferences. Here, we have extended this substrate profiling to cover four prostaglandin glycerol esters, namely, 15-deoxy-Δ(12,14)-prostaglandin J2-2-glycerol (15d-PGJ2-G), PGD2-G, PGE2-G, and PGF2 α-G. We found that the three enzymes hydrolyzed the tested substrates, albeit with distinct rates and preferences. Although human ABHD12 (hABHD12) showed only marginal activity toward PGE2-G, hABHD6 preferentially hydrolyzed PGD2-G, and human MAGL (hMAGL) robustly hydrolyzed all four. This was particularly intriguing for MAGL activity toward 15d-PGJ2-G whose hydrolysis rate rivaled that of the best monoacylglycerol substrates. Molecular modeling studies combined with kinetic analysis supported favorable interaction with the hMAGL active site. Long and short MAGL isoforms shared a similar substrate profile, and hMAGL hydrolyzed 15d-PGJ2-G also in living cells. The ability of 15d-PGJ2-G to activate the canonical nuclear factor erythroid 2-related factor (Nrf2) signaling pathway used by 15d-PGJ2 was assessed, and these studies revealed for the first time that 15d-PGJ2 and 15d-PGJ2-G similarly activated Nrf2 signaling as well as transcription of target genes of this pathway. Our study challenges previous claims regarding the ability of MAGL to catalyze PG-G hydrolysis and extend the MAGL substrate profile beyond the classic monoacylglycerols. PMID:25140003

  6. [Electromagnetic urological stimulator].

    PubMed

    Zaslavskiĭ AOi; Markarov, G S; Gelis, Iu S

    1997-01-01

    The paper deals with an electromagnetic urological stimulator which generates a modulated low-frequency electromagnetic field of nonthermal intensity and its brief technical data. It presents a treatment regimen for urolithiasis and recommendations how to use the above therapeutical agent to stimulate urinary function in patients with urolithiasis in order to inoperatively eliminate urinary calculi and sand which form following extracorporeal shockwave lithotripsy.

  7. Stimulating your appetite.

    PubMed

    Whitfield, L

    1998-01-01

    A number of legal and illegal drugs can help stimulate appetite and are used for people with HIV to prevent wasting. Stimulating hunger is important because lower calorie intake and poor absorption of nutrients are associated with wasting. The uses and potential drawbacks of marijuana, thalidomide (Synovir), Marinol, and Megace are described. PMID:11365223

  8. Evidence for a luteotropic role of peroxisome proliferator-activated receptor gamma: expression and in vitro effects on enzymatic and hormonal activities in corpora lutea of pseudopregnant rabbits.

    PubMed

    Zerani, Massimo; Maranesi, Margherita; Brecchia, Gabriele; Gobbetti, Anna; Boiti, Cristiano; Parillo, Francesco

    2013-03-01

    The expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and its role in corpora lutea (CL) function were studied in pseudopregnant rabbits. Corpora lutea were collected at an early stage (Day 4), midstage (Day 9), and late stage (Day 13) of pseudopregnancy. Immunohistochemistry found evidence for the presence of PPARgamma in the perinuclear cytoplasm and nucleus of all the luteal cells; immunoreactivity decreased from the early to the late stage, with immunonegativity of the nuclei of late stage CL. PPARgamma mRNA transcript was expressed in all the luteal stages with the lowest level in the late stage. In CL cultured in vitro, the PPARgamma agonist (15-deoxy delta12,14 prostaglandin J2 [15d-PGJ2], 200 nM) increased and the antagonist (T0070907, 50 nM) decreased progesterone secretion at early and midluteal stages, whereas 15d-PGJ2 reduced and T0070907 increased PGF2alpha at the same stages. Prostaglandin-endoperoxide synthase 2 (PTGS2) activity was reduced by 15d-PGJ2 and increased by T0070907 in CL of early and midluteal stages. Conversely, 15d-PGJ2 increased and T0070907 reduced 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity in early and midluteal stage CL. PGE2 in vitro secretion as well as PTGS1 and 20alpha-HSD enzymatic activities were not affected by 15d-PGJ2 and T0070907 in any CL types. These results indicate that PPARgamma plays a luteotropic role in pseudopregnant rabbits, through PTGS2 down-regulation and 3beta-HSD up-regulation, with a consequent PGF2alpha decrease and progesterone increase.

  9. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2.

    PubMed

    Rajakariar, Ravindra; Hilliard, Mark; Lawrence, Toby; Trivedi, Seema; Colville-Nash, Paul; Bellingan, Geoff; Fitzgerald, Desmond; Yaqoob, Muhammad M; Gilroy, Derek W

    2007-12-26

    Hematopoietic prostaglandin D(2) synthase (hPGD(2)S) metabolizes cyclooxygenase (COX)-derived PGH(2) to PGD(2) and 15-deoxyDelta(12-14) PGJ(2) (15d-PGJ(2)). Unlike COX, the role of hPGD(2)S in host defense is ambiguous. PGD(2) can be either pro- or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ(2) and its relevance to pathophysiology remain controversial. Herein, studies on hPGD(2)S KO mice reveal that 15d-PGJ(2) is synthesized in a self-resolving peritonitis, detected by using liquid chromatography-tandem MS. Together with PGD(2) working on its DP1 receptor, 15d-PGJ(2) controls the balance of pro- vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD(2)S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD(2)S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ(2) is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy. PMID:18077391

  10. Optically stimulated luminescence dosimetry

    NASA Astrophysics Data System (ADS)

    McKeever, Stephen W. S.

    2001-09-01

    Models and the conceptual framework necessary for an understanding of optically stimulated luminescence (OSL) are described. Examples of various OSL readout schemes are described, along with examples of the use of OSL in radiation dosimetry.

  11. Deep brain stimulation

    MedlinePlus

    ... the brain The neurostimulator, which puts out the electric current. The stimulator is similar to a heart pacemaker . It is usually placed under the skin near the collarbone, but may be ... pulses travel from the neurostimulator, along the extension ...

  12. ACTH stimulation test

    MedlinePlus

    ... Groot LJ, de Kretser DM, et al, eds. Endocrinology: Adult and Pediatric . 7th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 102. Chernecky CC, Berger BJ. ACTH stimulation test - diagnostic. In: ... . 13th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap ...

  13. Geothermal Well Stimulation

    SciTech Connect

    Campbell, D. A.; Morris, C. W.; Sinclair, A. R.; Hanold, R. J.; Vetter, O. J.

    1981-03-01

    The stimulation of geothermal wells presents some new and challenging problems. Formation temperatures in the 300-600 F range can be expected. The behavior of stimulation fluids, frac proppants, and equipment at these temperatures in a hostile brine environment must be carefully evaluated before performance expectations can be determined. In order to avoid possible damage to the producing horizon of the formation, high temperature chemical compatibility between the in situ materials and the stimulation materials must be verified. Perhaps most significant of all, in geothermal wells the required techniques must be capable of bringing about the production of very large amounts of fluid. This necessity for high flow rates represents a significant departure from conventional petroleum well stimulation and demands the creation of very high near-wellbore permeability and/or fractures with very high flow conductivity.

  14. Cleome rutidosperma and Euphorbia thymifolia Suppress Inflammatory Response via Upregulation of Phase II Enzymes and Modulation of NF-κB and JNK Activation in LPS-Stimulated BV2 Microglia.

    PubMed

    Ding, Hsiou-Yu; Wu, Pei-Shan; Wu, Ming-Jiuan

    2016-01-01

    Cleome rutidosperma DC. and Euphorbia thymifolia L. are herbal medicines used in traditional Indian and Chinese medicine to treat various illnesses. Reports document that they have antioxidant and anti-inflammatory activities; nonetheless, the molecular mechanisms involved in their anti-inflammatory actions have not yet been elucidated. The anti-neuroinflammatory activities and underlying mechanisms of ethanol extracts of Cleome rutidosperma (CR) and Euphorbia thymifolia (ET) were studied using lipopolysaccharide (LPS)-stimulated microglial cell line BV2. The morphology changes and production of pro-inflammatory mediators were assayed. Gene expression of inflammatory genes such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1β, and CC chemokine ligand (CCL)-2, as well as phase II enzymes such as heme oxygenase (HO)-1, the modifier subunit of glutamate cysteine ligase (GCLM) and NAD(P)H quinone dehydrogenase 1 (NQO1), were further investigated using reverse transcription quantitative-PCR (RT-Q-PCR) and Western blotting. The effects of CR and ET on mitogen activated protein kinases (MAPKs) and nuclear factor (NF)-κB signaling pathways were examined using Western blotting and specific inhibitors. CR and ET suppressed BV2 activation, down-regulated iNOS and COX-2 expression and inhibited nitric oxide (NO) overproduction without affecting cell viability. They reduced LPS-mediated tumor necrosis factor (TNF) and IL-6 production, attenuated IL-1β and CCL2 expression, but upregulated HO-1, GCLM and NQO1 expression. They also inhibited p65 NF-κB phosphorylation and modulated Jun-N terminal kinase (JNK) activation in BV2 cells. SP600125, the JNK inhibitor, significantly augmented the anti-IL-6 activity of ET. NF-κB inhibitor, Bay 11-7082, enhanced the anti-IL-6 effects of both CR and ET. Znpp, a competitive inhibitor of HO-1, attenuated the anti-NO effects of CR and ET. Our results show that CR and ET exhibit anti

  15. Cleome rutidosperma and Euphorbia thymifolia Suppress Inflammatory Response via Upregulation of Phase II Enzymes and Modulation of NF-κB and JNK Activation in LPS-Stimulated BV2 Microglia

    PubMed Central

    Ding, Hsiou-Yu; Wu, Pei-Shan; Wu, Ming-Jiuan

    2016-01-01

    Cleome rutidosperma DC. and Euphorbia thymifolia L. are herbal medicines used in traditional Indian and Chinese medicine to treat various illnesses. Reports document that they have antioxidant and anti-inflammatory activities; nonetheless, the molecular mechanisms involved in their anti-inflammatory actions have not yet been elucidated. The anti-neuroinflammatory activities and underlying mechanisms of ethanol extracts of Cleome rutidosperma (CR) and Euphorbia thymifolia (ET) were studied using lipopolysaccharide (LPS)-stimulated microglial cell line BV2. The morphology changes and production of pro-inflammatory mediators were assayed. Gene expression of inflammatory genes such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1β, and CC chemokine ligand (CCL)-2, as well as phase II enzymes such as heme oxygenase (HO)-1, the modifier subunit of glutamate cysteine ligase (GCLM) and NAD(P)H quinone dehydrogenase 1 (NQO1), were further investigated using reverse transcription quantitative-PCR (RT-Q-PCR) and Western blotting. The effects of CR and ET on mitogen activated protein kinases (MAPKs) and nuclear factor (NF)-κB signaling pathways were examined using Western blotting and specific inhibitors. CR and ET suppressed BV2 activation, down-regulated iNOS and COX-2 expression and inhibited nitric oxide (NO) overproduction without affecting cell viability. They reduced LPS-mediated tumor necrosis factor (TNF) and IL-6 production, attenuated IL-1β and CCL2 expression, but upregulated HO-1, GCLM and NQO1 expression. They also inhibited p65 NF-κB phosphorylation and modulated Jun-N terminal kinase (JNK) activation in BV2 cells. SP600125, the JNK inhibitor, significantly augmented the anti-IL-6 activity of ET. NF-κB inhibitor, Bay 11-7082, enhanced the anti-IL-6 effects of both CR and ET. Znpp, a competitive inhibitor of HO-1, attenuated the anti-NO effects of CR and ET. Our results show that CR and ET exhibit anti

  16. Vagus Nerve Stimulation

    PubMed Central

    Howland, Robert H.

    2014-01-01

    The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuroendocrine-immune axis to maintain homeostasis through its afferent and efferent pathways. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve, including manual or electrical stimulation. Left cervical VNS is an approved therapy for refractory epilepsy and for treatment resistant depression. Right cervical VNS is effective for treating heart failure in preclinical studies and a phase II clinical trial. The effectiveness of various forms of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, metabolic syndrome, and heart disease might be mediated by the vagus nerve. VNS deserves further study for its potentially favorable effects on cardiovascular, cerebrovascular, metabolic, and other physiological biomarkers associated with depression morbidity and mortality. PMID:24834378

  17. New York Canyon Stimulation

    SciTech Connect

    Raemy, Bernard

    2012-06-21

    The New York Canyon Stimulation Project was to demonstrate the commercial application of Enhanced Geothermal System techniques in Buena Vista Valley area of Pershing County, Nevada. From October 2009 to early 2012, TGP Development Company aggressively implemented Phase I of Pre-Stimulation and Site/Wellbore readiness. This included: geological studies; water studies and analyses and procurement of initial permits for drilling. Oversubscription of water rights and lack of water needed for implementation of EGS were identified and remained primary obstacles. Despite extended efforts to find alternative solutions, the water supply circumstances could not be overcome and led TGP to determine a "No Go" decision and initiate project termination in April 2012.

  18. Muscle Stimulation Technology

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Under a Goddard Space Flight Center contract, Electrologic of America was able to refine the process of densely packing circuitry on personal computer boards, providing significant contributions to the closed-loop systems for the Remote Manipulator System Simulator. The microcircuitry work was then applied to the StimMaster FES Ergometer, an exercise device used to stimulate muscles suffering from paralysis. The electrical stimulation equipment was developed exclusively for V-Care Health Systems, Inc. Product still commercially available as of March 2002.

  19. What does galvanic vestibular stimulation stimulate?

    PubMed

    Wardman, Daniel L; Fitzpatrick, Richard C

    2002-01-01

    The technique of galvanic vestibular stimulation (GVS) has been used for a long time. The stimulus produces stereotyped automatic postural and ocular responses. The mechanisms underlying these responses are not understood although they are commonly attributed to altered otolith output. Based on animal studies, it seems reasonable to assume that vestibular afferents from the otoliths and semicircular canals are affected similarly by GVS. With this assumption, and anatomical knowledge of the vestibular apparatus, a model is developed to describe the expected responses of vestibular afferents to percutaneous GVS and the physiological implications of this altered sensory signal. Bilateral bipolar GVS, the most commonly used technique, should produce a canal signal consistent with a strong ear-down roll towards the cathodal side, a smaller nose-to-cathode yaw, but no pitch signal. Bilateral bipolar GVS should also produce an otolith signal consistent with tilt towards the cathodal side or a translational acceleration towards the anodal side. The expected responses for other configurations of GVS are also described. The model appears consistent with published data on the ocular and postural responses to GVS, and suggests other testable hypotheses concerning postural, ocular and perceptual responses to GVS.

  20. Transcranial brain stimulation: closing the loop between brain and stimulation

    PubMed Central

    Karabanov, Anke; Thielscher, Axel; Siebner, Hartwig Roman

    2016-01-01

    Purpose of review To discuss recent strategies for boosting the efficacy of noninvasive transcranial brain stimulation to improve human brain function. Recent findings Recent research exposed substantial intra- and inter-individual variability in response to plasticity-inducing transcranial brain stimulation. Trait-related and state-related determinants contribute to this variability, challenging the standard approach to apply stimulation in a rigid, one-size-fits-all fashion. Several strategies have been identified to reduce variability and maximize the plasticity-inducing effects of noninvasive transcranial brain stimulation. Priming interventions or paired associative stimulation can be used to ‘standardize’ the brain-state and hereby, homogenize the group response to stimulation. Neuroanatomical and neurochemical profiling based on magnetic resonance imaging and spectroscopy can capture trait-related and state-related variability. Fluctuations in brain-states can be traced online with functional brain imaging and inform the timing or other settings of transcranial brain stimulation. State-informed open-loop stimulation is aligned to the expression of a predefined brain state, according to prespecified rules. In contrast, adaptive closed-loop stimulation dynamically adjusts stimulation settings based on the occurrence of stimulation-induced state changes. Summary Approaches that take into account trait-related and state-related determinants of stimulation-induced plasticity bear considerable potential to establish noninvasive transcranial brain stimulation as interventional therapeutic tool. PMID:27224087

  1. Electromechanical Nerve Stimulator

    NASA Technical Reports Server (NTRS)

    Tcheng, Ping; Supplee, Frank H., Jr.; Prass, Richard L.

    1993-01-01

    Nerve stimulator applies and/or measures precisely controlled force and/or displacement to nerve so response of nerve measured. Consists of three major components connected in tandem: miniature probe with spherical tip; transducer; and actuator. Probe applies force to nerve, transducer measures force and sends feedback signal to control circuitry, and actuator positions force transducer and probe. Separate box houses control circuits and panel. Operator uses panel to select operating mode and parameters. Stimulator used in research to characterize behavior of nerve under various conditions of temperature, anesthesia, ventilation, and prior damage to nerve. Also used clinically to assess damage to nerve from disease or accident and to monitor response of nerve during surgery.

  2. Optically stimulated luminescence dosimetry

    NASA Astrophysics Data System (ADS)

    McKeever, Stephen W.

    1999-02-01

    Optically Stimulated Luminescence (OSL) dosimetry is attractive to the health physics and dosimetry community due to its all-optical character, fast data acquisition and the avoidance of heating the detector. Until recently there was no luminescent material sensitive enough to radiation, and at the same time suitable for stimulation with visible light, for use in this application. However, anion-deficient aluminum oxide doped with carbon (Al2O3:C) appears to be not only an extremely sensitive thermoluminescence (TL) material, but is also well-suited to OSL applications. Several OSL readout protocols have been suggested, including cw-OSL, pulsed OSL (POSL), and 'delayed' OSL (DOSL). The paper discusses the physical mechanisms that give rise to the OSL signals and the dependence of these signals upon absorbed dose. Example applications of the use of OSL from Al2O3:C in environmental radiation and ultraviolet-B dosimetry are discussed.

  3. Sacral nerve stimulation.

    PubMed

    Matzel, K E; Stadelmaier, U; Besendörfer, M

    2004-01-01

    The current concept of recruiting residual function of an inadequate pelvic organ by electrostimulation involves stimulation of the sacral spinal nerves at the level of the sacral canal. The rationale for applying SNS to fecal incontinence was based on clinical observations of its effect on bowel habits and anorectal continence function in urologic patients (increased anorectal angulation and anal canal closure pressure) and on anatomic considerations: dissection demonstrated a dual peripheral nerve supply of the striated pelvic floor muscles that govern these functions. Because the sacral spinal nerve site is the most distal common location of this dual nerve supply, stimulating here can elicit both functions. Since the first application of SNS in fecal incontinence in 1994, this technique has been improved, the patient selection process modified, and the spectrum of indications expanded. At present SNS has been applied in more than 1300 patients with fecal incontinence limited.

  4. Cognitive stimulation in brainstorming.

    PubMed

    Dugosh, K L; Paulus, P B; Roland, E J; Yang, H C

    2000-11-01

    Research on group brainstorming has demonstrated that it is less effective for generating large numbers of ideas than individual brainstorming, yet various scholars have presumed that group idea sharing should enhance cognitive stimulation and idea production. Three experiments examined the potential of cognitive stimulation in brainstorming. Experiments 1 and 2 used a paradigm in which individuals were exposed to ideas on audiotape as they were brainstorming, and Experiment 3 used the electronic brainstorming paradigm. Evidence was obtained for enhanced idea generation both during and after idea exposure. The attentional set of the participant and the content of the exposure manipulation (number of ideas, presence of irrelevant information) influenced this effect. These results are consistent with a cognitive perspective on group brainstorming.

  5. Stimulated Raman photoacoustic imaging

    PubMed Central

    Yakovlev, Vladislav V.; Zhang, Hao F.; Noojin, Gary D.; Denton, Michael L.; Thomas, Robert J.; Scully, Marlan O.

    2010-01-01

    Achieving label-free, molecular-specific imaging with high spatial resolution in deep tissue is often considered the grand challenge of optical imaging. To accomplish this goal, significant optical scattering in tissues has to be overcome while achieving molecular specificity without resorting to extrinsic labeling. We demonstrate the feasibility of developing such an optical imaging modality by combining the molecularly specific stimulated Raman excitation with the photoacoustic detection. By employing two ultrashort excitation laser pulses, separated in frequency by the vibrational frequency of a targeted molecule, only the specific vibrational level of the target molecules in the illuminated tissue volume is excited. This targeted optical absorption generates ultrasonic waves (referred to as stimulated Raman photoacoustic waves) which are detected using a traditional ultrasonic transducer to form an image following the design of the established photoacoustic microscopy. PMID:21059930

  6. Raft River well stimulation experiments: geothermal reservoir well stimulation program

    SciTech Connect

    Not Available

    1980-08-01

    The Geothermal Reservoir Well Stimulation Program (GRWSP) performed two field experiments at the Raft River KGRA in 1979. Wells RRGP-4 and RRGP-5 were selected for the hydraulic fracture stimulation treatments. The well selection process, fracture treatment design, field execution, stimulation results, and pre- and post-job evaluations are presented.

  7. Human Tissue Stimulator

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Neurodyne Corporation Human Tissue Stimulator (HTS) is a totally implantable system used for treatment of chronic pain and involuntary motion disorders by electrical stimulation. It was developed by Pacesetter Systems, Inc. in cooperation with the Applied Physics Laboratory. HTS incorporates a nickel cadmium battery, telemetry and command systems technologies of the same type as those used in NASA's Small Astronomy Satellite-3 in microminiature proportions so that the implantable element is the size of a deck of cards. The stimulator includes a rechargeable battery, an antenna and electronics to receive and process commands and to report on its own condition via telemetry, a wireless process wherein instrument data is converted to electrical signals and sent to a receiver where signals are presented as usable information. The HTS is targeted to nerve centers or to particular areas of the brain to provide relief from intractable pain or arrest involuntary motion. The nickel cadmium battery can be recharged through the skin. The first two HTS units were implanted last year and have been successful. Extensive testing is required before HTS can be made available for general use.

  8. Eicosanoid modulation by the short-chain fatty acid n-butyrate in human monocytes.

    PubMed

    Kovarik, Johannes J; Hölzl, Markus A; Hofer, Johannes; Waidhofer-Söllner, Petra; Sobanov, Yury; Koeffel, René; Saemann, Marcus D; Mechtcheriakova, Diana; Zlabinger, Gerhard J

    2013-07-01

    n-Butyrate deriving from bacterial fermentation in the mammalian intestine is a key determinant in gastrointestinal homeostasis. We examined the effects of this short-chain fatty acid and Toll-like receptor 2 (TLR) and TLR4 engagement on inflammatory/immunity-associated genes, cyclo-oxygenases (COXs), prostaglandins (PGs) and leukotrienes (LTs) in human monocytes. Before RNA isolation, freshly isolated human monocytes were co-incubated for different time-points with 1 mm n-butyrate alone or in combination with bacterial stimuli. Based on a knowledge-driven approach, a signature of 180 immunity/inflammation-associated genes was picked and real-time PCR analysis was performed. Pathway analysis was carried out using a web-based database analysing program. Based on these gene expression studies the findings were evaluated at the protein/mediator level by Western blot analysis, FACS and ELISA. Following co-incubation with n-butyrate and lipopolysaccharide, key enzymes of the eicosanoid pathway, like PTGS2 (COX-2), TXS, ALOX5, LTA4H and LTC4S, were significantly up-regulated compared with stimulation with lipopolysaccharide alone. Furthermore, release of the lipid mediators PGE(2), 15d-PGJ(2), LTB(4) and thromboxane B(2) was increased by n-butyrate. Regarding signalling, n-butyrate had no additional effect on mitogen-activated protein kinase and interfered differently with early and late phases of nuclear factor-κB signalling. Our results suggest that among many other mediators of eicosanoid signalling n-butyrate massively induces PGE(2) production by increasing the expression of PTGS2 (COX-2) in monocytes following TLR4 and TLR2 activation and induces secretion of LTB(4) and thromboxane B(2). This underscores the role of n-butyrate as a crucial mediator of gut-specific immunity.

  9. Expression of Peroxisome Proliferator-Activated Receptor γ (PPARγ) in Human Transitional Bladder Cancer and its Role in Inducing Cell Death1

    PubMed Central

    Guan, You-Fei; Zhang, Ya-Hua; Breyer, Richard M; Davis, Linda; Breyer, Matthew D

    1999-01-01

    Abstract The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), in human bladder cancers. In situ hybridization shows that PPARγ mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARγ was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor α (RXRα), a 9-cis-retinoic acid stimulated (9-cis-RA) heterodimeric partner of PPARγ, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARγ agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRα ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPARγ activators, ciglitazone and 15-deoxy-Δ2,14-PGJ2 (15dPGJ2). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, P21WAF1/CIP1 and p16INK4, and reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARγ target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP), the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARγ is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers. PMID:10935488

  10. Regulation of hemeoxygenase-1 gene expression by Nrf2 and c-Jun in tertiary butylhydroquinone-stimulated rat primary astrocytes

    SciTech Connect

    Park, Jin-Sun; Kim, Hee-Sun

    2014-05-16

    Highlights: • tBHQ increased HO-1 mRNA and protein levels in rat primary astrocytes. • tBHQ enhanced HO-1 gene transcription in an ARE-dependent manner. • tBHQ increased the nuclear translocation and DNA binding of Nrf2 and c-Jun to ARE. • Nrf2 and c-Jun are involved in the differential modulation of HO-1 expression. • Nrf2 and c-Jun regulate HO-1 expression via their coordinated interaction. - Abstract: Hemeoxygenase-1 (HO-1) is a phase II antioxidant enzyme that is primarily involved in detoxification and cytoprotection in a variety of tissues. However, the mechanism underlying HO-1 gene expression remains unclear. In the present study, we investigated the regulation of HO-1 expression in primary cultured astrocytes by using the natural antioxidant compound tertiary butylhydroquinone (tBHQ). We found that tBHQ increased HO-1 mRNA and protein levels. Promoter analysis revealed that tBHQ enhanced HO-1 gene transcription in an antioxidant response element (ARE)-dependent manner. In addition, tBHQ increased the nuclear translocation and DNA binding of Nrf2 and c-Jun to ARE. Small interfering RNA (siRNA) experiments demonstrated that Nrf2 and c-Jun are involved in the differential modulation of HO-1 expression. Thus, Nrf2 knockdown reduced the basal level of HO-1 expression but did not affect the fold induction by tBHQ. On the other hand, knockdown of c-Jun diminished tBHQ-mediated induction of HO-1 without affecting basal expression. The data suggest that Nrf2 generally modulates the basal expression of HO-1, while c-Jun mediates HO-1 induction in response to tBHQ. The results of co-immunoprecipitation assays demonstrated a physical interaction between Nrf2 and c-Jun in tBHQ-treated astrocytes. The results suggest that Nrf2 and c-Jun regulate HO-1 expression via their coordinated interaction in tBHQ-treated rat primary astrocytes.

  11. Stimulated parametric emission microscopy

    NASA Astrophysics Data System (ADS)

    Isobe, Keisuke; Kataoka, Shogo; Murase, Rena; Watanabe, Wataru; Higashi, Tsunehito; Kawakami, Shigeki; Matsunaga, Sachihiro; Fukui, Kiichi; Itoh, Kazuyoshi

    2006-01-01

    We propose a novel microscopy technique based on the four-wave mixing (FWM) process that is enhanced by two-photon electronic resonance induced by a pump pulse along with stimulated emission induced by a dump pulse. A Ti:sapphire laser and an optical parametric oscillator are used as light sources for the pump and dump pulses, respectively. We demonstrate that our proposed FWM technique can be used to obtain a one-dimensional image of ethanol-thinned Coumarin 120 solution sandwiched between a hole-slide glass and a cover slip, and a two-dimensional image of a leaf of Camellia sinensis.

  12. Dorsal column stimulator applications

    PubMed Central

    Yampolsky, Claudio; Hem, Santiago; Bendersky, Damián

    2012-01-01

    Background: Spinal cord stimulation (SCS) has been used to treat neuropathic pain since 1967. Following that, technological progress, among other advances, helped SCS become an effective tool to reduce pain. Methods: This article is a non-systematic review of the mechanism of action, indications, results, programming parameters, complications, and cost-effectiveness of SCS. Results: In spite of the existence of several studies that try to prove the mechanism of action of SCS, it still remains unknown. The mechanism of action of SCS would be based on the antidromic activation of the dorsal column fibers, which activate the inhibitory interneurons within the dorsal horn. At present, the indications of SCS are being revised constantly, while new applications are being proposed and researched worldwide. Failed back surgery syndrome (FBSS) is the most common indication for SCS, whereas, the complex regional pain syndrome (CRPS) is the second one. Also, this technique is useful in patients with refractory angina and critical limb ischemia, in whom surgical or endovascular treatment cannot be performed. Further indications may be phantom limb pain, chronic intractable pain located in the head, face, neck, or upper extremities, spinal lumbar stenosis in patients who are not surgical candidates, and others. Conclusion: Spinal cord stimulation is a useful tool for neuromodulation, if an accurate patient selection is carried out prior, which should include a trial period. Undoubtedly, this proper selection and a better knowledge of its underlying mechanisms of action, will allow this cutting edge technique to be more acceptable among pain physicians. PMID:23230533

  13. Central nervous system stimulants.

    PubMed

    George, A J

    2000-03-01

    Three major types of CNS stimulant are currently abused in sport: amphetamine, cocaine and caffeine. Each drug type has its own characteristic mechanism of action on CNS neurones and their associated receptors and nerve terminals. Amphetamine is widely abused in sports requiring intense anaerobic exercise where it prolongs the tolerance to anaerobic metabolism. It is addictive, and chronic abuse causes marked behavioural change and sometimes psychosis. Major sports abusing amphetamine are cycling, American football, ice-hockey and baseball. Cocaine increases tolerance to intense exercise, yet most of its chronic effects on energy metabolism are negative. Its greatest effects seem to be as a central stimulant and the enhancement of short-term anaerobic exercise. It is highly addictive and can cause cerebral and cardiovascular fatalities. Caffeine enhances fatty acid metabolism leading to glucose conservation, which appears to benefit long-distance endurance events such as skiing. Caffeine is also addictive, and chronic abuse can lead to cardiac damage. Social abuse of each of the three drugs is often difficult to distinguish from their abuse in sport.

  14. Identification of heme oxygenase-1 stimulators by a convenient ELISA-based bilirubin quantification assay.

    PubMed

    Rücker, Hannelore; Amslinger, Sabine

    2015-01-01

    The upregulation of heme oxygenase-1 (HO-1) has proven to be a useful tool for fighting inflammation. In order to identify new HO-1 inducers, an efficient screening method was developed which can provide new lead structures for drug research. We designed a simple ELISA-based HO-1 enzyme activity assay, which allows for the screening of 12 compounds in parallel in the setting of a 96-well plate. The well-established murine macrophage cell line RAW264.7 is used and only about 26µg of protein from whole cell lysates is needed for the analysis of HO-1 activity. The quantification of HO-1 activity is based on an indirect ELISA using the specific anti-bilirubin antibody 24G7 to quantify directly bilirubin in the whole cell lysate, applying a horseradish peroxidase-tagged antibody together with ortho-phenylenediamine and H2O2 for detection. The bilirubin is produced on the action of HO enzymes by converting their substrate heme to biliverdin and additional recombinant biliverdin reductase together with NADPH at pH 7.4 in buffer. This sensitive assay allows for the detection of 0.57-82pmol bilirubin per sample in whole cell lysates. Twenty-three small molecules, mainly natural products with an α,β-unsaturated carbonyl unit such as polyphenols, including flavonoids and chalcones, terpenes, an isothiocyanate, and the drug oltipraz were tested at typically 6 or 24h incubation with RAW264.7 cells. The activity of known HO-1 inducers was confirmed, while the chalcones cardamonin, flavokawain A, calythropsin, 2',3,4'-trihydroxy-4-methoxychalcone (THMC), and 2',4'-dihydroxy-3,4-dimethoxychalcone (DHDMC) were identified as new potent HO-1 inducers. The highest inductive power after 6h incubation was found at 10µM for DHDMC (6.1-fold), carnosol (3.9-fold), butein (3.1-fold), THMC (2.9-fold), and zerumbone (2.5-fold). Moreover, the time dependence of HO-1 protein production for DHDMC was compared to its enzyme activity, which was further evaluated in the presence of

  15. A linearized current stimulator for deep brain stimulation.

    PubMed

    Shen, Ding-Lan; Chu, Yu-Jung

    2010-01-01

    This paper develops the front end of the stimulator which is applied in the implantable deep brain stimulation (DBS) for the therapy of Parkinson's disease. This stimulator adopts the low power switched-capacitor DAC accompanying with voltage-to-current transconductance amplifiers to obtain the adjustable output currents. The proposed distortion cancellation technique improves the linearity of the current stimulator. Multiple transconductance amplifiers sharing a single DAC save the circuit area. The biphasic stimulation waveform is generated from the bridge switching technique and the programmable pulse. This stimulation circuit provides the 0 approximately 165 microA current for a typical loading of 10 kΩ, 8 approximately 120 micros pulse width, and 126 approximately 244 Hz frequencies with a 0.35 microm CMOS technology at 3.3 V supply voltage. PMID:21096724

  16. Engagement Sensitive Visual Stimulation.

    PubMed

    Kumar, Deepesh; Dutta, Anirban; Das, Abhijit; Lahiri, Uttama

    2016-06-13

    Stroke is one of leading cause of death and disability worldwide. Early detection during golden hour and treatment of individual neurological dysfunction in stroke using easy-to-access biomarkers based on a simple-to-use, cost-effective, clinically-valid screening tool can bring a paradigm shift in healthcare, both urban and rural. In our research we have designed a quantitative automatic home-based oculomotor assessment tool that can play an important complementary role in prognosis of neurological disorders like stroke for the neurologist. Once the patient has been screened for stroke, the next step is to design proper rehabilitation platform to alleviate the disability. In addition to the screening platform, in our research, we work in designing virtual reality based rehabilitation exercise platform that has the potential to deliver visual stimulation and in turn contribute to improving one's performance. PMID:27478569

  17. Stimulated radiative laser cooling

    NASA Astrophysics Data System (ADS)

    Muys, P.

    2008-04-01

    Building a refrigerator based on the conversion of heat into optical energy is an ongoing engineering challenge. Under well-defined conditions, spontaneous anti-Stokes fluorescence of a dopant material in a host matrix is capable of lowering the host temperature. The fluorescence is conveying away a part of the thermal energy stored in the vibrational oscillations of the host lattice. In particular, applying this principle to the cooling of (solid-state) lasers opens up many potential device applications, especially in the domain of high-power lasers. In this paper, an alternative optical cooling scheme is outlined, leading to the radiative cooling of solid-state lasers. It is based on converting the thermal energy stored in the host into optical energy by means of a stimulated nonlinear process, rather than a spontaneous process. This should lead to better cooling efficiencies and a higher potential of applying the principle for device applications.

  18. Stimulated rotational Raman scattering

    NASA Astrophysics Data System (ADS)

    Parazzoli, C. G.; Rafanelli, G. L.; Capps, D. M.; Drutman, C.

    1989-03-01

    The effect of Stimulated Rotational Raman Scattering (SRRS) processes on high energy laser directed energy weapon systems was studied. The program had 3 main objectives; achieving an accurate description of the physical processes involved in SRRS; developing a numerical algorithm to confidently evaluate SRRS-induced losses in the propagation of high energy laser beams in the uplink and downlink segments of the optical trains of various strategic defense system scenarios; and discovering possible methods to eliminate, or at least reduce, the deleterious effects of SRRS on the energy deposition on target. The following topics are discussed: the motivation for the accomplishments of the DOE program; the Semiclassical Theory of Non-Resonant SRRS for Diatomic Homonuclear Molecules; and then the following appendices; Calculation of the Dipole Transition Reduced Matrix Element, Guided Tour of Hughes SRRS Code, Running the Hughes SRRS Code, and Hughes SRRS Code Listing.

  19. Myeloperoxidase Stimulates Neutrophil Degranulation.

    PubMed

    Grigorieva, D V; Gorudko, I V; Sokolov, A V; Kostevich, V A; Vasilyev, V B; Cherenkevich, S N; Panasenko, O M

    2016-08-01

    Myeloperoxidase, heme enzyme of azurophilic granules in neutrophils, is released into the extracellular space in the inflammation foci. In neutrophils, it stimulates a dose-dependent release of lactoferrin (a protein of specific granules), lysozyme (a protein of specific and azurophilic granules), and elastase (a protein of azurophilic granules). 4-Aminobenzoic acid hydrazide, a potent inhibitor of peroxidase activity of myeloperoxidase, produced no effect on neutrophil degranulation. Using signal transduction inhibitors (genistein, methoxyverapamil, wortmannin, and NiCl2), we demonstrated that myeloperoxidase-induced degranulation of neutrophils resulted from enzyme interaction with the plasma membrane and depends on activation of tyrosine kinases, phosphatidylinositol 3-kinases (PI3K), and calcium signaling. Myeloperoxidase modified by oxidative/halogenation stress (chlorinated and monomeric forms of the enzyme) lost the potency to activate neutrophil degranulation. PMID:27597056

  20. Engagement Sensitive Visual Stimulation

    PubMed Central

    Kumar, Deepesh; Dutta, Anirban; Das, Abhijit; Lahiri, Uttama

    2016-01-01

    Stroke is one of leading cause of death and disability worldwide. Early detection during golden hour and treatment of individual neurological dysfunction in stroke using easy-to-access biomarkers based on a simple-to-use, cost-effective, clinically-valid screening tool can bring a paradigm shift in healthcare, both urban and rural. In our research we have designed a quantitative automatic home-based oculomotor assessment tool that can play an important complementary role in prognosis of neurological disorders like stroke for the neurologist. Once the patient has been screened for stroke, the next step is to design proper rehabilitation platform to alleviate the disability. In addition to the screening platform, in our research, we work in designing virtual reality based rehabilitation exercise platform that has the potential to deliver visual stimulation and in turn contribute to improving one’s performance. PMID:27478569

  1. Spiral scan peripheral nerve stimulation.

    PubMed

    King, K F; Schaefer, D J

    2000-07-01

    Time-varying magnetic fields induce electric fields that can cause physiological stimulation. Stimulation has been empirically characterized as a function of dB/dt and duration based on experiments using trapezoidal and sinusoidal gradient waveforms with constant ramp time, amplitude, and direction. For two-dimensional (2D) spiral scans, the readout gradient waveforms are frequency- and amplitude-modulated sinusoids on two orthogonal axes in quadrature. The readout gradient waveform therefore rotates with amplitude and angular velocity that are generally not constant. It does not automatically follow that spiral stimulation thresholds can be predicted using available stimulation models. We scanned 18 normal volunteers with a 2D spiral scan and measured global thresholds for axial, sagittal, and coronal planes. We concluded that the stimulation model evaluated accurately predicts slew rate-limited spiral mean stimulation thresholds, if the effective ramp time is chosen to be the half-period at the end of the spiral readout.

  2. Hydromechanical stimulation of bioluminescent plankton.

    PubMed

    Blaser, Stefan; Kurisu, Futoshi; Satoh, Hiroyasu; Mino, Takashi

    2002-01-01

    The response of the bioluminescent dinoflagellate Pyrocystis fusiformis was investigated for different hydraulic conditions ('hydromechanical stimulation'). Pipe flow and oscillating shear produced luminescence, whereas changes in hydrostatic pressure were not stimulating. More intense fluid motion led to higher intensity, mainly due to a higher probability of cell response. The organism was also able to emit light in a glucose-salt mixture. The experiments suggest that the cells are effectively stimulated if the flow conditions change in time.

  3. AN ELISA ASSAY FOR HEME OXYGENASE (HO-1)

    EPA Science Inventory

    An ELISA assay for heme oxygenase (HO-l )

    Abstract

    A double antibody capture ELISA for the HO-l protein has been developed to separately quantitate HO-I protein. The use of 2.5% NP40 detergent greatly assists in freeing HO-l protein from membranes and/or other cel...

  4. Optically stimulated differential impedance spectroscopy

    DOEpatents

    Maxey, Lonnie C; Parks, II, James E; Lewis, Sr., Samuel A; Partridge, Jr., William P

    2014-02-18

    Methods and apparatuses for evaluating a material are described. Embodiments typically involve use of an impedance measurement sensor to measure the impedance of a sample of the material under at least two different states of illumination. The states of illumination may include (a) substantially no optical stimulation, (b) substantial optical stimulation, (c) optical stimulation at a first wavelength of light, (d) optical stimulation at a second wavelength of light, (e) a first level of light intensity, and (f) a second level of light intensity. Typically a difference in impedance between the impedance of the sample at the two states of illumination is measured to determine a characteristic of the material.

  5. Electrical stimulation: a societal perspective.

    PubMed

    Gater, D R; McDowell, S M; Abbas, J J

    2000-01-01

    Societal perspective on functional electrical stimulation is colored by media influence, popular thought, and political climate as much as by the science that supports it. The purpose of this article is to examine how these influences facilitate or inhibit the application of electrical stimulation in today's world and to describe the challenges facing the use of electrical stimulation in the future. Emphasis will be placed on perceived need, cost, and available resources and how these factors must be addressed to utilize functional electrical stimulation successfully in society.

  6. Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

    PubMed

    Sun, Bao-liang; He, Mei-qing; Han, Xiang-yu; Sun, Jing-yi; Yang, Ming-feng; Yuan, Hui; Fan, Cun-dong; Zhang, Shuai; Mao, Lei-lei; Li, Da-wei; Zhang, Zong-yong; Zheng, Cheng-bi; Yang, Xiao-yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

  7. Atomic oxygen stimulated outgassing

    NASA Technical Reports Server (NTRS)

    Linton, Roger C.; Reynolds, John M.

    1991-01-01

    The passive Long Duration Exposure Facility (LDEF) Experiment A0034, Atomic Oxygen Simulated Outgassing, consisted of two identical one-sixth tray modules, exposing selected thermal control coatings to atomic oxygen and the combined space environment on the leading edge and, for reference, to the relative wake environment on the trailing edge. Optical mirrors were included adjacent to the thermal coatings for deposition of outgassing products. Ultraviolet grade windows and metal covers were provided for additional assessment of the effects of the various environmental factors. Preliminary results indicate that orbital atomic oxygen is both a degrading and a optically restorative factor in the thermo-optical properties of selected thermal coatings. There is evidence of more severe optical degradation on collector mirrors adjacent to coatings that were exposed to the RAM-impinging atomic oxygen. This evidence of atomic oxygen stimulated outgassing is discussed in relation to alternative factors that could affect degradation. The general effects of the space environment on the experiment hardware as well as the specimens are discussed.

  8. EOR by stimulated microflora

    SciTech Connect

    Svarovskaya, L.I.; Altunina, L.K.; Rozhenkova, Z.A.; Bulavin, V.D.

    1995-12-31

    A combined microbiological and physico-chemical method for EOR has been developed for flooded West Siberia oil fields with formation temperature of 45{degrees}-95{degrees}C (318-365K). Formation water includes rich and various biocenoses numbering up to 2 x 10{sup 7} cells per ml. Representatives of genera, i.e, Pseudomonas, Bacillus, Actinomyces, Micrococcus, Mycobacterium, Sarcina, etc. were found to be the most widely distributed microorganisms. The method is based on injection of systems exhibiting high oil displacing capacity and at the same time being an additional nitrous nutrient for endemic populations of microorganisms. Their injection into formation water favors biomass growth by 4-6 orders and promotes syntheses of biosurfactants, biopolymers, acids, etc., and gaseous products. The features of residual oil displacement have been studied on laboratory models using a combined microbiological and physico-chemical method. A curve for the yield of residual oil is presented by two peaks. The first peak is stipulated by the washing action of oil displacement system, and the second one by the effect of metabolites produced at stimulation of biogenic processes. Oil displacement index increases by 15%-30%.

  9. Subliminal Stimulation: Hoax or Reality?

    ERIC Educational Resources Information Center

    Trank, Douglas M.

    Subliminal stimulation is defined as that which is perceived by an individual below the threshold of awareness or cognizance. This article traces the history of research in subliminal stimulation to illustrate that under certain circumstances and conditions, this behavioral phenomenon does occur. Although subliminal stimuli do affect human…

  10. Stimulating Language: Insights from TMS

    ERIC Educational Resources Information Center

    Devlin, Joseph T.; Watkins, Kate E.

    2007-01-01

    Fifteen years ago, Pascual-Leone and colleagues used transcranial magnetic stimulation (TMS) to investigate speech production in pre-surgical epilepsy patients and in doing so, introduced a novel tool into language research. TMS can be used to non-invasively stimulate a specific cortical region and transiently disrupt information processing. These…

  11. Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring.

    PubMed

    Kuriyan, A E; Lehmann, G M; Kulkarni, A A; Woeller, C F; Feldon, S E; Hindman, H B; Sime, P J; Huxlin, K R; Phipps, R P

    2012-01-01

    A critical component of corneal scarring is the TGFβ-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In this study, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPARγ) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-methyl ester (CDDO-Me) and 15-deoxy-Δ(-12,14)-prostaglandin J(2) (15d-PGJ(2)) for inhibiting TGFβ-induced myofibroblast differentiation in vitro. TGFβ was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ(2) were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (αSMA, collagen I, and fibronectin) and mRNA (αSMA and collagen III). The role of PPARγ in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGFβ-induced αSMA expression via Western blotting and immunofluorescence. Both electrophilic PPARγ ligands (CDDO-Me and 15d-PGJ(2)) potently inhibited TGFβ-induced myofibroblast differentiation, but PPARγ was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPARγ ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPARγ ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ(2) are strong inhibitors of TGFβ-induced corneal fibroblast to myofibroblast differentiation in vitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models.

  12. Essential role for hematopoietic prostaglandin D2 synthase in the control of delayed type hypersensitivity.

    PubMed

    Trivedi, Seema G; Newson, Justine; Rajakariar, Ravindra; Jacques, Thomas S; Hannon, Robert; Kanaoka, Yoshihide; Eguchi, Naomi; Colville-Nash, Paul; Gilroy, Derek W

    2006-03-28

    Hematopoietic prostaglandin D(2) synthase (hPGD(2)S) metabolizes cyclooxygenase-derived prostaglandin (PG) H(2) to PGD(2), which is dehydrated to cyclopentenone PGs, including 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). PGD(2) acts through two receptors (DP1 and DP2/CRTH2), whereas 15d-PGJ(2) can activate peroxisome proliferator-activated receptors or inhibit a range of proinflammatory signaling pathways, including NF-kappaB. Despite eliciting asthmatic and allergic reactions through the generation of PGD(2), it is not known what role hPGD(2)S plays in T helper (Th)1-driven adaptive immunity. To investigate this question, the severity and duration of a delayed type hypersensitivity reaction was examined in hPGD(2)S knockout and transgenic mice. Compared with their respective controls, knockouts displayed a more severe inflammatory response that failed to resolve, characterized histologically as persistent acute inflammation, whereas transgenic mice had little detectable inflammation. Lymphocytes isolated from inguinal lymph nodes of hPGD(2)S(-/-) animals showed hyperproliferation and increased IL-2 synthesis effects that were rescued by 15d-PGJ(2), but not PGD(2), working through either of its receptors. Crucially, 15d-PGJ(2) exerted its suppressive effects through the inhibition of NF-kappaB activation and not through peroxisome proliferator-activated receptor signaling. In contrast, lymph node cultures from transgenics proliferated more slowly and synthesized significantly less IL-2 than controls. Therefore, contrary to its role in driving Th2-like responses, this report shows that hPGD(2)S may act as an internal braking signal essential for bringing about the resolution of Th1-driven delayed type hypersensitivity reactions. Consequently, hPGD(2)S-derived cyclopentenone PGs may protect against inflammatory diseases, where T lymphocytes play a pathogenic role, as in rheumatoid arthritis, atopic eczema, and chronic rejection. PMID:16547141

  13. Nanomaterial-Enabled Neural Stimulation.

    PubMed

    Wang, Yongchen; Guo, Liang

    2016-01-01

    Neural stimulation is a critical technique in treating neurological diseases and investigating brain functions. Traditional electrical stimulation uses electrodes to directly create intervening electric fields in the immediate vicinity of neural tissues. Second-generation stimulation techniques directly use light, magnetic fields or ultrasound in a non-contact manner. An emerging generation of non- or minimally invasive neural stimulation techniques is enabled by nanotechnology to achieve a high spatial resolution and cell-type specificity. In these techniques, a nanomaterial converts a remotely transmitted primary stimulus such as a light, magnetic or ultrasonic signal to a localized secondary stimulus such as an electric field or heat to stimulate neurons. The ease of surface modification and bio-conjugation of nanomaterials facilitates cell-type-specific targeting, designated placement and highly localized membrane activation. This review focuses on nanomaterial-enabled neural stimulation techniques primarily involving opto-electric, opto-thermal, magneto-electric, magneto-thermal and acousto-electric transduction mechanisms. Stimulation techniques based on other possible transduction schemes and general consideration for these emerging neurotechnologies are also discussed.

  14. Nanomaterial-Enabled Neural Stimulation

    PubMed Central

    Wang, Yongchen; Guo, Liang

    2016-01-01

    Neural stimulation is a critical technique in treating neurological diseases and investigating brain functions. Traditional electrical stimulation uses electrodes to directly create intervening electric fields in the immediate vicinity of neural tissues. Second-generation stimulation techniques directly use light, magnetic fields or ultrasound in a non-contact manner. An emerging generation of non- or minimally invasive neural stimulation techniques is enabled by nanotechnology to achieve a high spatial resolution and cell-type specificity. In these techniques, a nanomaterial converts a remotely transmitted primary stimulus such as a light, magnetic or ultrasonic signal to a localized secondary stimulus such as an electric field or heat to stimulate neurons. The ease of surface modification and bio-conjugation of nanomaterials facilitates cell-type-specific targeting, designated placement and highly localized membrane activation. This review focuses on nanomaterial-enabled neural stimulation techniques primarily involving opto-electric, opto-thermal, magneto-electric, magneto-thermal and acousto-electric transduction mechanisms. Stimulation techniques based on other possible transduction schemes and general consideration for these emerging neurotechnologies are also discussed. PMID:27013938

  15. Vagal Nerve Stimulation Therapy: What Is Being Stimulated?

    PubMed Central

    Kember, Guy; Ardell, Jeffrey L.; Armour, John A.; Zamir, Mair

    2014-01-01

    Vagal nerve stimulation in cardiac therapy involves delivering electrical current to the vagal sympathetic complex in patients experiencing heart failure. The therapy has shown promise but the mechanisms by which any benefit accrues is not understood. In this paper we model the response to increased levels of stimulation of individual components of the vagal sympathetic complex as a differential activation of each component in the control of heart rate. The model provides insight beyond what is available in the animal experiment in as much as allowing the simultaneous assessment of neuronal activity throughout the cardiac neural axis. The results indicate that there is sensitivity of the neural network to low level subthreshold stimulation. This leads us to propose that the chronic effects of vagal nerve stimulation therapy lie within the indirect pathways that target intrinsic cardiac local circuit neurons because they have the capacity for plasticity. PMID:25479368

  16. Electrical stimulation in exercise training

    NASA Technical Reports Server (NTRS)

    Kroll, Walter

    1994-01-01

    Electrical stimulation has a long history of use in medicine dating back to 46 A.D. when the Roman physician Largus found the electrical discharge of torpedo fishes useful in the treatment of pain produced by headache and gout. A rival Greek physician, Dioscorides, discounted the value of the torpedo fish for headache relief but did recommend its use in the treatment of hemorrhoids. In 1745, the Leyden jar and various sized electrostatic generators were used to treat angina pectoris, epilepsy, hemiplegia, kidney stones, and sciatica. Benjamin Franklin used an electrical device to treat successfully a young woman suffering from convulsive fits. In the late 1800's battery powered hydroelectric baths were used to treat chronic inflammation of the uterus while electrified athletic supporters were advertised for the treatment of male problems. Fortunately, such an amusing early history of the simple beginnings of electrical stimulation did not prevent eventual development of a variety of useful therapeutic and rehabilitative applications of electrical stimulation. Over the centuries electrical stimulation has survived as a modality in the treatment of various medical disorders with its primary application being in the rehabilitation area. Recently, a surge of new interest in electrical stimulation has been kindled by the work of a Russian sport scientist who reported remarkable muscle strength and endurance improvements in elite athletes. Yakov Kots reported his research on electric stimulation and strength improvements in 1977 at a Canadian-Soviet Exchange Symposium held at Concordia University in Montreal. Since then an explosion of new studies has been seen in both sport science and in medicine. Based upon the reported works of Kots and the present surge of new investigations, one could be misled as to the origin of electrical stimulation as a technique to increase muscle strength. As a matter of fact, electric stimulation has been used as a technique to improve

  17. Digital electronic bone growth stimulator

    DOEpatents

    Kronberg, J.W.

    1995-05-09

    A device is described for stimulating bone tissue by applying a low level alternating current signal directly to the patient`s skin. A crystal oscillator, a binary divider chain and digital logic gates are used to generate the desired waveforms that reproduce the natural electrical characteristics found in bone tissue needed for stimulating bone growth and treating osteoporosis. The device, powered by a battery, contains a switch allowing selection of the correct waveform for bone growth stimulation or osteoporosis treatment so that, when attached to the skin of the patient using standard skin contact electrodes, the correct signal is communicated to the underlying bone structures. 5 figs.

  18. Digital electronic bone growth stimulator

    DOEpatents

    Kronberg, James W.

    1995-01-01

    A device for stimulating bone tissue by applying a low level alternating current signal directly to the patient's skin. A crystal oscillator, a binary divider chain and digital logic gates are used to generate the desired waveforms that reproduce the natural electrical characteristics found in bone tissue needed for stimulating bone growth and treating osteoporosis. The device, powered by a battery, contains a switch allowing selection of the correct waveform for bone growth stimulation or osteoporosis treatment so that, when attached to the skin of the patient using standard skin contact electrodes, the correct signal is communicated to the underlying bone structures.

  19. N-acetylcysteine and 15 deoxy-{delta}12,14-prostaglandin J2 exert a protective effect against autoimmune thyroid destruction in vivo but not against interleukin-1{alpha}/interferon {gamma}-induced inhibitory effects in thyrocytes in vitro.

    PubMed

    Poncin, Sylvie; Colin, Ides M; Decallonne, Brigitte; Clinckspooor, Isabelle; Many, Marie-Christine; Denef, Jean-François; Gérard, Anne-Catherine

    2010-07-01

    Reactive oxygen species (ROS) are crucial for thyroid hormonogenesis, and their production is kept under tight control. Oxidative stress (OS) is toxic for thyrocytes in an inflammatory context. In vitro, Th1 pro-inflammatory cytokines have already been shown to decrease thyroid-specific protein expression. In the present study, OS level and its impact on thyroid function were analyzed in vitro in Th1 cytokine (interleukin [IL]-1alpha/interferon [IFN] gamma)-incubated thyrocytes (rat and human), as well as in vivo in thyroids from nonobese diabetic mice, a model of spontaneous autoimmune thyroiditis. N-acetylcysteine (NAC) and prostaglandin, 15 deoxy-(Delta12,14)-prostaglandinJ2 (15dPGJ2), were used for their antioxidant and anti-inflammatory properties, respectively. ROS production and OS were increased in IL-1alpha/IFNgamma-incubated thyrocytes and in destructive thyroiditis. In vitro, NAC not only reduced ROS production below control levels, but further decreased the expression of thyroid-specific proteins in addition to IL-1alpha/IFNgamma-inhibitory effects. Thus, besides ROS, other intracellular intermediaries likely mediate Th1 cytokine effects. In vivo, NAC and 15dPGJ2 reduced OS and the immune infiltration, thereby leading to a restoration of thyroid morphology. It is therefore likely that NAC and 15dPGJ2 mainly exert their protective effects by acting on infiltrating inflammatory cells rather than directly on thyrocytes.

  20. Magnetically stimulated fluid flow patterns

    ScienceCinema

    Martin, Jim; Solis, Kyle

    2016-07-12

    Sandia National Laboratories' Jim Martin and Kyle Solis explain research on the effects of magnetic fields on fluid flows and how they stimulate vigorous flows. Fluid flow is a necessary phenomenon in everything from reactors to cooling engines in cars.

  1. Demultiplexer circuit for neural stimulation

    DOEpatents

    Wessendorf, Kurt O; Okandan, Murat; Pearson, Sean

    2012-10-09

    A demultiplexer circuit is disclosed which can be used with a conventional neural stimulator to extend the number of electrodes which can be activated. The demultiplexer circuit, which is formed on a semiconductor substrate containing a power supply that provides all the dc electrical power for operation of the circuit, includes digital latches that receive and store addressing information from the neural stimulator one bit at a time. This addressing information is used to program one or more 1:2.sup.N demultiplexers in the demultiplexer circuit which then route neural stimulation signals from the neural stimulator to an electrode array which is connected to the outputs of the 1:2.sup.N demultiplexer. The demultiplexer circuit allows the number of individual electrodes in the electrode array to be increased by a factor of 2.sup.N with N generally being in a range of 2-4.

  2. Magnetically stimulated fluid flow patterns

    SciTech Connect

    Martin, Jim; Solis, Kyle

    2014-03-06

    Sandia National Laboratories' Jim Martin and Kyle Solis explain research on the effects of magnetic fields on fluid flows and how they stimulate vigorous flows. Fluid flow is a necessary phenomenon in everything from reactors to cooling engines in cars.

  3. Evoked response to taste stimulations.

    PubMed

    Wada, Masashi

    2005-01-01

    For the recording of gustatory evoked responses, the tip of a stimulator is pressed vertically on one side of the tongue until the trigger pulses are generated by a switch attached to the bottom of the stimulator. According to our results, no detectable response was observed in the absence of taste. The positive waves were distinguishable by using the technique of superimposition before averaging, and the positive wave was made clearer by averaging.

  4. Geothermal Reservoir Well Stimulation Program: technology transfer

    SciTech Connect

    Not Available

    1980-05-01

    The following are included: review of available data from previous fracturing stimulation operations, stimulation process variables, fracturing fluid design, hydraulic fracture design, stimulation case histories, and selected bibliography. (MHR)

  5. 95 stimulations in 63 wells

    SciTech Connect

    Horton, A.I.

    1982-02-01

    Since 1976, extensive studies on the nature of the Eastern gas shales and the production potential from stimulated shale wells have been conducted through joint efforts of industry and the Department of Energy (DOE). Prior to development of this project, the conventional method of stimulating the shales was borehole shooting, and conventional hydraulic fracturing of the shale was just beginning. DOE-industry investigations under the Eastern Gas Shales Project have experimented with other types of stimulations, including massive hydraulic fracturing, foam fracturing, cryogenic fracturing, chemical explosives, and novel treatments. Two of the latter have used (1) nitrogen and (2) oil assisted with nitrogen. Two other treatments, which were unsuccessful, were (1) an open hole packer-stage frac and (2) a kerosene frac. These were operational and conceptual failures. Details of the stimulations and production data, where available, have been complied and studied. The experience that has been gained may prove helpful to those considering stimulation technology in future well drilling ventures in the shale. However, the limited data available in regions of similar geologic factors preclude a thorough analysis of stimulation effectiveness.

  6. Brain Stimulation for Torsion Dystonia

    PubMed Central

    Fox, Michael D.; Alterman, Ron L.

    2016-01-01

    Dystonia is a heterogeneous neurological disorder characterized by abnormal muscle contractions for which standard medical therapy is often inadequate. For such patients, therapeutic brain stimulation is becoming increasingly utilized. Here we review the evidence and effect sizes for treating different types of dystonia with different types of brain stimulation. Strong (level B) evidence supports the use of deep brain stimulation (DBS) for the treatment of primary generalized or segmental dystonia, especially DYT-1, as well as for patients with cervical dystonia. Large effect sizes have also been reported for DBS treatment of tardive dystonia, writer’s cramp, cranial dystonia, myoclonus dystonia, and off-state dystonia associated with Parkinson’s disease. Lesser benefit is generally seen in dystonia secondary to structural brain damage. Other brain stimulation techniques including epidural cortical stimulation and noninvasive brain stimulation have been investigated, but generally report smaller effect sizes in a more limited number of patients. Recent advances relevant to patient selection, surgical approach, DBS programming, and mechanism of action are discussed. PMID:25894231

  7. Theoretical investigation on the pumping effect of stimulated Brillouin scattering on stimulated Raman scattering in water

    NASA Astrophysics Data System (ADS)

    Shi, J.; Chen, X.; Ouyang, M.; Gong, W.; Su, Y.; Liu, D.

    2012-02-01

    The pumping effect of stimulated Brillouin scattering on stimulated Raman scattering is investigated theoretically through the coupled wave equations of stimulated Brillouin scattering and stimulated Raman scattering. The numerical simulations are in agreement with the experimental results. They indicate that the backward stimulated Raman scattering is excited and amplified collectively by both pump laser and stimulated Brillouin scattering.

  8. Emerging neural stimulation technologies for bladder dysfunctions.

    PubMed

    Lee, Jee Woong; Kim, Daejeong; Yoo, Sangjin; Lee, Hyungsup; Lee, Gu-Haeng; Nam, Yoonkey

    2015-03-01

    In the neural engineering field, physiological dysfunctions are approached by identifying the target nerves and providing artificial stimulation to restore the function. Neural stimulation and recording technologies play a central role in this approach, and various engineering devices and stimulation techniques have become available to the medical community. For bladder control problems, electrical stimulation has been used as one of the treatments, while only a few emerging neurotechnologies have been used to tackle these problems. In this review, we introduce some recent developments in neural stimulation technologies including microelectrode array, closed-loop neural stimulation, optical stimulation, and ultrasound stimulation.

  9. Neuroprotection trek--the next generation: neuromodulation I. Techniques--deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation

    NASA Technical Reports Server (NTRS)

    Andrews, Russell J.

    2003-01-01

    Neuromodulation denotes controlled electrical stimulation of the central or peripheral nervous system. The three forms of neuromodulation described in this paper-deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation-were chosen primarily for their demonstrated or potential clinical usefulness. Deep brain stimulation is a completely implanted technique for improving movement disorders, such as Parkinson's disease, by very focal electrical stimulation of the brain-a technique that employs well-established hardware (electrode and pulse generator/battery). Vagus nerve stimulation is similar to deep brain stimulation in being well-established (for the treatment of refractory epilepsy), completely implanted, and having hardware that can be considered standard at the present time. Vagus nerve stimulation differs from deep brain stimulation, however, in that afferent stimulation of the vagus nerve results in diffuse effects on many regions throughout the brain. Although use of deep brain stimulation for applications beyond movement disorders will no doubt involve placing the stimulating electrode(s) in regions other than the thalamus, subthalamus, or globus pallidus, the use of vagus nerve stimulation for applications beyond epilepsy-for example, depression and eating disorders-is unlikely to require altering the hardware significantly (although stimulation protocols may differ). Transcranial magnetic stimulation is an example of an external or non-implanted, intermittent (at least given the current state of the hardware) stimulation technique, the clinical value of which for neuromodulation and neuroprotection remains to be determined.

  10. Electrical stimulation and motor recovery.

    PubMed

    Young, Wise

    2015-01-01

    In recent years, several investigators have successfully regenerated axons in animal spinal cords without locomotor recovery. One explanation is that the animals were not trained to use the regenerated connections. Intensive locomotor training improves walking recovery after spinal cord injury (SCI) in people, and >90% of people with incomplete SCI recover walking with training. Although the optimal timing, duration, intensity, and type of locomotor training are still controversial, many investigators have reported beneficial effects of training on locomotor function. The mechanisms by which training improves recovery are not clear, but an attractive theory is available. In 1949, Donald Hebb proposed a famous rule that has been paraphrased as "neurons that fire together, wire together." This rule provided a theoretical basis for a widely accepted theory that homosynaptic and heterosynaptic activity facilitate synaptic formation and consolidation. In addition, the lumbar spinal cord has a locomotor center, called the central pattern generator (CPG), which can be activated nonspecifically with electrical stimulation or neurotransmitters to produce walking. The CPG is an obvious target to reconnect after SCI. Stimulating motor cortex, spinal cord, or peripheral nerves can modulate lumbar spinal cord excitability. Motor cortex stimulation causes long-term changes in spinal reflexes and synapses, increases sprouting of the corticospinal tract, and restores skilled forelimb function in rats. Long used to treat chronic pain, motor cortex stimuli modify lumbar spinal network excitability and improve lower extremity motor scores in humans. Similarly, epidural spinal cord stimulation has long been used to treat pain and spasticity. Subthreshold epidural stimulation reduces the threshold for locomotor activity. In 2011, Harkema et al. reported lumbosacral epidural stimulation restores motor control in chronic motor complete patients. Peripheral nerve or functional electrical

  11. Deep brain stimulation: new techniques.

    PubMed

    Hariz, Marwan

    2014-01-01

    The technology of the hardware used in deep brain stimulation (DBS), and the mode of delivering the stimulation have not significantly evolved since the start of the modern era of DBS 25 years ago. However, new technology is now being developed along several avenues. New features of the implantable pulse generator (IPG) allow fractionation of the electric current into variable proportions between different contacts of the multi-polar lead. Another design consists in leads that allow selective current steering from directionally placed electrode contacts that would deliver the stimulation in a specific direction or even create a directional shaped electric field that would conform to the anatomy of the brain target aimed at, avoiding adjacent structures, and thus avoiding side effects. Closed loop adaptive stimulation technologies are being developed, allowing a tracking of the pathological local field potential of the brain target, and delivering automatically the stimulation to suppress the pathological activity as soon as it is detected and for as long as needed. This feature may contribute to a DBS therapy "on demand", instead of continuously. Finally, advances in imaging technology are providing "new" brain targets, and increasingly allowing DBS to be performed accurately while avoiding the risks of microelectrode recording. PMID:24262179

  12. Evoked Electromyographically Controlled Electrical Stimulation

    PubMed Central

    Hayashibe, Mitsuhiro

    2016-01-01

    Time-variant muscle responses under electrical stimulation (ES) are often problematic for all the applications of neuroprosthetic muscle control. This situation limits the range of ES usage in relevant areas, mainly due to muscle fatigue and also to changes in stimulation electrode contact conditions, especially in transcutaneous ES. Surface electrodes are still the most widely used in noninvasive applications. Electrical field variations caused by changes in the stimulation contact condition markedly affect the resulting total muscle activation levels. Fatigue phenomena under functional electrical stimulation (FES) are also well known source of time-varying characteristics coming from muscle response under ES. Therefore, it is essential to monitor the actual muscle state and assess the expected muscle response by ES so as to improve the current ES system in favor of adaptive muscle-response-aware FES control. To deal with this issue, we have been studying a novel control technique using evoked electromyography (eEMG) signals to compensate for these muscle time-variances under ES for stable neuroprosthetic muscle control. In this perspective article, I overview the background of this topic and highlight important points to be aware of when using ES to induce the desired muscle activation regardless of the time-variance. I also demonstrate how to deal with the common critical problem of ES to move toward robust neuroprosthetic muscle control with the Evoked Electromyographically Controlled Electrical Stimulation paradigm. PMID:27471448

  13. Laser stimulation for pain research

    NASA Astrophysics Data System (ADS)

    Clark, Stuart; Dickinson, Mark R.; King, Terence A.; Jones, Anthony; Chen, Andrew; Derbyshire, Stuart; Townsend, D. W.; Kinahan, Paul E.; Mintun, M. A.; Nichols, T.

    1996-01-01

    Pain is a serious medical problem; it inflicts huge economic loss and personal suffering. Pain signals are conducted via small, non- and partially myelinated A-delta and C nerve fibers and lasers are particularly well suited to stimulating these fibers. Large myelinated fibers convey touch and vibration information and these fibers are also discharged when contact thermodes and other touch pain stimuli are used and this would give a more muddled signal for functional imaging experiments. The advantages of lasers over conventional methods of pain stimulation are good temporal resolution, no variable parameters are involved such as contact area and they give very reproducible results. Accurate inter-stimulus changes can be achieved by computer control of the laser pulse duration, pulse height and repetition rate and this flexibility enables complex stimulation paradigms to be realized. We present a flexible carbon dioxide laser system designed to generate these stimuli for the study of human cerebral pain responses. We discuss the advantages within research of this system over other methods of pain stimulation such as thermal, electrical and magnetic. The stimulator is used in conjunction with functional magnetic resonance imaging, positron emission tomography and electrophysiological methods of imaging the brain's activity. This combination is a powerful tool for the study of pain-induced activity in different areas of the brain. An accurate understanding of the brain's response to pain will help in research into the areas of rheumatoid arthritis and chronic back pain.

  14. Wireless magnetothermal deep brain stimulation.

    PubMed

    Chen, Ritchie; Romero, Gabriela; Christiansen, Michael G; Mohr, Alan; Anikeeva, Polina

    2015-03-27

    Wireless deep brain stimulation of well-defined neuronal populations could facilitate the study of intact brain circuits and the treatment of neurological disorders. Here, we demonstrate minimally invasive and remote neural excitation through the activation of the heat-sensitive capsaicin receptor TRPV1 by magnetic nanoparticles. When exposed to alternating magnetic fields, the nanoparticles dissipate heat generated by hysteresis, triggering widespread and reversible firing of TRPV1(+) neurons. Wireless magnetothermal stimulation in the ventral tegmental area of mice evoked excitation in subpopulations of neurons in the targeted brain region and in structures receiving excitatory projections. The nanoparticles persisted in the brain for over a month, allowing for chronic stimulation without the need for implants and connectors. PMID:25765068

  15. Technology for Peripheral Nerve Stimulation.

    PubMed

    Parker, John L; Cameron, Tracy

    2015-01-01

    Peripheral nerve stimulation (PNS) has been in use for over 50 years to treat patients suffering from chronic pain who have failed conservative treatments. Despite this long history, the devices being used have changed very little. In fact, current PNS technology was developed specifically for spinal cord stimulation. The use of technology developed for other applications in PNS has led to an unnecessary number of device complications and the limited adoption of this promising therapy. The following chapter provides an overview of PNS technology throughout the years, outlining both the benefits and limitations. We will briefly explore the electrophysiology of PNS stimulation, with an emphasis on technology and indication-specific devices. Finally, design and technical requirements of an ideal PNS device will be discussed.

  16. The Electrical Stimulation Modifies the Cerebral Function

    NASA Astrophysics Data System (ADS)

    Rocha, Luisa Lilia; López-Meraz, María Leonor; Cuéllar-Herrera, Manola; Neri-Bazán., Leticia

    2002-08-01

    Electrical stimulation has been used for therapeuthic purposes. In this review, we present the clinical and scientific bases for using electrical stimulation as a treatment for pharmacological refractory epilepsy. We also describe results in receptors of inhibitory neurotransmitters obtained in rat brain with or without epilepsy, undergoing brain stimulation. Brain electrical stimulation may improve our understanding of brain function and neuroplasticity.

  17. Retinal Stimulation on Rabbit Using Complementary Metal Oxide Semiconductor Based Multichip Flexible Stimulator toward Retinal Prosthesis

    NASA Astrophysics Data System (ADS)

    Tokuda, Takashi; Asano, Ryosuke; Sugitani, Sachie; Taniyama, Mari; Terasawa, Yasuo; Nunoshita, Masahiro; Nakauchi, Kazuaki; Fujikado, Takashi; Tano, Yasuo; Ohta, Jun

    2008-04-01

    The Functionality of a complementary metal oxide semiconductor (CMOS) LSI-based, multichip flexible retinal stimulator was demonstrated in retinal stimulation experiments on rabbits. A 1×4-configured multichip stimulator was fabricated for application to experiments on animals. An experimental procedure including surgical operations was developed, and retinal stimulation was performed with the fabricated multichip stimulator. Neural responses on the visual cortex were successfully evoked by the fabricated stimulator. The stimulator is confirmed to be applicable to acute animal experiments.

  18. Chemosensory stimulation during sleep - Arousal responses to gustatory stimulation.

    PubMed

    Stuck, B A; Moutsis, T T; Bingel, U; Sommer, J U

    2016-05-13

    The processing of nociceptive, visual, vibrotactile, thermal and acoustic stimuli during sleep has been extensively investigated in the past. Recently, interest has focused on the impact of olfactory stimulation on sleep. In contrast to all other sensory systems, olfactory stimulation does not lead to an increased arousal frequency, regardless of hedonicity and concentration. The impact of the second chemosensory system, gustation, on sleep however has not been investigated to date. Twenty-one normosmic and normogeusic volunteers of both genders, aged 19-33 years, participated in the trial. Stimulation was performed with a gustometer using the following aqueous solutions: saccharose 20% (sweet), sodium chloride (NaCl) 7.5% (salty), citrate 5% (sour), and quinine 0.02% (bitter). A tasteless solution was used as negative control. Capsaicin, a strong trigeminal stimulus, served as positive control. Primary outcome was arousal frequency per stimulus in each sleep stage, as assessed with polysomnography. The frequency of arousals decreased in deeper sleep stages (N1: 211 arousals of 333 stimuli=63%, N2: 676/2728=25%, N3: 43/1378=3%, REM: 57/1010=6%). Statistically significant differences in terms of arousal frequency were found in N2 between the negative control and NaCl 100 μl (p<0.001), saccharose 100 μl, citrate 50 μl & 100 μl, and quinine 100 μl (p<0.05). Capsaicin led to complete awakenings in 94% of stimuli (30/32). These results demonstrate that gustatory stimulation during sleep induces arousals depending on stimulus intensity and sleep stage, which is different to olfactory stimulation and may be related to differences in central processing of the two chemosensory systems. PMID:26921652

  19. The role of aldo-keto reductase 1C3 (AKR1C3)-mediated prostaglandin D2 (PGD2) metabolism in keloids.

    PubMed

    Mantel, Alon; Newsome, Austin; Thekkudan, Theresa; Frazier, Robert; Katdare, Meena

    2016-01-01

    Keloids are progressively expanding scars, mostly prevalent in individuals of African descent. Previous data identified increased mast cell number and activation state in keloids suggesting a role in disease progression. The major eicosanoid secreted by mast cells is prostaglandin D2 (PGD2), a relatively unstable pro-inflammatory mediator which can be spontaneously converted to 15-deoxy-(Delta12,14)-prostaglandin J2(15d-PGJ2) or enzymatically metabolized to 9α,11β-PGF2 by aldo-keto reductase 1C3 (AKR1C3). In this work, we investigated the possible role of PGD2 and its metabolites in keloids using CRL1762 keloid fibroblasts (KF) and immunohistochemical staining. Our data suggested approximately 3-fold increase of tryptase-positive mast cell count in keloids compared with normal skin. Furthermore, AKR1C3 was overexpressed in the fibrotic area of keloids while relatively weak staining detected in normal skin. Metabolism of PGD2 to 9α,11β-PGF2 by both, KF and normal fibroblasts, was dependent on AKR1C3 as this reaction was attenuated in the presence of the AKR1C3 inhibitor, 2'-hydroxyflavanone, or in cells with decreased AKR1C3 expression. 15d-PGJ2, but not the other tested PGs, inhibited KF proliferation, attenuated KF-mediated collagen gel contraction and increased caspase-3 activation. In addition, treatment with 15d-PGJ2 activated P38-MAPK, induced reactive oxygen species and upregulated superoxide dismutase-1 (SOD-1). Finally, inhibition of P38-MAPK further augmented 15d-PGJ2-induced caspase-3 cleavage and attenuated its effect on SOD-1 transcription. This work suggests that localized dual inhibition of AKR1C3 and P38-MAPK may inhibit keloid progression. Inhibiting AKR1C3 activity may generate oxidative environment due to redirection of PGD2 metabolism towards 15d-PGJ2 while inhibition of P38-MAPK will sensitize keloid cells to ROS-induced apoptosis. PMID:26308156

  20. Selenoprotein-dependent Up-regulation of Hematopoietic Prostaglandin D2 Synthase in Macrophages Is Mediated through the Activation of Peroxisome Proliferator-activated Receptor (PPAR) γ*

    PubMed Central

    Gandhi, Ujjawal H.; Kaushal, Naveen; Ravindra, Kodihalli C.; Hegde, Shailaja; Nelson, Shakira M.; Narayan, Vivek; Vunta, Hema; Paulson, Robert F.; Prabhu, K. Sandeep

    2011-01-01

    The plasticity of macrophages is evident from their dual role in inflammation and resolution of inflammation that are accompanied by changes in the transcriptome and metabolome. Along these lines, we have previously demonstrated that the micronutrient selenium increases macrophage production of arachidonic acid (AA)-derived anti-inflammatory 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and decreases the proinflammatory PGE2. Here, we hypothesized that selenium modulated the metabolism of AA by a differential regulation of various prostaglandin (PG) synthases favoring the production of PGD2 metabolites, Δ12-PGJ2 and 15d-PGJ2. A dose-dependent increase in the expression of hematopoietic-PGD2 synthase (H-PGDS) by selenium and a corresponding increase in Δ12-PGJ2 and 15d-PGJ2 in RAW264.7 macrophages and primary bone marrow-derived macrophages was observed. Studies with organic non-bioavailable forms of selenium and the genetic manipulation of cellular selenium incorporation machinery indicated that selenoproteins were necessary for H-PGDS expression and 15d-PGJ2 production. Treatment of selenium-deficient macrophages with rosiglitazone, a peroxisome proliferator-activated receptor γ ligand, up-regulated H-PGDS. Furthermore, electrophoretic mobility shift assays indicated the presence of an active peroxisome proliferator-activated receptor-response element in murine Hpgds promoter suggesting a positive feedback mechanism of H-PGDS expression. Alternatively, the expression of nuclear factor-κB-dependent thromboxane synthase and microsomal PGE2 synthase was down-regulated by selenium. Using a Friend virus infection model of murine leukemia, the onset of leukemia was observed only in selenium-deficient and indomethacin-treated selenium-supplemented mice but not in the selenium-supplemented group or those treated with 15d-PGJ2. These results suggest the importance of selenium in the shunting of AA metabolism toward the production of PGD2 metabolites, which may have

  1. Infant Stimulation Curriculum. Revised Edition.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Herschel W. Nisonger Center.

    Presented is the Infant Stimulation Curriculum (developed by the Developmentally Delayed Infant Outreach Project) for parents and teachers to use with children who are developmentally between birth and 36 months of age. Published in a card format at a sixth grade readability level, the curriculum includes introductory cards providing information…

  2. Activities to Stimulate Critical Thinking.

    ERIC Educational Resources Information Center

    Haynes, Thomas B.; Schroeder, Connie

    1989-01-01

    Describes sample vocational activities that stimulate critical thinking: (1) setting up an accounting system (business education); (2) developing a marketing plan (marketing education); (3) developing a fertilizer application plan (agricultural education); (4) making the best purchase (home economics); (5) planning a repair/remodeling project…

  3. Aversive Stimulation -- Criteria for Application.

    ERIC Educational Resources Information Center

    O'Donnell, Patrick A.; Ohlson, Glenn A.

    Criteria for applying aversive stimulation with severely handicapped children are examined, and practical and ethical issues are considered. Factors seen to influence punishment outcomes include timing, intensity, and schedule of reinforcement. Suggested is the need for further research on the comparative effectiveness of positive and negative…

  4. Stimulation of phagocytosis by sulforaphane

    SciTech Connect

    Suganuma, Hiroyuki; Fahey, Jed W.; Bryan, Kelley E.; Healy, Zachary R.; Talalay, Paul

    2011-02-04

    Research highlights: {yields} Sulforaphane stimulates the phagocytosis of RAW 264.7 macrophages under conditions of serum deprivation. {yields} This effect does not require Nrf2-dependent induction of phase 2 genes. {yields} Inactivation of macrophage migration inhibitory factor (MIF) by sulforaphane may be involved in stimulation of phagocytosis by sulforaphane. -- Abstract: Sulforaphane, a major isothiocyanate derived from cruciferous vegetables, protects living systems against electrophile toxicity, oxidative stress, inflammation, and radiation. A major protective mechanism is the induction of a network of endogenous cytoprotective (phase 2) genes that are regulated by transcription factor Nrf2. To obtain a more detailed understanding of the anti-inflammatory and immunomodulatory effects of sulforaphane, we evaluated its effect on the phagocytosis activity of RAW 264.7 murine macrophage-like cells by measuring the uptake of 2-{mu}m diameter polystyrene beads. Sulforaphane raised the phagocytosis activity of RAW 264.7 cells but only in the absence or presence of low concentrations (1%) of fetal bovine serum. Higher serum concentrations depressed phagocytosis and abolished its stimulation by sulforaphane. This stimulation did not depend on the induction of Nrf2-regulated genes since it occurred in peritoneal macrophages of nrf2{sup -/-} mice. Moreover, a potent triterpenoid inducer of Nrf2-dependent genes did not stimulate phagocytosis, whereas sulforaphane and another isothiocyanate (benzyl isothiocyanate) had comparable inducer potencies. It has been shown recently that sulforaphane is a potent and direct inactivator of macrophage migration inhibitory factor (MIF), an inflammatory cytokine. Moreover, the addition of recombinant MIF to RAW 264.7 cells attenuated phagocytosis, but sulforaphane-inactivated MIF did not affect phagocytosis. The inactivation of MIF may therefore be involved in the phagocytosis-enhancing activity of sulforaphane.

  5. Stimulation of alpha7 nicotinic acetylcholine receptor by nicotine attenuates inflammatory response in macrophages and improves survival in experimental model of sepsis through heme oxygenase-1 induction.

    PubMed

    Tsoyi, Konstantin; Jang, Hwa Jin; Kim, Jong Woo; Chang, Hong Kyung; Lee, Young Soo; Pae, Hyun-Ock; Kim, Hye Jung; Seo, Han Geuk; Lee, Jae Heun; Chung, Hun-Taeg; Chang, Ki Churl

    2011-06-01

    Activation of nicotinic acetylcholine receptor alpha7 subunit (α7nAChR) by nicotine leads to the improved survival rate in experimental model of sepsis. Previously, we demonstrated that heme oxygenase (HO)-1 inducers or carbon monoxide significantly increased survival of lipopolysaccharide (LPS)-induced and cecal ligation and puncture-induced septic mice by reduction of high mobility group box 1 release, a late mediator of sepsis. However, that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation has not been elucidated. Here we show that HO-1-inducible effect by nicotine was mediated through sequential event-Ca(2+) influx, classical protein kinase C activation, and reactive oxygen species production-which activates phosphoinositol-3-kinase/Akt/Nrf-2 pathway. In addition, HO-1 is required for nicotine-mediated suppression of tumor necrosis factor-α, inducible nitric oxide synthase, and high mobility group box 1 expression induced by LPS in macrophages, as evidenced by the fact that nicotine failed to inhibit production of these mediators when HO-1 was suppressed. Importantly, nicotine-induced survival rate was reduced by inhibition of HO-1 in LPS- and cecal ligation and puncture-treated septic mice. Collectively, these data suggest that activation of α7nAChR by nicotine is critical in the regulation of anti-inflammatory process, which could be mediated through HO-1 expression. Thus, we conclude that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation.

  6. Somato stimulation and acupuncture therapy.

    PubMed

    Zhao, Jing-Jun; Rong, Pei-Jing; Shi, Li; Ben, Hui; Zhu, Bing

    2016-05-01

    Acupuncture is an oldest somato stimulus medical technique. As the most representative peripheral nerve stimulation therapy, it has a complete system of theory and application and is applicable to a large population. This paper expounds the bionic origins of acupuncture and analyzes the physiological mechanism by which acupuncture works. For living creatures, functionally sound viscera and effective endurance of pain are essential for survival. This paper discusses the way in which acupuncture increases the pain threshold of living creatures and the underlying mechanism from the perspective of bionics. Acupuncture can also help to adjust visceral functions and works most effectively in facilitating the process of digestion and restraining visceral pain. This paper makes an in-depth overview of peripheral nerve stimulation therapy represented by acupuncture. We look forward to the revival of acupuncture, a long-standing somato stimulus medicine, in the modern medical systems.

  7. Multisensory stimulation in stroke rehabilitation.

    PubMed

    Johansson, Barbro Birgitta

    2012-01-01

    The brain has a large capacity for automatic simultaneous processing and integration of sensory information. Combining information from different sensory modalities facilitates our ability to detect, discriminate, and recognize sensory stimuli, and learning is often optimal in a multisensory environment. Currently used multisensory stimulation methods in stroke rehabilitation include motor imagery, action observation, training with a mirror or in a virtual environment, and various kinds of music therapy. Non-invasive brain stimulation has showed promising preliminary results in aphasia and neglect. Patient heterogeneity and the interaction of age, gender, genes, and environment are discussed. Randomized controlled longitudinal trials starting earlier post-stroke are needed. The advance in brain network science and neuroimaging enabling longitudinal studies of structural and functional networks are likely to have an important impact on patient selection for specific interventions in future stroke rehabilitation. It is proposed that we should pay more attention to age, gender, and laterality in clinical studies.

  8. Multisensory Stimulation in Stroke Rehabilitation

    PubMed Central

    Johansson, Barbro Birgitta

    2012-01-01

    The brain has a large capacity for automatic simultaneous processing and integration of sensory information. Combining information from different sensory modalities facilitates our ability to detect, discriminate, and recognize sensory stimuli, and learning is often optimal in a multisensory environment. Currently used multisensory stimulation methods in stroke rehabilitation include motor imagery, action observation, training with a mirror or in a virtual environment, and various kinds of music therapy. Non-invasive brain stimulation has showed promising preliminary results in aphasia and neglect. Patient heterogeneity and the interaction of age, gender, genes, and environment are discussed. Randomized controlled longitudinal trials starting earlier post-stroke are needed. The advance in brain network science and neuroimaging enabling longitudinal studies of structural and functional networks are likely to have an important impact on patient selection for specific interventions in future stroke rehabilitation. It is proposed that we should pay more attention to age, gender, and laterality in clinical studies. PMID:22509159

  9. Stimulated Superconductivity at Strong Coupling

    SciTech Connect

    Bao, Ning; Dong, Xi; Silverstein, Eva; Torroba, Gonzalo; /Stanford U., ITP /Stanford U., Phys. Dept. /SLAC

    2011-08-12

    Stimulating a system with time dependent sources can enhance instabilities, thus increasing the critical temperature at which the system transitions to interesting low-temperature phases such as superconductivity or superfluidity. After reviewing this phenomenon in non-equilibrium BCS theory (and its marginal fermi liquid generalization) we analyze the effect in holographic superconductors. We exhibit a simple regime in which the transition temperature increases parametrically as we increase the frequency of the time-dependent source.

  10. Movement disorders induced by deep brain stimulation.

    PubMed

    Baizabal-Carvallo, José Fidel; Jankovic, Joseph

    2016-04-01

    Deep brain stimulation represents a major advance in the treatment of several types of movement disorders. However, during stimulation new movement disorders may emerge, thus limiting the positive effects of this therapy. These movement disorders may be induced by: 1) stimulation of the targeted nucleus, 2) stimulation of surrounding tracts and nuclei, and 3) as a result of dose adjustment of accompanying medications, such as reduction of dopaminergic drugs in patients with Parkinson's disease. Various dyskinesias, blepharospasm, and apraxia of eyelid opening have been described mainly with subthalamic nucleus stimulation, whereas hypokinesia and freezing of gait have been observed with stimulation of the globus pallidus internus. Other deep brain stimulation-related movement disorders include dyskinesias associated with stimulation of the globus pallidus externus and ataxic gait as a side effect of chronic bilateral stimulation of the ventral intermediate nucleus of thalamus. These movement disorders are generally reversible and usually resolved once the stimulation is reduced or turned off. This, however, typically leads to loss of benefit of the underlying movement disorder which can be re-gained by using different contacts, changing targets or stimulation parameters, and adjusting pharmacological therapy. New and innovative emerging technologies and stimulation techniques may help to prevent or overcome the various deep brain stimulation-induced movement disorders. In this review we aim to describe the clinical features, frequency, pathophysiology, and strategies for treatment of these iatrogenic movement disorders. PMID:26806438

  11. Interleukin-6 stimulates defective angiogenesis

    PubMed Central

    Gopinathan, Ganga; Milagre, Carla; Pearce, Oliver M.T.; Reynolds, Louise E.; Hodivala-Dilke, Kairbaan; Leinster, David A.; Zhong, Haihong; Hollingsworth, Robert E.; Thompson, Richard; Whiteford, James R.; Balkwill, Frances

    2015-01-01

    The cytokine interleukin-6 (IL-6) has a number of tumor-promoting activities in human and experimental cancers, but its potential as an angiogenic agent has not been fully investigated. Here we show that IL-6 can directly induce vessel sprouting in the ex vivo aortic ring model, as well as endothelial cell proliferation and migration, with similar potency to VEGF. However, IL-6-stimulated aortic ring vessel sprouts had defective pericyte coverage compared to VEGF-stimulated vessels. The mechanism of IL-6 action on pericytes involved stimulation of the Notch ligand Jagged1 as well as Angiopoietin2 (Ang2). When peritoneal xenografts of ovarian cancer were treated with an anti-IL-6 antibody, pericyte coverage of vessels was restored. In addition, in human ovarian cancer biopsies there was an association between levels of IL-6mRNA, Jagged1 and Ang2. Our findings have implications for the use of cancer therapies that target VEGF or IL-6 and for understanding abnormal angiogenesis in cancers, chronic inflammatory disease and stroke. PMID:26081809

  12. Gastric stimulation for weight loss.

    PubMed

    Mizrahi, Meir; Ben Ya'acov, Ami; Ilan, Yaron

    2012-05-21

    The prevalence of obesity is growing to epidemic proportions, and there is clearly a need for minimally invasive therapies with few adverse effects that allow for sustained weight loss. Behavior and lifestyle therapy are safe treatments for obesity in the short term, but the durability of the weight loss is limited. Although promising obesity drugs are in development, the currently available drugs lack efficacy or have unacceptable side effects. Surgery leads to long-term weight loss, but it is associated with morbidity and mortality. Gastric electrical stimulation (GES) has received increasing attention as a potential tool for treating obesity and gastrointestinal dysmotility disorders. GES is a promising, minimally invasive, safe, and effective method for treating obesity. External gastric pacing is aimed at alteration of the motility of the gastrointestinal tract in a way that will alter absorption due to alteration of transit time. In addition, data from animal models and preliminary data from human trials suggest a role for the gut-brain axis in the mechanism of GES. This may involve alteration of secretion of hormones associated with hunger or satiety. Patient selection for gastric stimulation therapy seems to be an important determinant of the treatment's outcome. Here, we review the current status, potential mechanisms of action, and possible future applications of gastric stimulation for obesity. PMID:22654422

  13. Deep Brain Stimulation Tested for Early Alzheimer's

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_160137.html Deep Brain Stimulation Tested for Early Alzheimer's Although treatment seems ... 2016 THURSDAY, July 28, 2016 (HealthDay News) -- Deep brain stimulation appears safe for people with early Alzheimer's ...

  14. Neuromuscular Electrical Stimulation for Skeletal Muscle Function

    PubMed Central

    Doucet, Barbara M.; Lam, Amy; Griffin, Lisa

    2012-01-01

    Lack of neural innervation due to neurological damage renders muscle unable to produce force. Use of electrical stimulation is a medium in which investigators have tried to find a way to restore movement and the ability to perform activities of daily living. Different methods of applying electrical current to modify neuromuscular activity are electrical stimulation (ES), neuromuscular electrical stimulation (NMES), transcutaneous electrical nerve stimulation (TENS), and functional electrical stimulation (FES). This review covers the aspects of electrical stimulation used for rehabilitation and functional purposes. Discussed are the various parameters of electrical stimulation, including frequency, pulse width/duration, duty cycle, intensity/amplitude, ramp time, pulse pattern, program duration, program frequency, and muscle group activated, and how they affect fatigue in the stimulated muscle. PMID:22737049

  15. Triphala herbal extract suppresses inflammatory responses in LPS-stimulated RAW 264.7 macrophages and adjuvant-induced arthritic rats via inhibition of NF-κB pathway.

    PubMed

    Kalaiselvan, Sowmiya; Rasool, Mahaboob Khan

    2016-07-01

    This study sought to explore the mechanism of anti-inflammatory effect of triphala in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and in adjuvant-induced arthritic rats. In stimulated RAW 264.7 cells, triphala (100-300 μg/ml) significantly suppressed production of inflammatory mediators (e.g. TNFα, IL-1β, IL-6, MCP-1, VEGF, NO, PGE2), intracellular free radicals and release of lysosomal enzymes (e.g. acid phosphatase, β-galactosidase, N-acetyl glucosamindase and cathepsin D) in a dose-related manner. With triphala, mRNA levels of genes for pro-inflammatory TNFα, IL-1β, IL-6 and MCP-1, inflammatory iNOS and COX-2 enzymes and NF-κBp65 were down-regulated in the stimulated cells; in contrast, there was up-regulation of heme oxygenase-1 (HO-1) expression. Western blot analyses revealed that triphala suppressed the protein expression of NF-κB p65 and p-NF-κB p65 in the stimulated cells, which subsequently reduced over-expression of TNFα, IL-17, iNOS and COX-2 in a manner similar to that observed with BAY 11-7082, an IκB kinase inhibitor. Immunofluorescence analysis revealed inhibition of p-NF-κB p65 nuclear translocation and COX-2 protein expression caused by triphala. Consistent with these findings, the animal studies presented confirmed that triphala exhibited anti-inflammatory effects in a rat adjuvant-induced arthritis model by reducing of inflammatory mediator (e.g. IL-17, COX-2 and RANKL) expression via inhibition of NF-κB activation. Taken together, the results here demonstrated that triphala has potential anti-inflammatory applications that could be used for the treatment of inflammatory disorders, including rheumatoid arthritis. PMID:27438966

  16. Electrical stimulation for epilepsy: stimulation of hippocampal foci.

    PubMed

    Velasco, F; Velasco, M; Velasco, A L; Menez, D; Rocha, L

    2001-01-01

    Subacute and chronic continuous electrical stimulation at the epileptic focus in the hippocampus or parahippocampal cortex at 130 Hz, 0.21-1.0 ms, 2.5-3.5 V (about 200-300 microA) induces a decrease in focal EEG epileptic interictal activity and also in the occurrence of clinical seizures. This may represent an alternative for the treatment of temporal lobe seizures originated in bilateral independent temporal lobe foci or occurring in patients where one is uncertain whether memory deficit might result from ablative procedures.

  17. Geothermal Reservoir Well Stimulation Program: technology transfer

    SciTech Connect

    Not Available

    1980-05-01

    Each of the following types of well stimulation techniques are summarized and explained: hydraulic fracturing; thermal; mechanical, jetting, and drainhole drilling; explosive and implosive; and injection methods. Current stimulation techniques, stimulation techniques for geothermal wells, areas of needed investigation, and engineering calculations for various techniques. (MHR)

  18. Modeling and Field Results from Seismic Stimulation

    SciTech Connect

    Majer, E.; Pride, S.; Lo, W.; Daley, T.; Nakagawa, Seiji; Sposito, Garrison; Roberts, P.

    2006-05-30

    Modeling the effect of seismic stimulation employing Maxwell-Boltzmann theory shows that the important component of stimulation is mechanical rather than fluid pressure effects. Modeling using Biot theory (two phases) shows that the pressure effects diffuse too quickly to be of practical significance. Field data from actual stimulation will be shown to compare to theory.

  19. Infant Habituation to Visual and Auditory Stimulation.

    ERIC Educational Resources Information Center

    Dunn, Jane; Haskins, Ron

    A total of 14 infants participated in this study of the recovery of visual orienting by crossmodal stimulation when no new visual information was present. The locus of the crossmodal stimulation (auditory stimulation) was discriminable to the subject. Infants in three age groups were tested on three occasions each separated by 30 days. No…

  20. Vomiting Center reanalyzed: An electrical stimulation study

    NASA Technical Reports Server (NTRS)

    Miller, A. D.; Wilson, V. J.

    1982-01-01

    Electrical stimulation of the brainstem of 15 decerebrate cats produced stimulus-bound vomiting in only 4 animals. Vomiting was reproducible in only one cat. Effective stimulating sites were located in the solitary tract and reticular formation. Restricted localization of a vomiting center, stimulation of which evoked readily reproducible results, could not be obtained.

  1. Brain stimulation and inhibitory control.

    PubMed

    Juan, Chi-Hung; Muggleton, Neil G

    2012-04-01

    Inhibitory control mechanisms are important in a range of behaviours to prevent execution of motor acts which, having been planned, are no longer necessary or appropriate. Examples of this can be seen in a range of sports, such as cricket and baseball, where the choice between execution and inhibition of a bat swing must be made in a very brief time window. Deficits in inhibitory control have been associated with problems in behavioural regulation in impulsive violence as well as a range of clinical disorders. The roles of various areas, including the frontal eye fields (FEF), the pre-supplementary motor area (pre-SMA) and the inferior frontal gyrus, in inhibitory control have been investigated using an inhibitory control task and both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Typically effects on response inhibition but no effects on response generation have been seen. The contributions of these areas to performance seem to differ with, for example, pre-SMA being involved when the task is relatively novel whereas this is not the case for FEF. The findings from brain stimulation studies offer both insight into which areas are necessary for effective inhibitory control and recent extension of findings for the role of the inferior frontal gyrus illustrate how the specific functions by which these areas contribute may be further clarified. Future work, including making use of the temporal specificity of TMS and combination of TMS/tDCS with other neuroimaging techniques, may further clarify the nature and functions played by the network of areas involved in inhibitory control. PMID:22494830

  2. Brain stimulation and inhibitory control.

    PubMed

    Juan, Chi-Hung; Muggleton, Neil G

    2012-04-01

    Inhibitory control mechanisms are important in a range of behaviours to prevent execution of motor acts which, having been planned, are no longer necessary or appropriate. Examples of this can be seen in a range of sports, such as cricket and baseball, where the choice between execution and inhibition of a bat swing must be made in a very brief time window. Deficits in inhibitory control have been associated with problems in behavioural regulation in impulsive violence as well as a range of clinical disorders. The roles of various areas, including the frontal eye fields (FEF), the pre-supplementary motor area (pre-SMA) and the inferior frontal gyrus, in inhibitory control have been investigated using an inhibitory control task and both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Typically effects on response inhibition but no effects on response generation have been seen. The contributions of these areas to performance seem to differ with, for example, pre-SMA being involved when the task is relatively novel whereas this is not the case for FEF. The findings from brain stimulation studies offer both insight into which areas are necessary for effective inhibitory control and recent extension of findings for the role of the inferior frontal gyrus illustrate how the specific functions by which these areas contribute may be further clarified. Future work, including making use of the temporal specificity of TMS and combination of TMS/tDCS with other neuroimaging techniques, may further clarify the nature and functions played by the network of areas involved in inhibitory control.

  3. Stimulated Parametric Emission Microscope Systems

    NASA Astrophysics Data System (ADS)

    Itoh, Kazuyoshi; Isobe, Keisuke

    2006-10-01

    We present a novel microscopy technique based on the fourwave mixing (FWM) process that is enhanced by two-photon electronic resonance induced by a pump pulse along with stimulated emission induced by a dump pulse. A Ti:sapphire laser and an optical parametric oscillator are used as light sources for the pump and dump pulses, respectively. We demonstrate that our FWM technique can be used to obtain two-dimensional microscopic images of an unstained leaf of Camellia sinensis and an unlabeled tobacco BY2 Cell.

  4. Stimulated Brillouin Scattering Microscopic Imaging

    PubMed Central

    Ballmann, Charles W.; Thompson, Jonathan V.; Traverso, Andrew J.; Meng, Zhaokai; Scully, Marlan O.; Yakovlev, Vladislav V.

    2015-01-01

    Two-dimensional stimulated Brillouin scattering microscopy is demonstrated for the first time using low power continuous-wave lasers tunable around 780 nm. Spontaneous Brillouin spectroscopy has much potential for probing viscoelastic properties remotely and non-invasively on a microscopic scale. Nonlinear Brillouin scattering spectroscopy and microscopy may provide a way to tremendously accelerate the data aquisition and improve spatial resolution. This general imaging setup can be easily adapted for specific applications in biology and material science. The low power and optical wavelengths in the water transparency window used in this setup provide a powerful bioimaging technique for probing the mechanical properties of hard and soft tissue. PMID:26691398

  5. Transcranial magnetic stimulation in neurology

    PubMed Central

    Eldaief, Mark C.; Press, Daniel Z.

    2013-01-01

    Summary Transcranial magnetic stimulation (TMS) is a neurophysiologic technique to noninvasively induce a controlled current pulse in a prespecified cortical target. This can be used to transiently disrupt the function of the targeted cortical region and explore causal relations to behavior, assess cortical reactivity, and map out functionally relevant brain regions, for example during presurgical assessments. Particularly when applied repetitively, TMS can modify cortical excitability and the effects can propagate trans-synaptically to interconnected cortical, subcortical, and spinal cord regions. As such, TMS can be used to assess the functional integrity of neural circuits and to modulate brain activity with potential therapeutic intent. PMID:24353923

  6. Multicolor stimulated Raman scattering microscopy

    NASA Astrophysics Data System (ADS)

    Lu, Fa-Ke; Ji, Minbiao; Fu, Dan; Ni, Xiaohui; Freudiger, Christian W.; Holtom, Gary; Xie, X. Sunney

    2012-08-01

    Stimulated Raman scattering (SRS) microscopy has opened up a wide range of biochemical imaging applications by probing a particular Raman-active molecule vibrational mode in the specimen. However, the original implementation with picosecond pulse excitation can only realize rapid chemical mapping with a single Raman band. Here we present a novel SRS microscopic technique using a grating-based pulse shaper for excitation and a grating-based spectrograph for detection to achieve simultaneous multicolor SRS imaging with high sensitivity and high acquisition speeds. In particular, we use a linear combination of the measured CH2 and CH3 stretching signals to map the distributions of protein and lipid contents simultaneously.

  7. Stimulated Brillouin Scattering Microscopic Imaging.

    PubMed

    Ballmann, Charles W; Thompson, Jonathan V; Traverso, Andrew J; Meng, Zhaokai; Scully, Marlan O; Yakovlev, Vladislav V

    2015-01-01

    Two-dimensional stimulated Brillouin scattering microscopy is demonstrated for the first time using low power continuous-wave lasers tunable around 780 nm. Spontaneous Brillouin spectroscopy has much potential for probing viscoelastic properties remotely and non-invasively on a microscopic scale. Nonlinear Brillouin scattering spectroscopy and microscopy may provide a way to tremendously accelerate the data aquisition and improve spatial resolution. This general imaging setup can be easily adapted for specific applications in biology and material science. The low power and optical wavelengths in the water transparency window used in this setup provide a powerful bioimaging technique for probing the mechanical properties of hard and soft tissue.

  8. Stimulated Brillouin Scattering Microscopic Imaging

    NASA Astrophysics Data System (ADS)

    Ballmann, Charles W.; Thompson, Jonathan V.; Traverso, Andrew J.; Meng, Zhaokai; Scully, Marlan O.; Yakovlev, Vladislav V.

    2015-12-01

    Two-dimensional stimulated Brillouin scattering microscopy is demonstrated for the first time using low power continuous-wave lasers tunable around 780 nm. Spontaneous Brillouin spectroscopy has much potential for probing viscoelastic properties remotely and non-invasively on a microscopic scale. Nonlinear Brillouin scattering spectroscopy and microscopy may provide a way to tremendously accelerate the data aquisition and improve spatial resolution. This general imaging setup can be easily adapted for specific applications in biology and material science. The low power and optical wavelengths in the water transparency window used in this setup provide a powerful bioimaging technique for probing the mechanical properties of hard and soft tissue.

  9. Tissue stimulator enclosure welding fixture

    NASA Technical Reports Server (NTRS)

    Mcclure, S. R.

    1977-01-01

    It was demonstrated that the thickness of the stimulator titanium enclosure is directly related to the battery recharge time cycle. Reduction of the titanium enclosure thickness from approximately 0.37 mm (0.015 inch) to 0.05 mm (0.002 inch) significantly reduced the recharge time cycle and thereby patient inconvenience. However, fabrication of titanium enclosures from the thinner material introduced problems in forming, holding, and welding that required improvement in state of the art shop practices. The procedures that were utilized to resolve these fabrication problems are described.

  10. Pumping effect of stimulated Brillouin scattering on stimulated Raman scattering in water

    NASA Astrophysics Data System (ADS)

    Liu, Dahe; Shi, Jinwei; Ouyang, Min; Chen, Xudong; Liu, Juan; He, Xingdao

    2009-09-01

    It is investigated experimentally that stimulated Raman scattering (SRS) can be enhanced by stimulated Brillouin scattering (SBS). Two physical mechanisms of these phenomena were analyzed. These phenomena show that not only the competition between SBS and SRS exists, the pumping effect of stimulated Brillouin scattering on back-stimulated Raman scattering is also a commonly existing rule regardless of the experimental conditions.

  11. Bubble stimulation efficiency of dinoflagellate bioluminescence.

    PubMed

    Deane, Grant B; Stokes, M Dale; Latz, Michael I

    2016-02-01

    Dinoflagellate bioluminescence, a common source of bioluminescence in coastal waters, is stimulated by flow agitation. Although bubbles are anecdotally known to be stimulatory, the process has never been experimentally investigated. This study quantified the flash response of the bioluminescent dinoflagellate Lingulodinium polyedrum to stimulation by bubbles rising through still seawater. Cells were stimulated by isolated bubbles of 0.3-3 mm radii rising at their terminal velocity, and also by bubble clouds containing bubbles of 0.06-10 mm radii for different air flow rates. Stimulation efficiency, the proportion of cells producing a flash within the volume of water swept out by a rising bubble, decreased with decreasing bubble radius for radii less than approximately 1 mm. Bubbles smaller than a critical radius in the range 0.275-0.325 mm did not stimulate a flash response. The fraction of cells stimulated by bubble clouds was proportional to the volume of air in the bubble cloud, with lower stimulation levels observed for clouds with smaller bubbles. An empirical model for bubble cloud stimulation based on the isolated bubble observations successfully reproduced the observed stimulation by bubble clouds for low air flow rates. High air flow rates stimulated more light emission than expected, presumably because of additional fluid shear stress associated with collective buoyancy effects generated by the high air fraction bubble cloud. These results are relevant to bioluminescence stimulation by bubbles in two-phase flows, such as in ship wakes, breaking waves, and sparged bioreactors.

  12. Infrared neural stimulation in the cochlea

    PubMed Central

    Richter, Claus-Peter; Rajguru, Suhrud; Bendett, Mark

    2014-01-01

    The application of photonics to manipulate and stimulate neurons and to study neural networks has gained momentum over the last decade. Two general methods have been used: the genetic expression of light or temperature sensitive ion channels in the plasma membrane of neurons (Optogenetics and Thermogenetics) and the direct stimulation of neurons using infrared radiation (Infrared Neural Stimulation, INS). Both approaches have their strengths and challenges, which are well understood with a profound understanding of the light tissue interaction(s). This paper compares the opportunities of the methods for the use in cochlear prostheses. Ample data are already available on the stimulation of the cochlea with INS. The data show that the stimulation is selective, feasible at rates that would be sufficient to encode acoustic information and may be beneficial over conventional pulsed electrical stimulation. A third approach, using lasers in stress confinement to generate pressure waves and to stimulate the functional cochlea mechanically will also be discussed. PMID:25075260

  13. Infrared neural stimulation in the cochlea.

    PubMed

    Richter, Claus-Peter; Rajguru, Suhrud; Bendett, Mark

    2013-03-01

    The application of photonics to manipulate and stimulate neurons and to study neural networks has gained momentum over the last decade. Two general methods have been used: the genetic expression of light or temperature sensitive ion channels in the plasma membrane of neurons (Optogenetics and Thermogenetics) and the direct stimulation of neurons using infrared radiation (Infrared Neural Stimulation, INS). Both approaches have their strengths and challenges, which are well understood with a profound understanding of the light tissue interaction(s). This paper compares the opportunities of the methods for the use in cochlear prostheses. Ample data are already available on the stimulation of the cochlea with INS. The data show that the stimulation is selective, feasible at rates that would be sufficient to encode acoustic information and may be beneficial over conventional pulsed electrical stimulation. A third approach, using lasers in stress confinement to generate pressure waves and to stimulate the functional cochlea mechanically will also be discussed. PMID:25075260

  14. Deep Brain Stimulation for Obesity

    PubMed Central

    Sussman, Eric S; Zhang, Michael; Pendharkar, Arjun V; Azagury, Dan E; Bohon, Cara; Halpern, Casey H

    2015-01-01

    Obesity is now the third leading cause of preventable death in the US, accounting for 216,000 deaths annually and nearly 100 billion dollars in health care costs. Despite advancements in bariatric surgery, substantial weight regain and recurrence of the associated metabolic syndrome still occurs in almost 20-35% of patients over the long-term, necessitating the development of novel therapies. Our continually expanding knowledge of the neuroanatomic and neuropsychiatric underpinnings of obesity has led to increased interest in neuromodulation as a new treatment for obesity refractory to current medical, behavioral, and surgical therapies. Recent clinical trials of deep brain stimulation (DBS) in chronic cluster headache, Alzheimer’s disease, and depression and obsessive-compulsive disorder have demonstrated the safety and efficacy of targeting the hypothalamus and reward circuitry of the brain with electrical stimulation, and thus provide the basis for a neuromodulatory approach to treatment-refractory obesity. In this study, we review the literature implicating these targets for DBS in the neural circuitry of obesity. We will also briefly review ethical considerations for such an intervention, and discuss genetic secondary-obesity syndromes that may also benefit from DBS. In short, we hope to provide the scientific foundation to justify trials of DBS for the treatment of obesity targeting these specific regions of the brain. PMID:26180683

  15. Braille line using electrical stimulation

    NASA Astrophysics Data System (ADS)

    Puertas, A.; Purés, P.; Echenique, A. M.; Ensinck, J. P. Graffigna y. G.

    2007-11-01

    Conceived within the field of Rehabilitation Technologies for visually impaired persons, the present work aims at enabling the blind user to read written material by means of a tactile display. Once he is familiarized to operate this system, the user will be able to achieve greater performance in study, academic and job activities, thus achieving a rapid and easier social inclusion. The devise accepts any kind of text that is computer-loadable (documents, books, Internet information, and the like) which, through digital means, can be read as Braille text on the pad. This tactile display is composed of an electrodes platform that simulate, through stimulation the writing/reading Braille characters. In order to perceive said characters in similar way to the tactile feeling from paper material, the skin receptor of fingers are stimulated electrically so as to simulate the same pressure and depressions as those of the paper-based counterpart information. Once designed and developed, the display was tested with blind subjects, with relatively satisfactory results. As a continuing project, this prototype is currently being improved as regards.

  16. Optogenetic stimulation of the auditory pathway

    PubMed Central

    Hernandez, Victor H.; Gehrt, Anna; Reuter, Kirsten; Jing, Zhizi; Jeschke, Marcus; Mendoza Schulz, Alejandro; Hoch, Gerhard; Bartels, Matthias; Vogt, Gerhard; Garnham, Carolyn W.; Yawo, Hiromu; Fukazawa, Yugo; Augustine, George J.; Bamberg, Ernst; Kügler, Sebastian; Salditt, Tim; de Hoz, Livia; Strenzke, Nicola; Moser, Tobias

    2014-01-01

    Auditory prostheses can partially restore speech comprehension when hearing fails. Sound coding with current prostheses is based on electrical stimulation of auditory neurons and has limited frequency resolution due to broad current spread within the cochlea. In contrast, optical stimulation can be spatially confined, which may improve frequency resolution. Here, we used animal models to characterize optogenetic stimulation, which is the optical stimulation of neurons genetically engineered to express the light-gated ion channel channelrhodopsin-2 (ChR2). Optogenetic stimulation of spiral ganglion neurons (SGNs) activated the auditory pathway, as demonstrated by recordings of single neuron and neuronal population responses. Furthermore, optogenetic stimulation of SGNs restored auditory activity in deaf mice. Approximation of the spatial spread of cochlear excitation by recording local field potentials (LFPs) in the inferior colliculus in response to suprathreshold optical, acoustic, and electrical stimuli indicated that optogenetic stimulation achieves better frequency resolution than monopolar electrical stimulation. Virus-mediated expression of a ChR2 variant with greater light sensitivity in SGNs reduced the amount of light required for responses and allowed neuronal spiking following stimulation up to 60 Hz. Our study demonstrates a strategy for optogenetic stimulation of the auditory pathway in rodents and lays the groundwork for future applications of cochlear optogenetics in auditory research and prosthetics. PMID:24509078

  17. Deep Brain Stimulation: Expanding Applications

    PubMed Central

    TEKRIWAL, Anand; BALTUCH, Gordon

    2015-01-01

    For over two decades, deep brain stimulation (DBS) has shown significant efficacy in treatment for refractory cases of dyskinesia, specifically in cases of Parkinson's disease and dystonia. DBS offers potential alleviation from symptoms through a well-tolerated procedure that allows personalized modulation of targeted neuroanatomical regions and related circuitries. For clinicians contending with how to provide patients with meaningful alleviation from often debilitating intractable disorders, DBSs titratability and reversibility make it an attractive treatment option for indications ranging from traumatic brain injury to progressive epileptic supra-synchrony. The expansion of our collective knowledge of pathologic brain circuitries, as well as advances in imaging capabilities, electrophysiology techniques, and material sciences have contributed to the expanding application of DBS. This review will examine the potential efficacy of DBS for neurologic and psychiatric disorders currently under clinical investigation and will summarize findings from recent animal models. PMID:26466888

  18. Vestibular stimulation by magnetic fields

    PubMed Central

    Ward, Bryan K.; Roberts, Dale C.; Della Santina, Charles C.; Carey, John P.; Zee, David S.

    2015-01-01

    Individuals working next to strong static magnetic fields occasionally report disorientation and vertigo. With the increasing strength of magnetic fields used for magnetic resonance imaging (MRI) studies, these reports have become more common. It was recently learned that humans, mice and zebrafish all demonstrate behaviors consistent with constant peripheral vestibular stimulation while inside a strong, static magnetic field. The proposed mechanism for this effect involves a Lorentz force resulting from the interaction of a strong static magnetic field with naturally occurring ionic currents flowing through the inner ear endolymph into vestibular hair cells. The resulting force within the endolymph is strong enough to displace the lateral semicircular canal cupula, inducing vertigo and the horizontal nystagmus seen in normal mice and in humans. This review explores the evidence for interactions of magnetic fields with the vestibular system. PMID:25735662

  19. Electrode array for neural stimulation

    DOEpatents

    Wessendorf, Kurt O.; Okandan, Murat; Stein, David J.; Yang, Pin; Cesarano, III, Joseph; Dellinger, Jennifer

    2011-08-16

    An electrode array for neural stimulation is disclosed which has particular applications for use in a retinal prosthesis. The electrode array can be formed as a hermetically-sealed two-part ceramic package which includes an electronic circuit such as a demultiplexer circuit encapsulated therein. A relatively large number (up to 1000 or more) of individually-addressable electrodes are provided on a curved surface of a ceramic base portion the electrode array, while a much smaller number of electrical connections are provided on a ceramic lid of the electrode array. The base and lid can be attached using a metal-to-metal seal formed by laser brazing. Electrical connections to the electrode array can be provided by a flexible ribbon cable which can also be used to secure the electrode array in place.

  20. Acupuncture stimulation and neuroendocrine regulation.

    PubMed

    Yu, Jung-Sheng; Zeng, Bai-Yun; Hsieh, Ching-Liang

    2013-01-01

    Acupuncture has been used to treat different conditions for at least 3000 years in China and has gained increasing acceptance worldwide. The acupuncture needle inserted into the muscle layer at the acupoint produces the so-called obtaining qi sensation that causes the excitation of A-δ and C-fibers of the muscle tissue, resulting in afferent signals. The afferent signals pass through the dorsal horn cells of the spinal cord ascending to the brain, such as the hypothalamus, enhancing the release of neuropeptides and hormones, and these afferent signals in the spinal segment may innervate the visceral organ, inducing effect on visceral function. Here, we reviewed the effect of acupuncture stimulation on neuropeptides and hormones, including β-endorphin, serotonin, oxytocin, adrenocorticotropic hormone, gonadotropin-releasing hormone, corticotrophin-releasing hormone, cholecystokinin, and acetylcholine, as well as insulin sensitivity, immunomodulation (anti-inflammation), and autonomic nerve activity. PMID:24215920

  1. [Use of erythropoiesis stimulating agents].

    PubMed

    Lapierre, A; Souquet, P-J

    2014-02-01

    Anemia is fairly common in lung neoplasms and adequate management can influence both the prognosis and the quality of life of patients. Anemia can stem from diverse mechanisms, and its management must include the search for correctable causes (iron deficiency, inflammation, disease- or treatment-related), and their subsequent treatment. Use of erythropoiesis stimulating agents, namely recombinant erythropoietin, results in hemoglobin increase, fewer blood transfusions, and better quality of life. However, there is also a significant increase in thromboembolic risk associated with this treatment, and their effect on overall survival is still debated. Thus, their use must be restricted to patients treated with palliative intent, receiving chemotherapy but no radiotherapy, with a baseline hemoglobin level under 100 g/L, and target hemoglobin level must not exceed 120 g/L.

  2. Mimicking muscle activity with electrical stimulation

    NASA Astrophysics Data System (ADS)

    Johnson, Lise A.; Fuglevand, Andrew J.

    2011-02-01

    Functional electrical stimulation is a rehabilitation technology that can restore some degree of motor function in individuals who have sustained a spinal cord injury or stroke. One way to identify the spatio-temporal patterns of muscle stimulation needed to elicit complex upper limb movements is to use electromyographic (EMG) activity recorded from able-bodied subjects as a template for electrical stimulation. However, this requires a transfer function to convert the recorded (or predicted) EMG signals into an appropriate pattern of electrical stimulation. Here we develop a generalized transfer function that maps EMG activity into a stimulation pattern that modulates muscle output by varying both the pulse frequency and the pulse amplitude. We show that the stimulation patterns produced by this transfer function mimic the active state measured by EMG insofar as they reproduce with good fidelity the complex patterns of joint torque and joint displacement.

  3. Increased skin temperature during transcutaneous electrical stimulation.

    PubMed

    Abram, S E; Asiddao, C B; Reynolds, A C

    1980-01-01

    Conflicting reports have appeared in the literature concerning the effects of transcutaneous electrical nerve stimulation on skin temperature. This report studied 33 patients with chronic pain involving one extremity (13 upper, 20 lower) to determine whether changes in sympathetic tone, as reflected in skin temperature, occurred in response to electrical stimulation of painful areas. Stimulation was carried out for 20 to 45 minutes. Skin temperatures were measured from the thumbs or great toes of stimulated and contralateral extremities before and during stimulation. Skin temperature rose 2.5 +/- 0.7 (mean +/- SEM) in both the ipsilateral and contralateral extremity in patients who experienced relief of pain during stimulation. There was no significant change in skin temperature in patients who experienced no relief.

  4. Analysis of Facial Expression by Taste Stimulation

    NASA Astrophysics Data System (ADS)

    Tobitani, Kensuke; Kato, Kunihito; Yamamoto, Kazuhiko

    In this study, we focused on the basic taste stimulation for the analysis of real facial expressions. We considered that the expressions caused by taste stimulation were unaffected by individuality or emotion, that is, such expressions were involuntary. We analyzed the movement of facial muscles by taste stimulation and compared real expressions with artificial expressions. From the result, we identified an obvious difference between real and artificial expressions. Thus, our method would be a new approach for facial expression recognition.

  5. A Microcomputer-Based Neurophysiological Stimulator

    PubMed Central

    Halter, John

    1979-01-01

    A neurophysiological stimulator is presented which utilizes TTL hardware controlled by a microcomputer. Up to four channels of stimulation are provided, each of which consists of a TTL-Based Pulse Generator. Operating parameters are entered into the stimulator via a front panel in a format familiar to the clinician. Operating parameters may be investigated and modified at any time by another computer, thereby enabling the implementation of more complex clinical procedures. ImagesFigure 1Figure 4

  6. Geothermal Reservoir Well Stimulation Program: technology transfer

    SciTech Connect

    Not Available

    1980-05-01

    A literature search on reservoir and/or well stimulation techniques suitable for application in geothermal fields is presented. The literature on stimulation techniques in oil and gas field applications was also searched and evaluated as to its relevancy to geothermal operations. The equivalent low-temperature work documented in the open literature is cited, and an attempt is made to evaluate the relevance of this information as far as high-temperature stimulation work is concerned. Clays play an important role in any stimulation work. Therefore, special emphasis has been placed on clay behavior anticipated in geothermal operations. (MHR)

  7. Transcranial Direct Current Stimulation in Stroke Recovery

    PubMed Central

    Schlaug, Gottfried; Renga, Vijay; Nair, Dinesh

    2009-01-01

    TDCS - Transcranial Direct Current Stimulation - is an emerging technique of non-invasive brain stimulation that has been found useful in examining cortical function in normal subjects and in facilitating treatments of various neurological disorders. A better understanding of adaptive as well as maladaptive post-stroke neuroplasticity and its modulation through non-invasive brain stimulation has opened up experimental treatment options using TDCS for patients recovering from stroke. We will review TDCS’s role as a facilitator of stroke recovery, the different modes of transcranial direct current stimulation, and the potential mechanisms underlying the neural effects of TDCS. PMID:19064743

  8. Ovarian stimulation in patients with breast cancer.

    PubMed

    Muñoz, Elkin; González, Naira; Muñoz, Luis; Aguilar, Jesús; Velasco, Juan A García

    2015-01-01

    Breast cancer is the most prevalent malignancy among women under 50. Improvements in diagnosis and treatment have yielded an important decrease in mortality in the last 20 years. In many cases, chemotherapy and radiotherapy develop side effects on the reproductive function. Therefore, before the anti-cancer treatment impairs fertility, clinicians should offer some techniques for fertility preservation for women planning motherhood in the future. In order to obtain more available oocytes for IVF, the ovary must be stimulated. New protocols which prevent exposure to increased estrogen during gonadotropin stimulation, measurements to avoid the delay in starting anti-cancer treatment or the outcome of ovarian stimulation have been addressed in this review. There is no evidence of association between ovarian stimulation and breast cancer. It seems that there are more relevant other confluent factors than ovarian stimulation. Factors that can modify the risk of breast cancer include: parity, age at full-term birth, age of menarche, and family history. There is an association between breast cancer and exogenous estrogen. Therefore, specific protocols to stimulate patients with breast cancer include anti-estrogen agents such as letrozole. By using letrozole plus recombinant follicular stimulating hormone, patients develop a multifollicular growth with only a mild increase in estradiol serum levels. Controlled ovarian stimulation (COS) takes around 10 days, and we discuss new strategies to start COS as soon as possible. Protocols starting during the luteal phase or after inducing the menses currently prevent a delay in starting ovarian stimulation. Patients with breast cancer have a poorer response to COS compared with patients without cancer who are stimulated with conventional protocols of gonadotropins. Although many centres offer fertility preservation and many patients undergo ovarian stimulation, there are not enough studies to evaluate the recurrence, breast cancer

  9. [Deep brain stimulation in schizophrenia].

    PubMed

    Kuhn, J; Bodatsch, M; Sturm, V; Lenartz, D; Klosterkötter, J; Uhlhaas, P J; Winter, C; Gründler, T O J

    2011-11-01

    Deep brain stimulation (DBS) has successfully advanced our treatment options for putative therapy-resistant neuropsychiatric diseases. Building on this strong foundation, more and more mental disorders in the stadium of therapy-resistance are considered as possible indications for DBS. Especially, schizophrenia with its associated severe and difficult to treat symptoms is gaining attention. This attention demands critical questions regarding the assumed mechanisms of DBS and its possible influence on the supposed pathophysiology of schizophrenia. Here, we synoptically compare current approaches and theories of DBS and discuss the feasibility of DBS in schizophrenia as well as the transferability from other psychiatric disorders successfully treated with DBS. For this we consider recent advances in animal models of schizophrenic symptoms, results regarding the influence of DBS on dopaminergic transmission as well as data concerning neural oscillation and synchronisation. In conclusion, the use of DBS for some symptoms of schizophrenia seems to be a promising approach, but the lack of a comprehensive theory of the mechanisms of DBS as well as its impact on schizophrenia might hinder the use of DBS for schizophrenia at this point in time.

  10. Transcranial Magnetic Stimulation for Schizophrenia.

    PubMed

    Dougall, Nadine; Maayan, Nicola; Soares-Weiser, Karla; McDermott, Lisa M; McIntosh, Andrew

    2015-11-01

    People with schizophrenia typically experience auditory hallucinations or delusions during acute episodes. Although effective drug treatments are available, many have intractable symptoms that do not recover between acute episodes. One proposed alternative to drug treatments is transcranial magnetic stimulation (TMS). To date, many research trials to assess effectiveness of TMS for people with symptoms of schizophrenia have been conducted worldwide. However, there is a lack of consensus on whether TMS should be recommended to be adopted in routine clinical practice. We conducted a systematic review of the literature for all relevant randomized controlled trials (RCTs) comparing TMS with sham or standard treatment. Forty-one trials (1473 participants) survived eligibility criteria and had extractable data. We found significant differences in favor of temporoparietal TMS compared with sham TMS for global state (7 RCTs, n = 224, MD: -0.5, 95% CI: -0.76 to -0.23) and for positive symptoms measured on the Positive and Negative Syndrome Scale (5 RCTs, n = 127, MD: -6.09, 95% CI: -10.95 to -1.22). However, we also found that the quality of trial reporting was frequently suboptimal and the risks of bias were strong or unascertainable for many trial aspects; this led to many results being graded as very low-quality evidence. On that basis, we were unable to definitively support or refute the routine use of TMS in clinical practice. Future definitive trials of TMS with rigorous processes and high-quality reporting are needed.

  11. Digital electronic bone growth stimulator

    DOEpatents

    Kronberg, J.W.

    1993-01-01

    The present invention relates to the electrical treatment of biological tissue. In particular, the present invention discloses a device that produces discrete electrical pulse trains for treating osteoporosis and accelerating bone growth. According to its major aspects and broadly stated, the present invention consists of an electrical circuit configuration capable of generating Bassett-type waveforms shown with alternative signals provide for the treatment of either fractured bones or osteoporosis. The signal generator comprises a quartz clock, an oscillator circuit, a binary divider chain, and a plurality of simple, digital logic gates. Signals are delivered efficiently, with little or no distortion, and uniformly distributed throughout the area of injury. Perferably, power is furnished by widely available and inexpensive radio batteries, needing replacement only once in several days. The present invention can be affixed to a medical cast without a great increase in either weight or bulk. Also, the disclosed stimulator can be used to treat osteoporosis or to strengthen a healing bone after the cast has been removed by attaching the device to the patient`s skin or clothing.

  12. Hyperthermia Stimulates HIV-1 Replication

    PubMed Central

    Roesch, Ferdinand; Meziane, Oussama; Kula, Anna; Nisole, Sébastien; Porrot, Françoise; Anderson, Ian; Mammano, Fabrizio; Fassati, Ariberto; Marcello, Alessandro; Benkirane, Monsef; Schwartz, Olivier

    2012-01-01

    HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42–45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38–40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity. PMID:22807676

  13. Three-dimensional visual stimulator

    NASA Astrophysics Data System (ADS)

    Takeda, Tsunehiro; Fukui, Yukio; Hashimoto, Keizo; Hiruma, Nobuyuki

    1995-02-01

    We describe a newly developed three-dimensional visual stimulator (TVS) that can change independently the directions, distances, sizes, luminance, and varieties of two sets of targets for both eyes. It consists of liquid crystal projectors (LCP's) that generate the flexible images of targets, Badal otometers that change target distances without changing the visual angles, and relay-lens systems that change target directions. A special control program is developed for real-time control of six motors and two LCP's in the TVS together with a three-dimensional optometer III that simultaneously measures eye movement, accommodation, pupil diameter, and head movement. distance, 0 to -20 D; direction, 16 horizontally and 15 vertically; size, 0-2 deg visual angle; and luminance, 10-2-10 2 cd/m2. The target images are refreshed at 60 Hz and speeds with which the target makes a smooth change (ramp stimuli) are size, 10 deg/s. A simple application demonstrates the performance.

  14. Electrocutaneous stimulation system for Braille reading.

    PubMed

    Echenique, Ana Maria; Graffigna, Juan Pablo; Mut, Vicente

    2010-01-01

    This work is an assistive technology for people with visual disabilities and aims to facilitate access to written information in order to achieve better social inclusion and integration into work and educational activities. Two methods of electrical stimulation (by current and voltage) of the mechanoreceptors was tested to obtain tactile sensations on the fingertip. Current and voltage stimulation were tested in a Braille cell and line prototype, respectively. These prototypes are evaluated in 33 blind and visually impaired subjects. The result of experimentation with both methods showed that electrical stimulation causes sensations of touch defined in the fingertip. Better results in the Braille characters reading were obtained with current stimulation (85% accuracy). However this form of stimulation causes uncomfortable sensations. The latter feeling was minimized with the method of voltage stimulation, but with low efficiency (50% accuracy) in terms of identification of the characters. We concluded that electrical stimulation is a promising method for the development of a simple and unexpensive Braille reading system for blind people. We observed that voltage stimulation is preferred by the users. However, more experimental tests must be carry out in order to find the optimum values of the stimulus parameters and increase the accuracy the Braille characters reading.

  15. Stimulated Cherenkov emission in gas dynamics

    SciTech Connect

    Kuzelev, M. V. Rukhadze, A. A.

    2008-11-15

    A linear theory is developed for stimulated Cherenkov emission from planar and cylindrical gas flows in gaseous environments. An analogy is demonstrated between Cherenkov emission in gas dynamics and stimulated Cherenkov electromagnetic emission from a charged particle beam in a medium.

  16. Passive Auditory Stimulation Improves Vision in Hemianopia

    PubMed Central

    Lewald, Jörg; Tegenthoff, Martin; Peters, Sören; Hausmann, Markus

    2012-01-01

    Techniques employed in rehabilitation of visual field disorders such as hemianopia are usually based on either visual or audio-visual stimulation and patients have to perform a training task. Here we present results from a completely different, novel approach that was based on passive unimodal auditory stimulation. Ten patients with either left or right-sided pure hemianopia (without neglect) received one hour of unilateral passive auditory stimulation on either their anopic or their intact side by application of repetitive trains of sound pulses emitted simultaneously via two loudspeakers. Immediately before and after passive auditory stimulation as well as after a period of recovery, patients completed a simple visual task requiring detection of light flashes presented along the horizontal plane in total darkness. The results showed that one-time passive auditory stimulation on the side of the blind, but not of the intact, hemifield of patients with hemianopia induced an improvement in visual detections by almost 100% within 30 min after passive auditory stimulation. This enhancement in performance was reversible and was reduced to baseline 1.5 h later. A non-significant trend of a shift of the visual field border toward the blind hemifield was obtained after passive auditory stimulation. These results are compatible with the view that passive auditory stimulation elicited some activation of the residual visual pathways, which are known to be multisensory and may also be sensitive to unimodal auditory stimuli as were used here. Trial Registration DRKS00003577 PMID:22666311

  17. [MRI compatibility of deep brain stimulator].

    PubMed

    Zhang, Yujing

    2013-07-01

    Deep brain stimulation (DBS) therapy develops rapidly in clinical application. The structures of deep brain stimulator and magnetic resonance imaging (MRI) equipment are introduced, the interactions are analyzed, and the two compatible problems of radio frequency (RF) heating and imaging artifact are summarized in this paper.

  18. Stimulation Activities: Age Birth to Five Years.

    ERIC Educational Resources Information Center

    Bloomgarden, Dave

    This handbook provides a collection of stimulation activities that encourage a child's physical and mental growth from birth to five years of age. Emphasis is placed on making stimulation aids that are inexpensive or can be made from scrap materials. Advice is given about ways to carry out designated activities. All activities have been tried and…

  19. Pseudomonas putida Stimulates Primordia on Agaricus bitorquis.

    PubMed

    Colauto, Nelson B; Fermor, Terry R; Eira, Augusto F; Linde, Giani A

    2016-04-01

    Casing layer is one step of Agaricus bisporus cultivation where there is a competitive environment with a high number of microorganisms and diversity interacting with mycelia. It is suggested that a minimal community of these microorganisms would be necessary to stimulate fructification. However, A. bisporus is not able to produce primordia in sterile casing layers or Petri dishes. Thus, the objective of this study was to characterize bacterial microbiota of casing layers from A. bisporus cultivation, isolate, identify and characterize the bacteria responsible for the stimulation of primordium and their action mechanism using Agaricus bitorquis as a primordium stimulation model. Bacterial and Pseudomonas spp. communities of different casing layers of A. bisporus cultivation were collected and quantified. It was concluded that Pseudomonas spp. corresponds to 75-85% of bacterial population of the casing layers in A. bisporus cultivation and among those 12% are Pseudomonas putida. Four biochemical assays were used to identify P. putida. In vitro primordium stimulation of living P. putida and non-living bacterial suspensions, after chemical or physical treatments, was tested using A. bitorquis as a primordium stimulation model. Primordium stimulation assay was registered by photographs, and micrographs of vertical cut of primordium were registered by scanning electron microscope. Interaction of living P. putida with A. bitorquis mycelia is capable of stimulating primordial instead of non-living bacterial suspensions. Stimulation of A. bitorquis primordia does not imply or is related to mycelial growth inhibition, but a hierarchical relation of primordium succession and development is suggested. PMID:26742772

  20. Ultraviolet Light: Some Considerations for Vision Stimulation.

    ERIC Educational Resources Information Center

    Knowlton, Marie

    1986-01-01

    The article examines evidence of visual impairment caused by excessive amounts of ultraviolet (UV) light. Among considerations when using a source of UV light for vision stimulation are the position of the child and teacher, use of window glass filters or protective glasses, and careful recordkeeping of all UV stimulation. (Author/JW)[

  1. Neurologic Complications of Psychomotor Stimulant Abuse.

    PubMed

    Sanchez-Ramos, Juan

    2015-01-01

    Psychomotor stimulants are drugs that act on the central nervous system (CNS) to increase alertness, elevate mood, and produce a sense of well-being. These drugs also decrease appetite and the need for sleep. Stimulants can enhance stamina and improve performance in tasks that have been impaired by fatigue or boredom. Approved therapeutic applications of stimulants include attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. These agents also possess potent reinforcing properties that can result in excessive self-administration and abuse. Chronic use is associated with adverse effects including psychosis, seizures, and cerebrovascular accidents, though these complications usually occur in individuals with preexisting risk factors. This chapter reviews the adverse neurologic consequences of chronic psychomotor stimulant use and abuse, with a focus on two prototypical stimulants methamphetamine and cocaine. PMID:26070756

  2. Relief of pain by transcutaneous stimulation.

    PubMed

    Loeser, J D; Black, R G; Christman, A

    1975-03-01

    A series of 198 patients with chronic pain of diverse etiology was carefully analyzed for epidemiologic and descriptive factors which might influence the response to transcutaneous stimulation. The overall series included 12 1/2% with long-term success, and 68% with partial or short-term relief. There were no consistent specific diagnoses, or epidemiologic or descriptive factors that made good results from stimulation predictable. Stimulation of the painful area itself was not always necessary for pain relief. Favorable responses to transcutaneous stimulation were usually correlated with the continued existence of significant sensory input from the painful region. The authors conclude that transcutaneous stimulation is a valuable therapeutic modality for some patients with chronic pain.

  3. Optical nerve stimulation for a vestibular prosthesis

    NASA Astrophysics Data System (ADS)

    Harris, David M.; Bierer, Steven M.; Wells, Jonathon D.; Phillips, James O.

    2009-02-01

    Infrared Nerve Stimulation (INS) offers several advantages over electrical stimulation, including more precise spatial selectivity and improved surgical access. In this study, INS and electrical stimulation were compared in their ability to activate the vestibular branch of the VIIIth nerve, as a potential way to treat balance disorders. The superior and lateral canals of the vestibular system of Guinea pigs were identified and approached with the aid of precise 3-D reconstructions. A monopolar platinum stimulating electrode was positioned near the ampullae of the canals, and biphasic current pulses were used to stimulate vestibular evoked potentials and eye movements. Thresholds and input/output functions were measured for various stimulus conditions. A short pulsed diode laser (Capella, Lockheed Martin-Aculight, Inc., Bothell WA) was placed in the same anatomical position and various stimulus conditions were evaluated in their ability to evoke similar potentials and eye movements.

  4. Advances in functional electrical stimulation (FES).

    PubMed

    Popović, Dejan B

    2014-12-01

    This review discusses the advancements that are needed to enhance the effects of electrical stimulation for restoring or assisting movement in humans with an injury/disease of the central nervous system. A complex model of the effects of electrical stimulation of peripheral systems is presented. The model indicates that both the motor and sensory systems are activated by electrical stimulation. We propose that a hierarchical hybrid controller may be suitable for functional electrical stimulation (FES) because this type of controller acts as a structural mimetic of its biological counterpart. Specific attention is given to the neural systems at the periphery with respect to the required electrodes and stimulators. Furthermore, we note that FES with surface electrodes is preferred for the therapy, although there is a definite advantage associated with implantable technology for life-long use. The last section of the review discusses the potential need to combine FES and robotic systems to provide assistance in some cases. PMID:25287528

  5. Stimulating the Comfort of Textile Electrodes in Wearable Neuromuscular Electrical Stimulation

    PubMed Central

    Zhou, Hui; Lu, Yi; Chen, Wanzhen; Wu, Zhen; Zou, Haiqing; Krundel, Ludovic; Li, Guanglin

    2015-01-01

    Textile electrodes are becoming an attractive means in the facilitation of surface electrical stimulation. However, the stimulation comfort of textile electrodes and the mechanism behind stimulation discomfort is still unknown. In this study, a textile stimulation electrode was developed using conductive fabrics and then its impedance spectroscopy, stimulation thresholds, and stimulation comfort were quantitatively assessed and compared with those of a wet textile electrode and a hydrogel electrode on healthy subjects. The equivalent circuit models and the finite element models of different types of electrode were built based on the measured impedance data of the electrodes to reveal the possible mechanism of electrical stimulation pain. Our results showed that the wet textile electrode could achieve similar stimulation performance as the hydrogel electrode in motor threshold and stimulation comfort. However, the dry textile electrode was found to have very low pain threshold and induced obvious cutaneous painful sensations during stimulation, in comparison to the wet and hydrogel electrodes. Indeed, the finite element modeling results showed that the activation function along the z direction at the depth of dermis epidermis junction of the dry textile electrode was significantly larger than that of the wet and hydrogel electrodes, thus resulting in stronger activation of pain sensing fibers. Future work will be done to make textile electrodes have similar stimulation performance and comfort as hydrogel electrodes. PMID:26193273

  6. Stimulating the Comfort of Textile Electrodes in Wearable Neuromuscular Electrical Stimulation.

    PubMed

    Zhou, Hui; Lu, Yi; Chen, Wanzhen; Wu, Zhen; Zou, Haiqing; Krundel, Ludovic; Li, Guanglin

    2015-07-16

    Textile electrodes are becoming an attractive means in the facilitation of surface electrical stimulation. However, the stimulation comfort of textile electrodes and the mechanism behind stimulation discomfort is still unknown. In this study, a textile stimulation electrode was developed using conductive fabrics and then its impedance spectroscopy, stimulation thresholds, and stimulation comfort were quantitatively assessed and compared with those of a wet textile electrode and a hydrogel electrode on healthy subjects. The equivalent circuit models and the finite element models of different types of electrode were built based on the measured impedance data of the electrodes to reveal the possible mechanism of electrical stimulation pain. Our results showed that the wet textile electrode could achieve similar stimulation performance as the hydrogel electrode in motor threshold and stimulation comfort. However, the dry textile electrode was found to have very low pain threshold and induced obvious cutaneous painful sensations during stimulation, in comparison to the wet and hydrogel electrodes. Indeed, the finite element modeling results showed that the activation function along the z direction at the depth of dermis epidermis junction of the dry textile electrode was significantly larger than that of the wet and hydrogel electrodes, thus resulting in stronger activation of pain sensing fibers. Future work will be done to make textile electrodes have similar stimulation performance and comfort as hydrogel electrodes.

  7. Electrical stimulation to accelerate wound healing

    PubMed Central

    Thakral, Gaurav; LaFontaine, Javier; Najafi, Bijan; Talal, Talal K.; Kim, Paul; Lavery, Lawrence A.

    2013-01-01

    Background There are several applications of electrical stimulation described in medical literature to accelerate wound healing and improve cutaneous perfusion. This is a simple technique that could be incorporated as an adjunctive therapy in plastic surgery. The objective of this review was to evaluate the results of randomized clinical trials that use electrical stimulation for wound healing. Method We identified 21 randomized clinical trials that used electrical stimulation for wound healing. We did not include five studies with treatment groups with less than eight subjects. Results Electrical stimulation was associated with faster wound area reduction or a higher proportion of wounds that healed in 14 out of 16 wound randomized clinical trials. The type of electrical stimulation, waveform, and duration of therapy vary in the literature. Conclusion Electrical stimulation has been shown to accelerate wound healing and increase cutaneous perfusion in human studies. Electrical stimulation is an adjunctive therapy that is underutilized in plastic surgery and could improve flap and graft survival, accelerate postoperative recovery, and decrease necrosis following foot reconstruction. PMID:24049559

  8. A fully implantable rodent neural stimulator

    NASA Astrophysics Data System (ADS)

    Perry, D. W. J.; Grayden, D. B.; Shepherd, R. K.; Fallon, J. B.

    2012-02-01

    The ability to electrically stimulate neural and other excitable tissues in behaving experimental animals is invaluable for both the development of neural prostheses and basic neurological research. We developed a fully implantable neural stimulator that is able to deliver two channels of intra-cochlear electrical stimulation in the rat. It is powered via a novel omni-directional inductive link and includes an on-board microcontroller with integrated radio link, programmable current sources and switching circuitry to generate charge-balanced biphasic stimulation. We tested the implant in vivo and were able to elicit both neural and behavioural responses. The implants continued to function for up to five months in vivo. While targeted to cochlear stimulation, with appropriate electrode arrays the stimulator is well suited to stimulating other neurons within the peripheral or central nervous systems. Moreover, it includes significant on-board data acquisition and processing capabilities, which could potentially make it a useful platform for telemetry applications, where there is a need to chronically monitor physiological variables in unrestrained animals.

  9. Computational modeling of epidural cortical stimulation

    NASA Astrophysics Data System (ADS)

    Wongsarnpigoon, Amorn; Grill, Warren M.

    2008-12-01

    Epidural cortical stimulation (ECS) is a developing therapy to treat neurological disorders. However, it is not clear how the cortical anatomy or the polarity and position of the electrode affects current flow and neural activation in the cortex. We developed a 3D computational model simulating ECS over the precentral gyrus. With the electrode placed directly above the gyrus, about half of the stimulus current flowed through the crown of the gyrus while current density was low along the banks deep in the sulci. Beneath the electrode, neurons oriented perpendicular to the cortical surface were depolarized by anodic stimulation, and neurons oriented parallel to the boundary were depolarized by cathodic stimulation. Activation was localized to the crown of the gyrus, and neurons on the banks deep in the sulci were not polarized. During regulated voltage stimulation, the magnitude of the activating function was inversely proportional to the thickness of the CSF and dura. During regulated current stimulation, the activating function was not sensitive to the thickness of the dura but was slightly more sensitive than during regulated voltage stimulation to the thickness of the CSF. Varying the width of the gyrus and the position of the electrode altered the distribution of the activating function due to changes in the orientation of the neurons beneath the electrode. Bipolar stimulation, although often used in clinical practice, reduced spatial selectivity as well as selectivity for neuron orientation.

  10. Numerical dosimetry of transcranial magnetic stimulation coils

    NASA Astrophysics Data System (ADS)

    Crowther, Lawrence; Hadimani, Ravi; Jiles, David

    2014-03-01

    Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique capable of stimulating neurons by means of electromagnetic induction. TMS can be used to map brain function and shows promise for the diagnosis and treatment of neurological and psychiatric disorders. Calculation of fields induced in the brain are necessary to accurately identify stimulated neural tissue during TMS. This allows the development of novel TMS coil designs capable of stimulating deeper brain regions and increasing the localization of stimulation that can be achieved. We have performed numerical calculations of magnetic and electric field with high-resolution anatomically realistic human head models to find these stimulated brain regions for a variety of proposed TMS coil designs. The realistic head models contain heterogeneous tissue structures and electrical conductivities, yielding superior results to those obtained from the simplified homogeneous head models that are commonly employed. The attenuation of electric field as a function of depth in the brain and the localization of stimulating field have been methodically investigated. In addition to providing a quantitative comparison of different TMS coil designs the variation of induced field between subjects has been investigated. We also show the differences in induced fields between adult, adolescent and child head models to preemptively identify potential safety issues in the application of pediatric TMS.

  11. Controlling illegal stimulants: a regulated market model

    PubMed Central

    Haden, Mark

    2008-01-01

    Prohibition of illegal drugs is a failed social policy and new models of regulation of these substances are needed. This paper explores a proposal for a post-prohibition, public health based model for the regulation of the most problematic drugs, the smokable and injectable stimulants. The literature on stimulant maintenance is explored. Seven foundational principles are suggested that could support this regulatory model of drug control that would reduce both health and social problems related to illegal stimulants. Some details of this model are examined and the paper concludes that drug policies need to be subject to research and based on evidence. PMID:18215317

  12. Electrical Cerebral Stimulation Modifies Inhibitory Systems

    NASA Astrophysics Data System (ADS)

    Cuéllar-Herrera, M.; Rocha, L.

    2003-09-01

    Electrical stimulation of the nervous tissue has been proposed as a method to treat some neurological disorders, such as epilepsy. Epileptic seizures result from excessive, synchronous, abnormal firing patterns of neurons that are located predominantly in the cerebral cortex. Many people with epilepsy continue presenting seizures even though they are under regimens of antiepileptic medications. An alternative therapy for treatment resistant epilepsy is cerebral electrical stimulation. The present study is focused to review the effects of different types of electrical stimulation and specifically changes in amino acids.

  13. Stimulation Technologies for Deep Well Completions

    SciTech Connect

    Stephen Wolhart

    2005-06-30

    The Department of Energy (DOE) is sponsoring the Deep Trek Program targeted at improving the economics of drilling and completing deep gas wells. Under the DOE program, Pinnacle Technologies conducted a study to evaluate the stimulation of deep wells. The objective of the project was to review U.S. deep well drilling and stimulation activity, review rock mechanics and fracture growth in deep, high-pressure/temperature wells and evaluate stimulation technology in several key deep plays. This report documents results from this project.

  14. Towards a Switched-Capacitor based Stimulator for efficient deep-brain stimulation.

    PubMed

    Vidal, Jose; Ghovanloo, Maysam

    2010-01-01

    We have developed a novel 4-channel prototype stimulation circuit for implantable neurological stimulators (INS). This Switched-Capacitor based Stimulator (SCS) aims to utilize charge storage and charge injection techniques to take advantage of both the efficiency of conventional voltage-controlled stimulators (VCS) and the safety and controllability of current-controlled stimulators (CCS). The discrete SCS prototype offers fine control over stimulation parameters such as voltage, current, pulse width, frequency, and active electrode channel via a LabVIEW graphical user interface (GUI) when connected to a PC through USB. Furthermore, the prototype utilizes a floating current sensor to provide charge-balanced biphasic stimulation and ensure safety. The stimulator was analyzed using an electrode-electrolyte interface (EEI) model as well as with a pair of pacing electrodes in saline. The primary motivation of this research is to test the feasibility and functionality of a safe, effective, and power-efficient switched-capacitor based stimulator for use in Deep Brain Stimulation. PMID:21095987

  15. Towards a Switched-Capacitor Based Stimulator for Efficient Deep-Brain Stimulation

    PubMed Central

    Vidal, Jose; Ghovanloo, Maysam

    2013-01-01

    We have developed a novel 4-channel prototype stimulation circuit for implantable neurological stimulators (INS). This Switched-Capacitor based Stimulator (SCS) aims to utilize charge storage and charge injection techniques to take advantage of both the efficiency of conventional voltage-controlled stimulators (VCS) and the safety and controllability of current-controlled stimulators (CCS). The discrete SCS prototype offers fine control over stimulation parameters such as voltage, current, pulse width, frequency, and active electrode channel via a LabVIEW graphical user interface (GUI) when connected to a PC through USB. Furthermore, the prototype utilizes a floating current sensor to provide charge-balanced biphasic stimulation and ensure safety. The stimulator was analyzed using an electrode-electrolyte interface (EEI) model as well as with a pair of pacing electrodes in saline. The primary motivation of this research is to test the feasibility and functionality of a safe, effective, and power-efficient switched-capacitor based stimulator for use in Deep Brain Stimulation. PMID:21095987

  16. Deep Brain Stimulation using Magnetic Fields

    NASA Astrophysics Data System (ADS)

    Jiles, David; Williams, Paul; Crowther, Lawrence; Iowa State University Team; Wolfson CentreMagnetics Team

    2011-03-01

    New applications for transcranial magnetic stimulation are developing rapidly for both diagnostic and therapeutic purposes. Therefore so is the demand for improved performance, particularly in terms of their ability to stimulate deeper regions of the brain and to do so selectively. The coil designs that are used presently are limited in their ability to stimulate the brain at depth and with high spatial focality. Consequently, any improvement in coil performance would have a significant impact in extending the usefulness of TMS in both clinical applications and academic research studies. New and improved coil designs have then been developed, modeled and tested as a result of this work. A large magnetizing coil, 300mm in diameter and compatible with a commercial TMS system has been constructed to determine its feasibility for use as a deep brain stimulator. The results of this work have suggested directions that could be pursued in order to further improve the coil designs.

  17. Stimulation Technologies for Deep Well Completions

    SciTech Connect

    2003-09-30

    The Department of Energy (DOE) is sponsoring the Deep Trek Program targeted at improving the economics of drilling and completing deep gas wells. Under the DOE program, Pinnacle Technologies is conducting a study to evaluate the stimulation of deep wells. The objective of the project is to assess U.S. deep well drilling & stimulation activity, review rock mechanics & fracture growth in deep, high pressure/temperature wells and evaluate stimulation technology in several key deep plays. An assessment of historical deep gas well drilling activity and forecast of future trends was completed during the first six months of the project; this segment of the project was covered in Technical Project Report No. 1. The second progress report covers the next six months of the project during which efforts were primarily split between summarizing rock mechanics and fracture growth in deep reservoirs and contacting operators about case studies of deep gas well stimulation.

  18. Mild stimulation in in vitro fertilization.

    PubMed

    Macklon, N S; Fauser, B C J M

    2003-11-01

    Current approaches to ovarian stimulation for in vitro fertilization (IVF) are aimed at optimizing the number of oocytes retrieved in a treatment cycle. This approach is not without risks. Moreover, as the true costs of multiple pregnancy become clearer, the need to produce multiple embryos for transfer is increasingly questioned. Increasing knowledge of the physiological mechanisms involved in follicular development and dominance has led to new strategies in ovarian stimulation for IVF. The clinical availability of GnRH antagonists allows the normal cycle to be harnessed and manipulated by mild interventions to produce sufficient oocytes for successful IVF treatment. Recent evidence suggests that oocyte quality after mild stimulation may be superior to that after conventional stimulation regimens.

  19. Follicle-stimulating hormone (FSH) blood test

    MedlinePlus

    ... the test done on certain days of your menstrual cycle. ... In women, FSH helps manage the menstrual cycle and stimulates the ovaries to produce eggs. The test is used to help diagnose or evaluate: Menopause Women who have polycystic ovary ...

  20. Implantable neurotechnologies: electrical stimulation and applications.

    PubMed

    Nag, Sudip; Thakor, Nitish V

    2016-01-01

    Neural stimulation using injected electrical charge is widely used both in functional therapies and as an experimental tool for neuroscience applications. Electrical pulses can induce excitation of targeted neural pathways that aid in the treatment of neural disorders or dysfunction of the central and peripheral nervous system. In this review, we summarize the recent trends in the field of electrical stimulation for therapeutic interventions of nervous system disorders, such as for the restoration of brain, eye, ear, spinal cord, nerve and muscle function. Neural prosthetic applications are discussed, and functional electrical stimulation parameters for treating such disorders are reviewed. Important considerations for implantable packaging and enhancing device reliability are also discussed. Neural stimulators are expected to play a profound role in implantable neural devices that treat disorders and help restore functions in injured or disabled nervous system. PMID:26753775

  1. Tactile stimulation lowers stress in fish.

    PubMed

    Soares, Marta C; Oliveira, Rui F; Ros, Albert F H; Grutter, Alexandra S; Bshary, Redouan

    2011-01-01

    In humans, physical stimulation, such as massage therapy, reduces stress and has demonstrable health benefits. Grooming in primates may have similar effects but it remains unclear whether the positive effects are due to physical contact or to its social value. Here we show that physical stimulation reduces stress in a coral reef fish, the surgeonfish Ctenochaetus striatus. These fish regularly visit cleaner wrasses Labroides dimidiatus to have ectoparasites removed. The cleanerfish influences client decisions by physically touching the surgeonfish with its pectoral and pelvic fins, a behaviour known as tactile stimulation. We simulated this behaviour by exposing surgeonfish to mechanically moving cleanerfish models. Surgeonfish had significantly lower levels of cortisol when stimulated by moving models compared with controls with access to stationary models. Our results show that physical contact alone, without a social aspect, is enough to produce fitness-enhancing benefits, a situation so far only demonstrated in humans. PMID:22086335

  2. Optogenetic stimulation of myelination (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Yang, In Hong; Lee, Hae Ung; Thakor, Nitish V.

    2016-03-01

    Myelination is governed by axon-glia interaction which is modulated by neural activity. Currently, the effects of subcellular activation of neurons which induce neural activity upon myelination are not well understood. To identify if subcellular neuronal stimulation can enhance myelination, we developed a novel system for focal stimulation of neural activity with optogenetic in a compartmentalized microfluidic platform. In our systems, stimulation for neurons in restricted subcellular parts, such as cell bodies and axons promoted oligodendrocyte differentiation and the myelination of axons the just as much as whole cell activation of neurons did. The number of premature O4 positive oligodendrocytes was reduced and the numbers of mature and myelin basic protein-positive oligodendrocytes was increased both by subcellular optogenetic stimulation.

  3. Electroencephalographic responses to intraoperative subthalamic stimulation.

    PubMed

    Colloca, Luana; Benedetti, Fabrizio; Bergamasco, Bruno; Vighetti, Sergio; Zibetti, Maurizio; Ducati, Alessandro; Lanotte, Michele; Lopiano, Leonardo

    2006-10-01

    This study reports the effects of intraoperative stimulation of the subthalamic nucleus on brain electrical activity in advanced Parkinson's patients. To our knowledge, this is the first study about electroencephalographic responses in the very early phase of deep brain stimulation, during the implantation of the electrodes. We found an increase of gamma band bilaterally over the sensorimotor cortex in the range 45-55 Hz, which was associated with clinical improvement as assessed by means of muscle rigidity decrease. These results indicate that the electroencephalographic gamma responses to deep brain stimulation are present at the very beginning of the treatment process, and may help better understand the short and long-tem effects of deep brain stimulation.

  4. Imbibition well stimulation via neural network design

    DOEpatents

    Weiss, William

    2007-08-14

    A method for stimulation of hydrocarbon production via imbibition by utilization of surfactants. The method includes use of fuzzy logic and neural network architecture constructs to determine surfactant use.

  5. Cardiovascular effects of afferent renal nerve stimulation.

    PubMed

    Stella, A; Weaver, L; Golin, R; Genovesi, S; Zanchetti, A

    1987-01-01

    Electrical stimulation of afferent renal nerves elicits an increase in arterial pressure and heart rate. The hypertensive response is presumably due to the widespread activation of the sympathetic nervous system leading to peripheral vasoconstriction. Interestingly, the kidney does not appear involved in this reflex excitatory response to afferent renal nerve stimulation since changes in vascular conductances and excretory functions are equal in both the innervated and denervated kidney, and secondary to changes in renal perfusion pressure. In addition, no changes in renin release from either kidneys are observed during afferent renal nerve stimulation. It is likely that the electrical stimulation of afferent renal nerves activates other reflexes exerting an inhibitory influence on efferent renal nerve activity. Indeed, neural renorenal reflexes which tonically inhibit renal functions have clearly been demonstrated. Furthermore, preferential inhibition of efferent renal nerve activity by cardiopulmonary and sinoaortic receptors has recently been shown during activation of other visceral afferents.

  6. Optogenetic stimulation of MCH neurons increases sleep.

    PubMed

    Konadhode, Roda Rani; Pelluru, Dheeraj; Blanco-Centurion, Carlos; Zayachkivsky, Andrew; Liu, Meng; Uhde, Thomas; Glen, W Bailey; van den Pol, Anthony N; Mulholland, Patrick J; Shiromani, Priyattam J

    2013-06-19

    Melanin concentrating hormone (MCH) is a cyclic neuropeptide present in the hypothalamus of all vertebrates. MCH is implicated in a number of behaviors but direct evidence is lacking. To selectively stimulate the MCH neurons the gene for the light-sensitive cation channel, channelrhodopsin-2, was inserted into the MCH neurons of wild-type mice. Three weeks later MCH neurons were stimulated for 1 min every 5 min for 24 h. A 10 Hz stimulation at the start of the night hastened sleep onset, reduced length of wake bouts by 50%, increased total time in non-REM and REM sleep at night, and increased sleep intensity during the day cycle. Sleep induction at a circadian time when all of the arousal neurons are active indicates that MCH stimulation can powerfully counteract the combined wake-promoting signal of the arousal neurons. This could be potentially useful in treatment of insomnia.

  7. [Stimulation of spermatogenesis: For whom? Why? How?].

    PubMed

    Bertrand-Delepine, J; Leroy, C; Rigot, J-M; Catteau-Jonard, S; Dewailly, D; Robin, G

    2016-09-01

    The stimulation of spermatogenesis is the best treatment of infertility for male hypogonadotropic-hypogonadism. The results are very pleasing because a real improvement of semen is sometimes obtained with spontaneous pregnants describing in the literature but after a long duration of treatment, often many months. Sometimes, the treatment improves the technical conditions of ICSI for the embryologists. Stimulation of spermatogenesis by gonadotrophins rFSH and/or hCG is the most used but others treatments, like pulsatile GnRH therapy or clomifene citrate can be used. The purpose of this review is to described the different protocols of stimulation of spermatogenesis and explain their results and finally to see if others indications of stimulation of spermatogenesis are existing. PMID:27475410

  8. Isocyperol, isolated from the rhizomes of Cyperus rotundus, inhibits LPS-induced inflammatory responses via suppression of the NF-κB and STAT3 pathways and ROS stress in LPS-stimulated RAW 264.7 cells.

    PubMed

    Seo, Yun-Ji; Jeong, Miran; Lee, Kyung-Tae; Jang, Dae Sik; Choi, Jung-Hye

    2016-09-01

    The rhizomes of Cyperus rotundus (cyperaceae) have been used in Korean traditional medicines for treating diverse inflammatory diseases. However, little is known about the biological activities of isocyperol, a sesquiterpene isolated from C. rotundus, and their associated molecular mechanisms. In this study, we found that isocyperol significantly inhibited lipopolysaccharide (LPS)-induced production of nitrite oxide (NO) and prostaglandin E2 (PGE2) and suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in RAW 264.7 macrophages. In addition, isocyperol downregulated the LPS-induced expression of several proinflammatory cytokines, such as interleukin-1beta (IL-1β), IL-6, and monocyte chemotactic protein-1 (MCP-1). Isocyperol treatment suppressed the LPS-induced nuclear translocation and transcriptional activation of nuclear factor-kappaB (NF-κB) in macrophages. Moreover, the activation of STAT3, another proinflammatory signal, was suppressed by isocyperol in LPS-stimulated RAW 264.7 cells. Isocyperol pretreatment also induced heme oxygenase-1 (HO-1) expression and reduced LPS-stimulated reactive oxygen species (ROS) accumulation in macrophages. Furthermore, isocyperol significantly increased the survival rate and attenuated serum levels of NO, PGE2, and IL-6 in LPS-induced septic shock mouse model. Taken together, these data indicate that isocyperol suppress septic shock through negative regulation of pro-inflammatory factors through inhibition of the NF-κB and STAT3 pathways and ROS. To our knowledge, this is the first report on the biological activity of isocyperol and its molecular mechanism of action. PMID:27240136

  9. Anti-Inflammatory and Analgesic Effects of Pyeongwisan on LPS-Stimulated Murine Macrophages and Mouse Models of Acetic Acid-Induced Writhing Response and Xylene-Induced Ear Edema

    PubMed Central

    Oh, You-Chang; Jeong, Yun Hee; Cho, Won-Kyung; Ha, Jeong-Ho; Gu, Min Jung; Ma, Jin Yeul

    2015-01-01

    Pyeongwisan (PW) is an herbal medication used in traditional East Asian medicine to treat anorexia, abdominal distension, borborygmus and diarrhea caused by gastric catarrh, atony and dilatation. However, its effects on inflammation-related diseases are unknown. In this study, we investigated the biological effects of PW on lipopolysaccharide (LPS)-mediated inflammation in macrophages and on local inflammation in vivo. We investigated the biological effects of PW on the production of inflammatory mediators, pro-inflammatory cytokines and related products as well as the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) in LPS-stimulated macrophages. Additionally, we evaluated the analgesic effect on the acetic acid-induced writhing response and the inhibitory activity on xylene-induced ear edema in mice. PW showed anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and interleukin-1β (IL-1β). In addition, PW strongly suppressed inducible nitric oxide synthase (iNOS), a NO synthesis enzyme, induced heme oxygenase-1 (HO-1) expression and inhibited NF-κB activation and MAPK phosphorylation. Also, PW suppressed TNF-α, IL-6 and IL-1β cytokine production in LPS-stimulated peritoneal macrophage cells. Furthermore, PW showed an analgesic effect on the writhing response and an inhibitory effect on mice ear edema. We demonstrated the anti-inflammatory effects and inhibitory mechanism in macrophages as well as inhibitory activity of PW in vivo for the first time. Our results suggest the potential value of PW as an inflammatory therapeutic agent developed from a natural substance. PMID:25569097

  10. Transcranial magnetic stimulation and the human brain

    NASA Astrophysics Data System (ADS)

    Hallett, Mark

    2000-07-01

    Transcranial magnetic stimulation (TMS) is rapidly developing as a powerful, non-invasive tool for studying the human brain. A pulsed magnetic field creates current flow in the brain and can temporarily excite or inhibit specific areas. TMS of motor cortex can produce a muscle twitch or block movement; TMS of occipital cortex can produce visual phosphenes or scotomas. TMS can also alter the functioning of the brain beyond the time of stimulation, offering potential for therapy.

  11. Intramolecular motion during stimulated surface processes

    SciTech Connect

    Burns, A.R.; Jennison, D.R.; Stechel, E.B. ); Li, Y.S. )

    1994-06-13

    Ammonia and deuterated ammonia exhibit an anomalously large isotope effect in their relative yields and rotational spinning energy for electron-stimulated desorption from Pt(111). Quantum-resolved desorption measurements and [ital ab] [ital initio], two-dimensional, potential energy calculations suggest that the desorbate undergoes a geometry change (molecular inversion) induced by the excited state. Inverted molecules deexcite to a repulsive hard wall potential and desorb. In general, [ital multidimensional] potential energy surfaces determine the dynamics of stimulated surface processes.

  12. Enhanced Cultivation Of Stimulated Murine B Cells

    NASA Technical Reports Server (NTRS)

    Sammons, David W.

    1994-01-01

    Method of in vitro cultivation of large numbers of stimulated murine B lymphocytes. Cells electrofused with other cells to produce hybridomas and monoclonal antibodies. Offers several advantages: polyclonally stimulated B-cell blasts cultivated for as long as 14 days, hybridomas created throughout culture period, yield of hybridomas increases during cultivation, and possible to expand polyclonally in vitro number of B cells specific for antigenic determinants first recognized in vivo.

  13. Closing the loop of deep brain stimulation

    PubMed Central

    Carron, Romain; Chaillet, Antoine; Filipchuk, Anton; Pasillas-Lépine, William; Hammond, Constance

    2013-01-01

    High-frequency deep brain stimulation is used to treat a wide range of brain disorders, like Parkinson's disease. The stimulated networks usually share common electrophysiological signatures, including hyperactivity and/or dysrhythmia. From a clinical perspective, HFS is expected to alleviate clinical signs without generating adverse effects. Here, we consider whether the classical open-loop HFS fulfills these criteria and outline current experimental or theoretical research on the different types of closed-loop DBS that could provide better clinical outcomes. In the first part of the review, the two routes followed by HFS-evoked axonal spikes are explored. In one direction, orthodromic spikes functionally de-afferent the stimulated nucleus from its downstream target networks. In the opposite direction, antidromic spikes prevent this nucleus from being influenced by its afferent networks. As a result, the pathological synchronized activity no longer propagates from the cortical networks to the stimulated nucleus. The overall result can be described as a reversible functional de-afferentation of the stimulated nucleus from its upstream and downstream nuclei. In the second part of the review, the latest advances in closed-loop DBS are considered. Some of the proposed approaches are based on mathematical models, which emphasize different aspects of the parkinsonian basal ganglia: excessive synchronization, abnormal firing-rate rhythms, and a deficient thalamo-cortical relay. The stimulation strategies are classified depending on the control-theory techniques on which they are based: adaptive and on-demand stimulation schemes, delayed and multi-site approaches, stimulations based on proportional and/or derivative control actions, optimal control strategies. Some of these strategies have been validated experimentally, but there is still a large reservoir of theoretical work that may point to ways of improving practical treatment. PMID:24391555

  14. Closing the loop of deep brain stimulation.

    PubMed

    Carron, Romain; Chaillet, Antoine; Filipchuk, Anton; Pasillas-Lépine, William; Hammond, Constance

    2013-01-01

    High-frequency deep brain stimulation is used to treat a wide range of brain disorders, like Parkinson's disease. The stimulated networks usually share common electrophysiological signatures, including hyperactivity and/or dysrhythmia. From a clinical perspective, HFS is expected to alleviate clinical signs without generating adverse effects. Here, we consider whether the classical open-loop HFS fulfills these criteria and outline current experimental or theoretical research on the different types of closed-loop DBS that could provide better clinical outcomes. In the first part of the review, the two routes followed by HFS-evoked axonal spikes are explored. In one direction, orthodromic spikes functionally de-afferent the stimulated nucleus from its downstream target networks. In the opposite direction, antidromic spikes prevent this nucleus from being influenced by its afferent networks. As a result, the pathological synchronized activity no longer propagates from the cortical networks to the stimulated nucleus. The overall result can be described as a reversible functional de-afferentation of the stimulated nucleus from its upstream and downstream nuclei. In the second part of the review, the latest advances in closed-loop DBS are considered. Some of the proposed approaches are based on mathematical models, which emphasize different aspects of the parkinsonian basal ganglia: excessive synchronization, abnormal firing-rate rhythms, and a deficient thalamo-cortical relay. The stimulation strategies are classified depending on the control-theory techniques on which they are based: adaptive and on-demand stimulation schemes, delayed and multi-site approaches, stimulations based on proportional and/or derivative control actions, optimal control strategies. Some of these strategies have been validated experimentally, but there is still a large reservoir of theoretical work that may point to ways of improving practical treatment. PMID:24391555

  15. Effect of neurovestibular stimulation on autonomic regulation

    NASA Technical Reports Server (NTRS)

    Costa, F.; Lavin, P.; Robertson, D.; Biaggioni, I.

    1995-01-01

    Conditions associated with nausea and vomiting, such as motion sickness or side effects of medications, are commonly associated with a clinical picture consistent with parasympathetic activation and sympathetic withdrawal. It can be postulated, therefore, that vestibular stimulation contributes to sympathetic withdrawal. To test this hypothesis five normal volunteers, 24-33 years old, were studied during caloric vestibular stimulation while monitoring muscle sympathetic nerve activity directly through a needle electrode placed in a peroneal nerve. The ear was irrigated with water at a flow rate of 450 ml/min and 37 degrees C. The water temperature was sequentially lowered by 7 degree C intervals until intolerable side effects developed or a temperature of 16 degrees C was reached. Nystagmus was induced in all subjects, but heart rate, blood pressure, muscle sympathetic nerve activity and plasma norepinephrine levels did not change significantly during or after caloric stimulation, even when the subjects felt dizzy and nauseated. No evidence of sympathetic withdrawal was observed in any subject either by muscle sympathetic nerve activity or plasma norepinephrine measurements. In conclusion, we have found that selective vestibular stimulation is not accompanied by significant changes in the sympathetic nervous system function. In particular, no sympathetic withdrawal was observed. It could be argued that lack of sympathetic stimulation is an inadequate response to the symptoms associated with caloric stimulation.

  16. Chronic network stimulation enhances evoked action potentials

    NASA Astrophysics Data System (ADS)

    Ide, A. N.; Andruska, A.; Boehler, M.; Wheeler, B. C.; Brewer, G. J.

    2010-02-01

    Neurons cultured on multielectrode arrays almost always lack external stimulation except during the acute experimental phase. We have investigated the effects of chronic stimulation during the course of development in cultured hippocampal neural networks by applying paired pulses at half of the electrodes for 0, 1 or 3 r/day for 8 days. Spike latencies increased from 4 to 16 ms as the distance from the stimulus increased from 200 to 1700 µm, suggesting an average of four synapses over this distance. Compared to no chronic stimulation, our results indicate that chronic stimulation increased evoked spike counts per stimulus by 50% at recording sites near the stimulating electrode and increased the instantaneous firing rate. On trials where both pulses elicited responses, spike count was 40-80% higher than when only one of the pulses elicited a response. In attempts to identify spike amplitude plasticity, we found mainly amplitude variation with different latencies suggesting recordings from neurons with different identities. These data suggest plastic network changes induced by chronic stimulation that enhance the reliability of information transmission and the efficiency of multisynaptic network communication.

  17. Considering optogenetic stimulation for cochlear implants.

    PubMed

    Jeschke, Marcus; Moser, Tobias

    2015-04-01

    Electrical cochlear implants are by far the most successful neuroprostheses and have been implanted in over 300,000 people worldwide. Cochlear implants enable open speech comprehension in most patients but are limited in providing music appreciation and speech understanding in noisy environments. This is generally considered to be due to low frequency resolution as a consequence of wide current spread from stimulation contacts. Accordingly, the number of independently usable stimulation channels is limited to less than a dozen. As light can be conveniently focused, optical stimulation might provide an alternative approach to cochlear implants with increased number of independent stimulation channels. Here, we focus on summarizing recent work on optogenetic stimulation as one way to develop optical cochlear implants. We conclude that proof of principle has been presented for optogenetic stimulation of the cochlea and central auditory neurons in rodents as well as for the technical realization of flexible μLED-based multichannel cochlear implants. Still, much remains to be done in order to advance the technique for auditory research and even more for eventual clinical translation. This article is part of a Special Issue entitled . PMID:25601298

  18. 15-Deoxy-{delta}{sup 12,14}-Prostaglandin J{sub 2} regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells

    SciTech Connect

    Rajasingh, Johnson; Bright, John J. . E-mail: jbright1@clarian.org

    2006-08-01

    Embryonic stem (ES) cells are genetically normal, pluripotent cells, capable of self-renewal and differentiation into all cell lineages. While leukemia inhibitory factor (LIF) maintains pluripotency in mouse ES cells, retinoic acid and other nuclear hormones induce neuro-glial differentiation in mouse and human ES cells in culture. Peroxisome-proliferator-activated receptors (PPARs) are ligand-dependent nuclear receptor transcription factors that regulate cell growth and differentiation in many cell types. However, the role of PPARs in the regulation of ES cell growth and differentiation is not known. In this study, we show that LIF induces proliferation and self-renewal of mouse D3-ES cells in culture. However, treatment with 15-Deoxy-{delta}{sup 12,14}-Prostaglandin J{sub 2} (15d-PGJ2), a natural ligand for PPAR{gamma}, or all-trans retinoic acid (ATRA) results in a dose-dependent decrease in proliferation and self-renewal in D3-ES cells. Immunoprecipitation and Western blot analyses showed that LIF induces tyrosine phosphorylation of JAK1, TYK2 and STAT3 in 30 min and treatment with 15d-PGJ2 or ATRA results in a dose-dependent decrease in LIF-induced phosphorylation of JAK1 and STAT3 in D3-ES cells. However, treatment of D3-ES cells with Ciglitazone or 15d-PGJ2 for 48 h in culture resulted in a dose-dependent increase in PPAR{gamma} protein expression. These results suggest that PPAR{gamma} agonists regulate LIF signaling through JAK-STAT pathway leading to growth and self-renewal of ES cells.

  19. Antimycotics suppress the Malassezia extract-induced production of CXC chemokine ligand 10 in human keratinocytes.

    PubMed

    Hau, Carren S; Kanda, Naoko; Makimura, Koichi; Watanabe, Shinichi

    2014-02-01

    Malassezia, a lipophilic yeast, exacerbates atopic dermatitis. Malassezia products can penetrate the disintegrated stratum corneum and encounter subcorneal keratinocytes in the skin of atopic dermatitis patients. Type 1 helper T (Th1) cells infiltrate chronic lesions with atopic dermatitis, and antimycotic agents improve its symptoms. We aimed to identify Malassezia-induced chemokines in keratinocytes and examine whether antimycotics suppressed this induction. Normal human keratinocytes were incubated with a Malassezia restricta extract and antimycotics. Chemokine expression was analyzed by enzyme-linked immunosorbent assays and real-time polymerase chain reaction. Signal transducer and activator of transcription (STAT)1 activity was examined by luciferase assays. The tyrosine-phosphorylation of STAT1 was analyzed by western blotting. The M. restricta extract increased the mRNA and protein expression of Th1-attracting CXC chemokine ligand (CXCL)10 and STAT1 activity and phosphorylation in keratinocytes, which was suppressed by a Janus kinase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine suppressed M. restricta extract-induced CXCL10 mRNA and protein expression and STAT1 activity and phosphorylation. These effects were similarly induced by 15-deoxy-Δ-(12,14) -prostaglandin J2 (15d-PGJ2 ), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes. The antimycotic-induced suppression of CXCL10 production and STAT1 activity was counteracted by a lipocalin-type prostaglandin D synthase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine may suppress the M. restricta-induced production of CXCL10 by inhibiting STAT1 through an increase in 15d-PGJ2 production in keratinocytes. These antimycotics may block the Th1-mediated inflammation triggered by Malassezia in the chronic phase of atopic dermatitis. PMID

  20. Enhancement of antitumor activity of docetaxel by celecoxib in lung tumors

    PubMed Central

    Shaik, Madhu Sudhan; Chatterjee, Abhijit; Jackson, Tanise; Singh, Mandip

    2010-01-01

    Our study investigates the effect of a highly selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the cytotoxicity of docetaxel in nude mice bearing A549 tumor xenografts and elucidates the molecular mechanisms of the antitumor effect of this combination. Female nu/nu mice, xenografted with s.c. A549 tumors were treated with either celecoxib (150 mg/kg/day), docetaxel (10 mg/kg) or a combination of both. The tumor tissues were quantified for the induction of apoptosis, intratumor levels/expressions of prostaglandin E2 (PGE2), 15 deoxy prostaglandin J2 (15-d PGJ2), microsomal prostaglandin E synthase (mPGES) and cytoplasmic phospholipase A2 (cPLA2). The combination of celecoxib with docetaxel significantly inhibited the tumor growth (p < 0.03) as compared to celecoxib or docetaxel alone, decreased the levels of PGE2 by 10-fold and increased the 15-d PGJ2 levels by 4-fold as compared to control. The combination also enhanced the peroxisome proliferator-activated receptor (PPAR)-γ expression, decreased the expression of cPLA2, mPGES and vascular endothelial growth factor (VEGF), but had no effect on the expression of COX-1 or COX-2 in tumor tissues. TUNEL staining of the tumor tissues showed a marked increase in the apoptosis in the combination group as compared to the celecoxib- or docetaxel-treated groups and this was associated with an increase in the intratumor p53 expression. In conclusion, the combination of celecoxib with docetaxel produces a greater antitumor effect in s.c. A549 tumors as compared to celecoxib or docetaxel alone and this effect is associated with concomitant alterations in the intratumor levels of PGE2 and 15-d PGJ2. PMID:16052515

  1. Selenoprotein Expression in Macrophages Is Critical for Optimal Clearance of Parasitic Helminth Nippostrongylus brasiliensis.

    PubMed

    Nelson, Shakira M; Shay, Ashley E; James, Jamaal L; Carlson, Bradley A; Urban, Joseph F; Prabhu, K Sandeep

    2016-02-01

    The plasticity of macrophages is evident in helminthic parasite infections, providing protection from inflammation. Previously we demonstrated that the micronutrient selenium induces a phenotypic switch in macrophage activation from a classically activated (pro-inflammatory; M1/CAM) toward an alternatively activated (anti-inflammatory; M2/AAM) phenotype, where cyclooxygenase (COX)-dependent cyclopentenone prostaglandin J2 (15d-PGJ2) plays a key role. Here, we hypothesize that dietary selenium modulates macrophage polarization toward an AAM phenotype to assist in the increasing clearance of adult Nippostrongylus brasiliensis, a gastrointestinal nematode parasite. Mice on a selenium-adequate (0.08 ppm) diet significantly augmented intestinal AAM presence while decreasing adult worms and fecal egg production when compared with infection of mice on selenium-deficient (<0.01 ppm) diet. Further increase in dietary selenium to supraphysiological levels (0.4 ppm) had very little or no impact on worm expulsion. Normal adult worm clearance and enhanced AAM marker expression were observed in the selenium-supplemented Trsp(fl/fl)Cre(WT) mice that express selenoproteins driven by tRNA(Sec) (Trsp), whereas N. brasiliensis-infected Trsp(fl/fl)Cre(LysM) selenium-supplemented mice showed a decreased clearance, with lowered intestinal expression of several AAM markers. Inhibition of the COX pathway with indomethacin resulted in delayed worm expulsion in selenium-adequate mice. This was rescued with 15d-PGJ2, which partially recapitulated the effect of selenium supplementation on fecal egg output in addition to increasing markers of AAMs in the small intestine. Antagonism of PPARγ blocked the effect of selenium. These results suggest that optimal expression of selenoproteins and selenium-dependent production of COX-derived endogenous prostanoids, such as Δ(12)-PGJ2 and 15d-PGJ2, may regulate AAM activation to enhance anti-helminthic parasite responses. PMID:26644468

  2. A microprocessor-based multichannel subsensory stochastic resonance electrical stimulator.

    PubMed

    Chang, Gwo-Ching

    2013-01-01

    Stochastic resonance electrical stimulation is a novel intervention which provides potential benefits for improving postural control ability in the elderly, those with diabetic neuropathy, and stroke patients. In this paper, a microprocessor-based subsensory white noise electrical stimulator for the applications of stochastic resonance stimulation is developed. The proposed stimulator provides four independent programmable stimulation channels with constant-current output, possesses linear voltage-to-current relationship, and has two types of stimulation modes, pulse amplitude and width modulation.

  3. Neuroethics of deep brain stimulation for mental disorders: brain stimulation reward in humans.

    PubMed

    Oshima, Hideki; Katayama, Yoichi

    2010-01-01

    The theoretical basis of some deep brain stimulation (DBS) trials undertaken in the early years was the phenomenon of "brain stimulation reward (BSR)," which was first identified in rats. The animals appeared to be rewarded by pleasure caused by the stimulation of certain brain regions (reward system), such as the septal area. "Self-stimulation" experiments, in which rats were allowed to stimulate their own brain by pressing a freely accessible lever, they quickly learned lever pressing and sometimes continued to stimulate until they exhausted themselves. BSR was also observed with DBS of the septal area in humans. DBS trials in later years were undertaken on other theoretical bases, but unexpected BSR was sometimes induced by stimulation of some areas, such as the locus coeruleus complex. When BSR was induced, the subjects experienced feelings that were described as "cheerful," "alert," "good," "well-being," "comfort," "relaxation," "joy," or "satisfaction." Since the DBS procedure is equivalent to a "self-stimulation" experiment, they could become "addicted to the stimulation itself" or "compulsive about the stimulation," and stimulate themselves "for the entire day," "at maximum amplitude" and, in some instances, "into convulsions." DBS of the reward system has recently been applied to alleviate anhedonia in patients with refractory major depression. Although this approach appears promising, there remains a difficult problem: who can adjust their feelings and reward-oriented behavior within the normal range? With a self-stimulation procedure, the BSR may become uncontrollable. To develop DBS to the level of a standard therapy for mental disorders, we need to discuss "Who has the right to control the mental condition?" and "Who makes decisions" on "How much control is appropriate?" in daily life. PMID:20885119

  4. Neuroethics of deep brain stimulation for mental disorders: brain stimulation reward in humans.

    PubMed

    Oshima, Hideki; Katayama, Yoichi

    2010-01-01

    The theoretical basis of some deep brain stimulation (DBS) trials undertaken in the early years was the phenomenon of "brain stimulation reward (BSR)," which was first identified in rats. The animals appeared to be rewarded by pleasure caused by the stimulation of certain brain regions (reward system), such as the septal area. "Self-stimulation" experiments, in which rats were allowed to stimulate their own brain by pressing a freely accessible lever, they quickly learned lever pressing and sometimes continued to stimulate until they exhausted themselves. BSR was also observed with DBS of the septal area in humans. DBS trials in later years were undertaken on other theoretical bases, but unexpected BSR was sometimes induced by stimulation of some areas, such as the locus coeruleus complex. When BSR was induced, the subjects experienced feelings that were described as "cheerful," "alert," "good," "well-being," "comfort," "relaxation," "joy," or "satisfaction." Since the DBS procedure is equivalent to a "self-stimulation" experiment, they could become "addicted to the stimulation itself" or "compulsive about the stimulation," and stimulate themselves "for the entire day," "at maximum amplitude" and, in some instances, "into convulsions." DBS of the reward system has recently been applied to alleviate anhedonia in patients with refractory major depression. Although this approach appears promising, there remains a difficult problem: who can adjust their feelings and reward-oriented behavior within the normal range? With a self-stimulation procedure, the BSR may become uncontrollable. To develop DBS to the level of a standard therapy for mental disorders, we need to discuss "Who has the right to control the mental condition?" and "Who makes decisions" on "How much control is appropriate?" in daily life.

  5. Parameter exploration of staircase-shape extracellular stimulation for targeted stimulation of myelinated axon.

    PubMed

    Ueno, Ayako; Karashima, Akihiro; Nakao, Mitsuyuki; Katayama, Norihiro

    2011-01-01

    Spatio-temporal dynamics of a mathematical model of myelinated axon in response to staircase-shape extracellular electrical stimulation, which was developed for selective nerve stimulation, is investigated by the computer simulation. It is shown that the response is classified into four types: subthreshold response, cathodic excitation, anodal block and anodal break excitation. Based on the simulation results, simple diagrams representing the response characteristics of the axon are constructed as functions of stimulation parameters and distance between the axon and electrode. The diagram would be useful for determining simulation parameters for dynamic targeted stimulation of myelinated axon. PMID:22254459

  6. Ring-shaped backward stimulated Raman scattering driven by stimulated Brillouin scattering.

    PubMed

    Feng, Chengyong; Diels, Jean-Claude; Xu, Xiaozhen; Arissian, Ladan

    2015-06-29

    Backward stimulated Raman scattering is generated in water, pumped by pre-compressed pulses from a single-cell stimulated Brillouin scattering pulse compressor. The maximum energy efficiency of 9% is achieved by employing a circularly-polarized pump pulse at its energy of 50 mJ, around which point the backward stimulated Raman scattering also exhibits a ring-shaped profile. The correlations between spatial and temporal profiles as well as the intensities of the backward stimulated Raman and the stimulated Brillouin scattering generated from Raman cell indicate that the ring-shaped backward stimulated Raman is driven by intense stimulated Brillouin scattering. We demonstrate the latter process to be much more efficient for the backward Raman generation than the conventional process in which the laser itself pumps a backward stimulated Raman beam. It is shown that a further increase in pump energy leads to a drop in efficiency, combined with a break-up of the ring pattern of backward stimulated Raman. These effects are associated with filament generation above a certain threshold.

  7. Aversive hypothalamic stimulation releases acetylcholine in the nucleus accumbens, and stimulation-escape decreases it.

    PubMed

    Rada, P V; Hoebel, B G

    2001-01-01

    Hypothalamic electrodes can generate positive reinforcement, as shown by self-stimulation, and negative reinforcement shown by stimulation-escape. It was hypothesized that acetylcholine (ACh) is released in the nucleus accumbens during the aversive state that underlies stimulation-escape. If this is correct, escape behavior should lower extracellular ACh. Rats were prepared with microdialysis probes in the accumbens (posterior shell region) and electrodes in the perifornical lateral hypothalamus. Animals learned to press a lever for 0.5 s trains of stimulation (typically 3600 responses/h). Then they were given automatic stimulation to determine which animals would also learn to press a lever to turn stimulation off for 5 s at a time (typically 75 responses/h). Accumbens microdialysis showed that automatic stimulation caused extracellular ACh to double, but only in the rats that were motivated to learn stimulation-escape. When allowed to escape stimulation, these animals lowered extracellular ACh significantly. It is concluded that ACh release in the accumbens is related to the neural state that animals work to escape.

  8. Hydraulic Fracture Stimulation and Acid Treatment of Well Baca 20; Geothermal Reservoir Well Stimulation Program

    SciTech Connect

    1983-07-01

    The U.S. Department of Energy-sponsored Geothermal Reservoir Well Stimulation Program was initiated in February 1979 to pursue industry interest in geothermal well stimulation work and to develop technical expertise in areas directly related to geothermal well stimulation activities. This report provides an overview of the two experiments conducted in the high-temperature reservoir in Baca, New Mexico. The report discusses resource and reservoir properties, and provides a description of the stimulation experiment, a description of the treatment evaluation, and a summary of the experiment costs. (DJE-2005)

  9. Cortical responses to C-fiber stimulation by intra-epidermal electrical stimulation: an MEG study.

    PubMed

    Motogi, Jun; Kodaira, Minori; Muragaki, Yoshihiro; Inui, Koji; Kakigi, Ryusuke

    2014-06-01

    Intra-epidermal electric stimulation (IES) is an alternative to laser stimulation for selective activation of cutaneous Aδ-fibers. IES is based on the fact that nociceptive fiber terminals are located in the epidermis, whereas receptors of other fibers end deep in the dermis. IES can selectively stimulate C-fibers if the electrode structure and stimulation parameters are carefully selected. However, stable selective stimulation of C-fibers using IES has proven difficult and cannot currently be used in clinical settings. The purpose of the present study was to determine if IES performed using a modified electrode reliably stimulates C-fibers. Magnetoencephalographic responses to IES to the foot were measured in seven healthy subjects. IES elicited somatosensory evoked fields in all subjects. The mean peak latency was 1,327 ± 116 ms in the opercular region contralateral to the stimulated side, 1,318 ± 90 ms in the opercular region ipsilateral to the stimulated side, and 1350 ± 139 ms in the primary somatosensory cortex. These results indicate that IES performed using the modified electrode can selectively stimulate C-fibers and may be a useful tool for pain research as well as clinical evaluation of peripheral small fiber function.

  10. The CRTH2 agonist Pyl A prevents lipopolysaccharide-induced fetal death but induces preterm labour

    PubMed Central

    Sykes, Lynne; Herbert, Bronwen R; MacIntyre, David A; Hunte, Emma; Ponnampalam, Sathana; Johnson, Mark R; Teoh, Tiong G; Bennett, Phillip R

    2013-01-01

    We have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-Δ 12,14-prostaglandin J2 (15dPGJ2) delays inflammation-induced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor-κB (NF-κB) by a mechanism yet to be elucidated. 15dPGJ2 is an agonist of the second prostaglandin D2 receptor, chemoattractant receptor homologous to the T helper 2 cell (CRTH2). In human T helper cells CRTH2 agonists induce the production of the anti-inflammatory interleukins IL-10 and IL-4. We hypothesized that CRTH2 is involved in the protective effect of 15dPGJ2 in inflammation-induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide (LPS) was administered to CD1 mice at embryonic day 16, ± CRTH2 agonist/vehicle controls. Mice were killed at 4.5 hr to assess fetal wellbeing and to harvest myometrium and pup brain for analysis of NF-κB, and T helper type 1/2 interleukins. To examine the effects of the CRTH2 agonist on LPS-induced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH2 agonist increased fetal survival from 20 to 100% in LPS-treated mice, and inhibited circular muscle contractility ex vivo. However, it augmented LPS-induced labour and significantly increased myometrial NF-κB, IL-1β, KC-GRO, interferon-γ and tumour necrosis factor-α. This suggests that the action of 15dPGJ2 is not via CRTH2 and therefore small molecule CRTH2 agonists are not likely to be beneficial for the prevention of inflammation-induced preterm labour. PMID:23374103

  11. Radiant energy required for infrared neural stimulation

    SciTech Connect

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; Xia, Nan; Stock, Stuart R.; Xiao, Xianghui; Richter, Claus-Peter

    2015-08-25

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.

  12. Radiant energy required for infrared neural stimulation

    DOE PAGES

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; Xia, Nan; Stock, Stuart R.; Xiao, Xianghui; Richter, Claus-Peter

    2015-08-25

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography wasmore » used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.« less

  13. Stimulants for the Control of Hedonic Appetite.

    PubMed

    Poulton, Alison S; Hibbert, Emily J; Champion, Bernard L; Nanan, Ralph K H

    2016-01-01

    The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behavior. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognized to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilization of this effective and inexpensive class of drug.

  14. Impulsivity, Stimulant Abuse, and Dopamine Receptor Signaling.

    PubMed

    London, E D

    2016-01-01

    The nonmedical use of amphetamine-type stimulants is a worldwide problem, with substantial medical and social consequences. Nonetheless, the identification of a pharmacological treatment for amphetamine use disorder remains elusive. Stimulant users exhibit neurochemical evidence of dopamine-system dysfunction as well as impulsive behaviors that may interfere with the success of treatments for their addiction. This review focuses on the potential role of dopaminergic neurotransmission in impulsivity, both in healthy individuals and chronic stimulant users who meet criteria for methamphetamine dependence. Presented are findings related to the potential contributions of signaling through dopamine D1- and D2-type receptors to self-control impulsivity in methamphetamine- dependent users. The information available points to signaling through striatal D2-type dopamine receptors as a potential therapeutic target for stimulant use disorders, but medications that target D2-type dopamine receptors have not been successful in treating stimulant-use disorders, possibly because D2-type receptors are downregulated. Other means to augment D2-type receptor signaling are therefore under consideration, and one promising approach is the addition of exercise training as an adjunct to behavioral treatment for addiction. PMID:27288074

  15. Radiant energy required for infrared neural stimulation

    PubMed Central

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; Xia, Nan; Stock, Stuart R.; Xiao, Xianghui; Richter, Claus-Peter

    2015-01-01

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS. PMID:26305106

  16. Dynamics of stimulated L → H transitions

    SciTech Connect

    Miki, K.; Diamond, P. H.; Xiao, W. W.; Hahn, S.-H.; Gürcan, Ö. D.; Tynan, G. R.

    2013-08-15

    We report on model studies of stimulated L → H transitions [K. Miki et al., Phys. Rev. Lett. 110, 195002 (2013)]. These studies use a reduced mesoscale model. Model studies reveal that L → H transition can be triggered by particle injection into a subcritical state (i.e., Pstimulated transition. For low ambient heating, strong injection is predicted to trigger a transient turbulence collapse. Repetitive injection at a period less than the lifetime of the collapsed state can thus maintain the turbulence collapse and so sustain a driven H-mode-like state. The total number of particles required to induce a transition by either injection or gas puffing is estimated. Results indicate that the total number of injected particles required is much smaller than that required for a transition by gas puffing. We thus show that internal injection is more efficient than gas puffing of comparable strength. We also observe that zonal flows do not play a critical role in stimulated transitions. For spontaneous transitions, the spike of the Reynolds work of turbulence on the zonal flow precedes the spike in the mean electric field shear. In contrast, we show that the two are coincident for stimulated transitions, suggesting that there is no causal link between zonal and mean flows for stimulated transitions.

  17. Stimulants for the Control of Hedonic Appetite

    PubMed Central

    Poulton, Alison S.; Hibbert, Emily J.; Champion, Bernard L.; Nanan, Ralph K. H.

    2016-01-01

    The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behavior. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognized to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilization of this effective and inexpensive class of drug. PMID:27199749

  18. Radiant energy required for infrared neural stimulation.

    PubMed

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; Xia, Nan; Stock, Stuart R; Xiao, Xianghui; Richter, Claus-Peter

    2015-08-25

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm(2), respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.

  19. Technological Advances in Deep Brain Stimulation.

    PubMed

    Ughratdar, Ismail; Samuel, Michael; Ashkan, Keyoumars

    2015-01-01

    Functional and stereotactic neurosurgery has always been regarded as a subspecialty based on and driven by technological advances. However until recently, the fundamentals of deep brain stimulation (DBS) hardware and software design had largely remained stagnant since its inception almost three decades ago. Recent improved understanding of disease processes in movement disorders as well clinician and patient demands has resulted in new avenues of development for DBS technology. This review describes new advances both related to hardware and software for neuromodulation. New electrode designs with segmented contacts now enable sophisticated shaping and sculpting of the field of stimulation, potentially allowing multi-target stimulation and avoidance of side effects. To avoid lengthy programming sessions utilising multiple lead contacts, new user-friendly software allows for computational modelling and individualised directed programming. Therapy delivery is being improved with the next generation of smaller profile, longer-lasting, re-chargeable implantable pulse generators (IPGs). These include IPGs capable of delivering constant current stimulation or personalised closed-loop adaptive stimulation. Post-implantation Magnetic Resonance Imaging (MRI) has long been an issue which has been partially overcome with 'MRI conditional devices' and has enabled verification of DBS lead location. Surgical technique is considering a shift from frame-based to frameless stereotaxy or greater role for robot assisted implantation. The challenge for these contemporary techniques however, will be in demonstrating equivalent safety and accuracy to conventional methods. We also discuss potential future direction utilising wireless technology allowing for miniaturisation of hardware. PMID:26406128

  20. Noninvasive brain stimulation improves language learning.

    PubMed

    Flöel, Agnes; Rösser, Nina; Michka, Olesya; Knecht, Stefan; Breitenstein, Caterina

    2008-08-01

    Anodal transcranial direct current stimulation (tDCS) is a reliable technique to improve motor learning. We here wanted to test its potential to enhance associative verbal learning, a skill crucial for both acquiring new languages in healthy individuals and for language reacquisition after stroke-induced aphasia. We applied tDCS (20 min, 1 mA) over the posterior part of the left peri-sylvian area of 19 young right-handed individuals while subjects acquired a miniature lexicon of 30 novel object names. Every subject participated in one session of anodal tDCS, one session of cathodal tDCS, and one sham session in a randomized and double-blinded design with three parallel versions of the miniature lexicon. Outcome measures were learning speed and learning success at the end of each session, and the transfer to the subjects' native language after the respective stimulation. With anodal stimulation, subjects showed faster and better associative learning as compared to sham stimulation. Mood ratings, reaction times, and response styles were comparable between stimulation conditions. Our results demonstrate that anodal tDCS is a promising technique to enhance language learning in healthy adults and may also have the potential to improve language reacquisition after stroke.

  1. An implantable neural stimulator for intraspinal microstimulation.

    PubMed

    Troyk, Philip R; Mushahwar, Vivian K; Stein, Richard B; Suh, Sungjae; Everaert, Dirk; Holinski, Brad; Hu, Zhe; DeMichele, Glenn; Kerns, Douglas; Kayvani, Kevin

    2012-01-01

    This paper reports on a wireless stimulator device for use in animal experiments as part of an ongoing investigation into intraspinal stimulation (ISMS) for restoration of walking in humans with spinal cord injury. The principle behind using ISMS is the activation of residual motor-control neural networks within the spinal cord ventral horn below the level of lesion following a spinal cord injury. The attractiveness to this technique is that a small number of electrodes can be used to induce bilateral walking patterns in the lower limbs. In combination with advanced feedback algorithms, ISMS has the potential to restore walking for distances that exceed that produced by other types of functional electrical stimulation. Recent acute animal experiments have demonstrated the feasibility of using ISMS to produce the coordinated walking patterns. Here we described a wireless implantable stimulation system to be used in chronic animal experiments and for providing the basis for a system suitable for use in humans. Electrical operation of the wireless system is described, including a demonstration of reverse telemetry for monitoring the stimulating electrode voltages. PMID:23366038

  2. Technological Advances in Deep Brain Stimulation.

    PubMed

    Ughratdar, Ismail; Samuel, Michael; Ashkan, Keyoumars

    2015-01-01

    Functional and stereotactic neurosurgery has always been regarded as a subspecialty based on and driven by technological advances. However until recently, the fundamentals of deep brain stimulation (DBS) hardware and software design had largely remained stagnant since its inception almost three decades ago. Recent improved understanding of disease processes in movement disorders as well clinician and patient demands has resulted in new avenues of development for DBS technology. This review describes new advances both related to hardware and software for neuromodulation. New electrode designs with segmented contacts now enable sophisticated shaping and sculpting of the field of stimulation, potentially allowing multi-target stimulation and avoidance of side effects. To avoid lengthy programming sessions utilising multiple lead contacts, new user-friendly software allows for computational modelling and individualised directed programming. Therapy delivery is being improved with the next generation of smaller profile, longer-lasting, re-chargeable implantable pulse generators (IPGs). These include IPGs capable of delivering constant current stimulation or personalised closed-loop adaptive stimulation. Post-implantation Magnetic Resonance Imaging (MRI) has long been an issue which has been partially overcome with 'MRI conditional devices' and has enabled verification of DBS lead location. Surgical technique is considering a shift from frame-based to frameless stereotaxy or greater role for robot assisted implantation. The challenge for these contemporary techniques however, will be in demonstrating equivalent safety and accuracy to conventional methods. We also discuss potential future direction utilising wireless technology allowing for miniaturisation of hardware.

  3. Stimulation of neutrophils by tumor necrosis factor

    SciTech Connect

    Klebanoff, S.J.; Vadas, M.A.; Harlan, J.M.; Sparks, L.H.; Gamble, J.R.; Agosti, J.M.; Waltersdorph, A.M.

    1986-06-01

    Human recombinant tumor necrosis factor (TNF) was shown to be a weak direct stimulus of the neutrophil respiratory burst and degranulation. The stimulation, as measured by iodination, H/sub 2/O/sub 2/ production, and lysozyme release, was considerably increased by the presence of unopsonized zymosan in the reaction mixture, an effect which was associated with the increased ingestion of the zymosan. TNF does not act as an opsonin but, rather, reacts with the neutrophil to increase its phagocytic activity. TNF-dependent phagocytosis, as measured indirectly by iodination, is inhibited by monoclonal antibodies (Mab) 60.1 and 60.3, which recognize different epitopes on the C3bi receptor/adherence-promoting surface glycoprotein of neutrophils. Other neutrophil stimulants, namely N-formyl-methionyl-leucyl-phenylalanine, the Ca2+ ionophore A23187, and phorbol myristic acetate, also increase iodination in the presence of zymosan; as with TNF, the effect of these stimulants is inhibited by Mab 60.1 and 60.3, whereas, in contrast to that of TNF, their stimulation of iodination is unaffected by an Mab directed against TNF. TNF may be a natural stimulant of neutrophils which promotes adherence to endothelial cells and to particles, leading to increased phagocytosis, respiratory burst activity, and degranulation.

  4. Stimulants for the Control of Hedonic Appetite.

    PubMed

    Poulton, Alison S; Hibbert, Emily J; Champion, Bernard L; Nanan, Ralph K H

    2016-01-01

    The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behavior. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognized to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilization of this effective and inexpensive class of drug. PMID:27199749

  5. Radiant energy required for infrared neural stimulation.

    PubMed

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; Xia, Nan; Stock, Stuart R; Xiao, Xianghui; Richter, Claus-Peter

    2015-01-01

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm(2), respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS. PMID:26305106

  6. Impacts of selected stimulation patterns on the perception threshold in electrocutaneous stimulation

    PubMed Central

    2011-01-01

    Background Consistency is one of the most important concerns to convey stable artificially induced sensory feedback. However, the constancy of perceived sensations cannot be guaranteed, as the artificially evoked sensation is a function of the interaction of stimulation parameters. The hypothesis of this study is that the selected stimulation parameters in multi-electrode cutaneous stimulation have significant impacts on the perception threshold. Methods The investigated parameters included the stimulated location, the number of active electrodes, the number of pulses, and the interleaved time between a pair of electrodes. Biphasic, rectangular pulses were applied via five surface electrodes placed on the forearm of 12 healthy subjects. Results Our main findings were: 1) the perception thresholds at the five stimulated locations were significantly different (p < 0.0001), 2) dual-channel simultaneous stimulation lowered the perception thresholds and led to smaller variance in perception thresholds compared to single-channel stimulation, 3) the perception threshold was inversely related to the number of pulses, and 4) the perception threshold increased with increasing interleaved time when the interleaved time between two electrodes was below 500 μs. Conclusions To maintain a consistent perception threshold, our findings indicate that dual-channel simultaneous stimulation with at least five pulses should be used, and that the interleaved time between two electrodes should be longer than 500 μs. We believe that these findings have implications for design of reliable sensory feedback codes. PMID:21306616

  7. Infrared neural stimulation: a new stimulation tool for central nervous system applications

    PubMed Central

    Chernov, Mykyta; Roe, Anna Wang

    2014-01-01

    Abstract. The traditional approach to modulating brain function (in both clinical and basic science applications) is to tap into the neural circuitry using electrical currents applied via implanted electrodes. However, it suffers from a number of problems, including the risk of tissue trauma, poor spatial specificity, and the inability to selectively stimulate neuronal subtypes. About a decade ago, optical alternatives to electrical stimulation started to emerge in order to address the shortcomings of electrical stimulation. We describe the use of one optical stimulation technique, infrared neural stimulation (INS), during which short (of the order of a millisecond) pulses of infrared light are delivered to the neural tissue. Very focal stimulation is achieved via a thermal mechanism and stimulation location can be quickly adjusted by redirecting the light. After describing some of the work done in the peripheral nervous system, we focus on the use of INS in the central nervous system to investigate functional connectivity in the visual and somatosensory areas, target specific functional domains, and influence behavior of an awake nonhuman primate. We conclude with a positive outlook for INS as a tool for safe and precise targeted brain stimulation. PMID:26157967

  8. The Effect of Early Stimulation: The Problem of Focus in Developmental Stimulation.

    ERIC Educational Resources Information Center

    Fowler, William

    Studies of the effect of environmental stimulation on an individual's development in either general or specific ability conclude that some specific stimulation should be introduced at an early age while a child is still malleable. An intense, persistent, and regular tutorial approach within the family encourages the development of a special talent…

  9. Magnetic fields in noninvasive brain stimulation.

    PubMed

    Vidal-Dourado, Marcos; Conforto, Adriana Bastos; Caboclo, Luis Otávio Sales Ferreira; Scaff, Milberto; Guilhoto, Laura Maria de Figueiredo Ferreira; Yacubian, Elza Márcia Targas

    2014-04-01

    The idea that magnetic fields could be used therapeutically arose 2000 years ago. These therapeutic possibilities were expanded after the discovery of electromagnetic induction by the Englishman Michael Faraday and the American Joseph Henry. In 1896, Arsène d'Arsonval reported his experience with noninvasive brain magnetic stimulation to the scientific French community. In the second half of the 20th century, changing magnetic fields emerged as a noninvasive tool to study the nervous system and to modulate neural function. In 1985, Barker, Jalinous, and Freeston presented transcranial magnetic stimulation, a relatively focal and painless technique. Transcranial magnetic stimulation has been proposed as a clinical neurophysiology tool and as a potential adjuvant treatment for psychiatric and neurologic conditions. This article aims to contextualize the progress of use of magnetic fields in the history of neuroscience and medical sciences, until 1985. PMID:23787954

  10. Metabolism of the stimulated rat spleen

    PubMed Central

    Mazur, Abraham

    1968-01-01

    Assay of the enzyme ferrochelatase in marrow, liver, spleen, and red cells has been employed to assess the extent of erythropoietic stimulation in animals bearing the Walker 256 carcinosarcoma and in rats treated by administration of phenylhydrazine, cobalt chloride, human urinary erythropoietin, or chronic blood loss. In all instances, the spleen sustains the most marked increase of ferrochelatase activity, per gram of tissue. Spleen erythropoietic activity stimulation was confirmed by quantitative measurements in respiring slices of 59Fe and 14C incorporation into hemoglobin and ferritin. Increased spleen ferrochelatase activity in cobalt chloride-treated rats is prevented by actinomycin D, indicating that stimulated synthesis of the enzyme is associated with the metabolism of RNA. PMID:5676519

  11. Magnetic fields in noninvasive brain stimulation.

    PubMed

    Vidal-Dourado, Marcos; Conforto, Adriana Bastos; Caboclo, Luis Otávio Sales Ferreira; Scaff, Milberto; Guilhoto, Laura Maria de Figueiredo Ferreira; Yacubian, Elza Márcia Targas

    2014-04-01

    The idea that magnetic fields could be used therapeutically arose 2000 years ago. These therapeutic possibilities were expanded after the discovery of electromagnetic induction by the Englishman Michael Faraday and the American Joseph Henry. In 1896, Arsène d'Arsonval reported his experience with noninvasive brain magnetic stimulation to the scientific French community. In the second half of the 20th century, changing magnetic fields emerged as a noninvasive tool to study the nervous system and to modulate neural function. In 1985, Barker, Jalinous, and Freeston presented transcranial magnetic stimulation, a relatively focal and painless technique. Transcranial magnetic stimulation has been proposed as a clinical neurophysiology tool and as a potential adjuvant treatment for psychiatric and neurologic conditions. This article aims to contextualize the progress of use of magnetic fields in the history of neuroscience and medical sciences, until 1985.

  12. Motilin stimulates pepsinogen secretion in Suncus murinus.

    PubMed

    Goswami, Chayon; Tanaka, Toru; Jogahara, Takamichi; Sakai, Takafumi; Sakata, Ichiro

    2015-07-01

    Motilin and ghrelin are gastrointestinal hormones that stimulate the migrating motor complex (MMC) of gastrointestinal motility during the fasting state. In this study, we examined the effect of motilin and ghrelin on pepsinogen secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. By using a gastric lumen-perfusion system, we found that the intravenous administration of carbachol and motilin stimulated pepsinogen secretion, the latter in a dose-dependent manner, whereas ghrelin had no effect. We then investigated the pathways of motilin-induced pepsinogen secretion using acetylcholine receptor antagonists. Treatment with atropine, a muscarinic acetylcholine receptor antagonist, completely inhibited both carbachol and motilin-induced pepsinogen secretion. Motilin-induced pepsinogen secretion was observed in the vagotomized suncus. This is the first report demonstrating that motilin stimulates pepsinogen secretion, and suggest that this effect occurs through a cholinergic pathway in suncus. PMID:25957475

  13. High frequency stimulation can block axonal conduction.

    PubMed

    Jensen, Alicia L; Durand, Dominique M

    2009-11-01

    High frequency stimulation (HFS) is used to control abnormal neuronal activity associated with movement, seizure, and psychiatric disorders. Yet, the mechanisms of its therapeutic action are not known. Although experimental results have shown that HFS suppresses somatic activity, other data has suggested that HFS could generate excitation of axons. Moreover it is unclear what effect the stimulation has on tissue surrounding the stimulation electrode. Electrophysiological and computational modeling literature suggests that HFS can drive axons at the stimulus frequency. Therefore, we tested the hypothesis that unlike cell bodies, axons are driven by pulse train HFS. This hypothesis was tested in fibers of the hippocampus both in-vivo and in-vitro. Our results indicate that although electrical stimulation could activate and drive axons at low frequencies (0.5-25 Hz), as the stimulus frequency increased, electrical stimulation failed to continuously excite axonal activity. Fiber tracts were unable to follow extracellular pulse trains above 50 Hz in-vitro and above 125 Hz in-vivo. The number of cycles required for failure was frequency dependent but independent of stimulus amplitude. A novel in-vitro preparation was developed, in which, the alveus was isolated from the remainder of the hippocampus slice. The isolated fiber tract was unable to follow pulse trains above 75 Hz. Reversible conduction block occurred at much higher stimulus amplitudes, with pulse train HFS (>150 Hz) preventing propagation through the site of stimulation. This study shows that pulse train HFS affects axonal activity by: (1) disrupting HFS evoked excitation leading to partial conduction block of activity through the site of HFS; and (2) generating complete conduction block of secondary evoked activity, as HFS amplitude is increased. These results are relevant for the interpretation of the effects of HFS for the control of abnormal neural activity such as epilepsy and Parkinson's disease. PMID

  14. Oxidants as stimulators of signal transduction.

    PubMed

    Suzuki, Y J; Forman, H J; Sevanian, A

    1997-01-01

    Redox (oxidation-reduction) reactions regulate signal transduction. Oxidants such as superoxide, hydrogen peroxide, hydroxyl radicals, and lipid hydroperoxides (i.e., reactive oxygen species) are now realized as signaling molecules under subtoxic conditions. Nitric oxide is also an example of a redox mediator. Reactive oxygen species induce various biological processes such as gene expression by stimulating signal transduction components such as Ca(2+)-signaling and protein phosphorylation. Various oxidants increase cytosolic Ca2+; however, the exact origin of Ca2+ is controversial. Ca2+ may be released from the endoplasmic reticulum, extracellular space, or mitochondria in response to oxidant-influence on Ca2+ pumps, channels, and transporters. Alternatively, oxidants may release Ca2+ from Ca2+ binding proteins. Various oxidants stimulate tyrosine as well as serine/threonine phosphorylation, and direct stimulation of protein kinases and inhibition of protein phosphatases by oxidants have been proposed as mechanisms. The oxidant-stimulation of the effector molecules such as phospholipase A2 as well as the activation of oxidative stress-responsive transcription factors may also depend on the oxidant-mediated activation of Ca(2+)-signaling and/or protein phosphorylation. In addition to the stimulation of signal transduction by oxidants, the observations that ligand-receptor interactions produce reactive oxygen species and that antioxidants block receptor-mediated signal transduction led to a proposal that reactive oxygen species may be second messengers for transcription factor activation, apoptosis, bone resorption, cell growth, and chemotaxis. Physiological significance of the role of biological oxidants in the regulation of signal transduction as well as the mechanisms of the oxidant-stimulation of signal transduction are discussed.

  15. 21 CFR 890.5860 - Ultrasound and muscle stimulator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Ultrasound and muscle stimulator. 890.5860 Section... Ultrasound and muscle stimulator. (a) Ultrasound and muscle stimulator for use in applying therapeutic deep heat for selected medical conditions—(1) Identification. An ultrasound and muscle stimulator for use...

  16. 21 CFR 890.5860 - Ultrasound and muscle stimulator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Ultrasound and muscle stimulator. 890.5860 Section... Ultrasound and muscle stimulator. (a) Ultrasound and muscle stimulator for use in applying therapeutic deep heat for selected medical conditions—(1) Identification. An ultrasound and muscle stimulator for use...

  17. 21 CFR 890.5860 - Ultrasound and muscle stimulator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Ultrasound and muscle stimulator. 890.5860 Section... Ultrasound and muscle stimulator. (a) Ultrasound and muscle stimulator for use in applying therapeutic deep heat for selected medical conditions—(1) Identification. An ultrasound and muscle stimulator for use...

  18. 21 CFR 890.5860 - Ultrasound and muscle stimulator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Ultrasound and muscle stimulator. 890.5860 Section... Ultrasound and muscle stimulator. (a) Ultrasound and muscle stimulator for use in applying therapeutic deep heat for selected medical conditions—(1) Identification. An ultrasound and muscle stimulator for use...

  19. 21 CFR 890.5860 - Ultrasound and muscle stimulator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Ultrasound and muscle stimulator. 890.5860 Section... Ultrasound and muscle stimulator. (a) Ultrasound and muscle stimulator for use in applying therapeutic deep heat for selected medical conditions—(1) Identification. An ultrasound and muscle stimulator for use...

  20. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  1. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  2. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  3. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  4. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  5. Pudendal Nerve Stimulation and Block by a Wireless Controlled Implantable Stimulator in Cats

    PubMed Central

    Yang, Guangning; Wang, Jicheng; Shen, Bing; Roppolo, James R.; de Groat, William C.; Tai, Changfeng

    2014-01-01

    Objective To determine the functionality of a wireless controlled implantable stimulator designed for stimulation and block of the pudendal nerve. Materials and Methods In 5 cats under α-chloralose anesthesia, the stimulator was implanted underneath the skin on the left side in the lower back along the sacral spine. Two tripolar cuff electrodes were implanted bilaterally on the pudendal nerves in addition to one bipolar cuff electrode that was implanted on the left side central to the tripolar cuff electrode. The stimulator provided high frequency (5-20 kHz) biphasic stimulation waveforms to the two tripolar electrodes and low frequency (1-100 Hz) rectangular pulses to the bipolar electrode. Bladder and urethral pressures were measured to determine the effects of pudendal nerve stimulation (PNS) or block. Results The maximal (70-100 cmH2O) urethral pressure generated by 20 Hz PNS applied via the bipolar electrode was completely eliminated by the pudendal nerve block induced by the high frequency stimulation (6-15 kHz, 6-10 V) applied via the two tripolar electrodes. In a partially filled bladder 20-30 Hz PNS (2-8 V, 0.2 ms) but not 5 Hz stimulation applied via the bipolar electrode elicited a large sustained bladder contraction (45.9±13.4 to 52.0±22 cmH2O). During cystometry, the 5 Hz PNS significantly (P<0.05) increased bladder capacity to 176.5±27.1% of control capacity. Conclusions The wireless controlled implantable stimulator successfully generated the required waveforms for stimulation and block of pudendal nerve, which will be useful for restoring bladder functions after spinal cord injury (SCI). PMID:24320615

  6. Lymphocyte stimulation by soluble subcellular fractions.

    PubMed

    Pegrum, G D; Thompson, E A; Lewis, C M; Grant, V A

    1976-04-01

    Nuclear material can produce inhibition or stimulation of healty leucocytes under different experimental conditions, Reactivity could not be produced in cultures using intact nuclei and allogeneic lymphocytes. The effect of nuclear and cytoplasm fractions was compared with that of whole cells on intact healthy lymphocytes. The HLA activity in the individual fractions was assessed. Stimulation was produced by certain nuclear and cytoplasmic fractions and these were closely related to the peaks of HLA activity. The response to these fractions showed less activity than that achieved in conventional one way MLC tests.

  7. Transcranial laser stimulation improves human cerebral oxygenation

    PubMed Central

    Tian, Fenghua; Hase, Snehal N.

    2016-01-01

    Background and Objective Transcranial laser stimulation of the brain with near‐infrared light is a novel form of non‐invasive photobiomodulation or low‐level laser therapy (LLLT) that has shown therapeutic potential in a variety of neurological and psychological conditions. Understanding of its neurophysiological effects is essential for mechanistic study and treatment evaluation. This study investigated how transcranial laser stimulation influences cerebral hemodynamics and oxygenation in the human brain in vivo using functional near‐infrared spectroscopy (fNIRS). Materials and Methods Two separate experiments were conducted in which 1,064‐nm laser stimulation was administered at (1) the center and (2) the right side of the forehead, respectively. The laser emitted at a power of 3.4 W and in an area of 13.6 cm2, corresponding to 0.25 W/cm2 irradiance. Stimulation duration was 10 minutes. Nine healthy male and female human participants of any ethnic background, in an age range of 18–40 years old were included in each experiment. Results In both experiments, transcranial laser stimulation induced an increase of oxygenated hemoglobin concentration (Δ[HbO2]) and a decrease of deoxygenated hemoglobin concentration (Δ[Hb]) in both cerebral hemispheres. Improvements in cerebral oxygenation were indicated by a significant increase of differential hemoglobin concentration (Δ[HbD] = Δ[HbO2] − Δ[Hb]). These effects increased in a dose‐dependent manner over time during laser stimulation (10 minutes) and persisted after laser stimulation (6 minutes). The total hemoglobin concentration (Δ[HbT] = Δ[HbO2] + Δ[Hb]) remained nearly unchanged in most cases. Conclusion Near‐infrared laser stimulation applied to the forehead can transcranially improve cerebral oxygenation in healthy humans. Lasers Surg. Med. 48:343–349, 2016. © 2016 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc. PMID:26817446

  8. Deep brain stimulation for movement disorders.

    PubMed

    Thevathasan, Wesley; Gregory, Ralph

    2010-02-01

    Deep brain stimulation is now considered a routine treatment option for selected patients with advanced Parkinson's disease, primary segmental and generalised dystonia, and essential tremor. The neurosurgeon is responsible for the accurate and safe placement of the electrodes and the neurologist for the careful selection of patients and titration of medication against the effects of stimulation. A multidisciplinary team approach involving specialist nurses, neuropsychologists and neurophysiologists is required for a successful outcome. In this article we will summarise the key points in patient selection, provide an overview of the surgical technique, and discuss the beneficial and adverse outcomes that can occur.

  9. Neural dynamics during repetitive visual stimulation

    NASA Astrophysics Data System (ADS)

    Tsoneva, Tsvetomira; Garcia-Molina, Gary; Desain, Peter

    2015-12-01

    Objective. Steady-state visual evoked potentials (SSVEPs), the brain responses to repetitive visual stimulation (RVS), are widely utilized in neuroscience. Their high signal-to-noise ratio and ability to entrain oscillatory brain activity are beneficial for their applications in brain-computer interfaces, investigation of neural processes underlying brain rhythmic activity (steady-state topography) and probing the causal role of brain rhythms in cognition and emotion. This paper aims at analyzing the space and time EEG dynamics in response to RVS at the frequency of stimulation and ongoing rhythms in the delta, theta, alpha, beta, and gamma bands. Approach.We used electroencephalography (EEG) to study the oscillatory brain dynamics during RVS at 10 frequencies in the gamma band (40-60 Hz). We collected an extensive EEG data set from 32 participants and analyzed the RVS evoked and induced responses in the time-frequency domain. Main results. Stable SSVEP over parieto-occipital sites was observed at each of the fundamental frequencies and their harmonics and sub-harmonics. Both the strength and the spatial propagation of the SSVEP response seem sensitive to stimulus frequency. The SSVEP was more localized around the parieto-occipital sites for higher frequencies (>54 Hz) and spread to fronto-central locations for lower frequencies. We observed a strong negative correlation between stimulation frequency and relative power change at that frequency, the first harmonic and the sub-harmonic components over occipital sites. Interestingly, over parietal sites for sub-harmonics a positive correlation of relative power change and stimulation frequency was found. A number of distinct patterns in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz) and beta (15-30 Hz) bands were also observed. The transient response, from 0 to about 300 ms after stimulation onset, was accompanied by increase in delta and theta power over fronto-central and occipital sites, which returned to baseline

  10. Nucleus accumbens stimulation in pathological obesity.

    PubMed

    Harat, Marek; Rudaś, Marcin; Zieliński, Piotr; Birska, Julita; Sokal, Paweł

    2016-01-01

    One of the potential treatment methods of obesity is deep brain stimulation (DBS) of nucleus accumbens. We describe the case of 19 years old woman with hypothalamic obesity. She weighted 151.4 kg before DBS and the non-surgical methods proved to be inefficient. She was treated with implantation of DBS electrode to nucleus accumbens bilaterally. Results were measured with body mass index and neuropsychological tests. Follow-up was 14 months. Fourteen months after surgery weight was 138 kg, BMI was 48.3. Neuropsychological test results were intact. The presented case supports the thesis of treatment of obesity with nucleus accumbens stimulation. PMID:27154450

  11. Stimulating Cognitive Processes in Beginning Readers.

    ERIC Educational Resources Information Center

    Morgan, Mary Ann; Wallace, Nancy

    Drawing from research on reading, this paper suggests various methods of stimulating cognition in beginning readers. Defining cognition as the process by which a person gains knowledge, or understands or comprehends, discussion in the paper centers on the following topics: (1) perceptive and cognitive skills; (2) prior experience; (3) knowledge of…

  12. Stimulate Students' Interest by Genetics Exordium Teaching

    ERIC Educational Resources Information Center

    Li, Yan

    2009-01-01

    Genetics is the important specialized course of bioscience and whether exordium is taught wonderfully or not plays the important and pivotal role. Well teaching exordium class may stimulate students, deep interest and intense desire for knowledge in this class. This text, according to teaching experience and taste, puts forward several teaching…

  13. Peripheral neural activity recording and stimulation system.

    PubMed

    Loi, D; Carboni, C; Angius, G; Angotzi, G N; Barbaro, M; Raffo, L; Raspopovic, S; Navarro, X

    2011-08-01

    This paper presents a portable, embedded, microcontroller-based system for bidirectional communication (recording and stimulation) between an electrode, implanted in the peripheral nervous system, and a host computer. The device is able to record and digitize spontaneous and/or evoked neural activities and store them in data files on a PC. In addition, the system has the capability of providing electrical stimulation of peripheral nerves, injecting biphasic current pulses with programmable duration, intensity, and frequency. The recording system provides a highly selective band-pass filter from 800 Hz to 3 kHz, with a gain of 56 dB. The amplification range can be further extended to 96 dB with a variable gain amplifier. The proposed acquisition/stimulation circuitry has been successfully tested through in vivo measurements, implanting a tf-LIFE electrode in the sciatic nerve of a rat. Once implanted, the device showed an input referred noise of 0.83 μVrms, was capable of recording signals below 10 μ V, and generated muscle responses to injected stimuli. The results demonstrate the capability of processing and transmitting neural signals with very low distortion and with a power consumption lower than 1 W. A graphic, user-friendly interface has been developed to facilitate the configuration of the entire system, providing the possibility to activate stimulation and monitor recordings in real time.

  14. Quantum theory of laser-stimulated desorption

    NASA Technical Reports Server (NTRS)

    Slutsky, M. S.; George, T. F.

    1978-01-01

    A quantum theory of laser-stimulated desorption (LSDE) is presented and critically analyzed. It is shown how LSDE depends on laser-pulse characteristics and surface-lattice dynamics. Predictions of the theory for a Debye model of the lattice dynamics are compared to recent experimental results.

  15. Stimulating Cultural Appetites: An Experiential Gourmet Approach

    ERIC Educational Resources Information Center

    Chavez, Carolyn I.; Hu Poirier, Vickie

    2007-01-01

    This article is an extension of a presentation that won "Best Exercise" at the Eastern Academy of Management, 1998. The authors introduce an experiential gourmet approach using "food stories" to stimulate an aura of acceptance and appreciation for human commonalities before delving into human differences. The authors use a semester long…

  16. Computer Games Functioning as Motivation Stimulants

    ERIC Educational Resources Information Center

    Lin, Grace Hui Chin; Tsai, Tony Kung Wan; Chien, Paul Shih Chieh

    2011-01-01

    Numerous scholars have recommended computer games can function as influential motivation stimulants of English learning, showing benefits as learning tools (Clarke and Dede, 2007; Dede, 2009; Klopfer and Squire, 2009; Liu and Chu, 2010; Mitchell, Dede & Dunleavy, 2009). This study aimed to further test and verify the above suggestion,…

  17. Magnetic Stimulation Studies of Foveal Representation

    ERIC Educational Resources Information Center

    Lavidor, Michal; Walsh, Vincent

    2004-01-01

    The right and left visual fields each project to the contralateral cerebral hemispheres, but the extent of the functional overlap of the two hemifields along the vertical meridian is still under debate. After presenting the spatial, temporal, and functional specifications of Transcranial Magnetic Stimulation (TMS), we show that TMS is particularly…

  18. Novel transcranial magnetic stimulation coil for mice

    NASA Astrophysics Data System (ADS)

    March, Stephen; Stark, Spencer; Crowther, Lawrence; Hadimani, Ravi; Jiles, David

    2014-03-01

    Transcranial magnetic stimulation (TMS) shows potential for non-invasive treatment of various neurological disorders. Significant work has been performed on the design of coils used for TMS on human subjects but few reports have been made on the design of coils for use on the brains of animals such as mice. This work is needed as TMS studies utilizing mice can allow rapid preclinical development of TMS for human disorders but the coil designs developed for use on humans are inadequate for optimal stimulation of the much smaller mouse brain. A novel TMS coil has been developed with the goal of inducing strong and focused electric fields for the stimulation of small animals such as mice. Calculations of induced electric fields were performed utilizing an MRI derived inhomogeneous model of an adult male mouse. Mechanical and thermal analysis of this new TMS helmet-coil design have also been performed at anticipated TMS operating conditions to ensure mechanical stability of the new coil and establish expected linear attraction and rotational force values. Calculated temperature increases for typical stimulation periods indicate the helmet-coil system is capable of operating within established medical standards. A prototype of the coil has been fabricated and characterization results are presented.

  19. Motor-Cognitive Stimulation of the Elderly

    ERIC Educational Resources Information Center

    Cao, Ana Rey; Lacruz, Inmaculada Canales; Pais, Maria Ines Taboas

    2011-01-01

    This article shows the cognitive and motor-perceptive effects of the application of a cognitive stimulating program through motor function on 234 elderly people. The assessment was carried out prior to and after the program. Significant improvements in the experimental group were observed (p [less than or equal to] 0.05) in six of the eight…

  20. Transcutaneous Electrical Nerve Stimulation: Research Update.

    ERIC Educational Resources Information Center

    Johns, Florene Carnicelli

    Currently, research is being performed in the area of nonsurgical and nonchemical means for influencing the body's threshold for pain. Today, transcutaneous electrical nerve stimulation (TENS) is being widely used for this purpose. Application of this treatment can be confusing, however, because determining such things as selection of the proper…

  1. Causal Measurement Models: Can Criticism Stimulate Clarification?

    ERIC Educational Resources Information Center

    Markus, Keith A.

    2016-01-01

    In their 2016 work, Aguirre-Urreta et al. provided a contribution to the literature on causal measurement models that enhances clarity and stimulates further thinking. Aguirre-Urreta et al. presented a form of statistical identity involving mapping onto the portion of the parameter space involving the nomological net, relationships between the…

  2. Backward stimulated Raman scattering in water

    NASA Astrophysics Data System (ADS)

    Tcherniega, N.; Sokolovskaia, A.; Kudriavtseva, A. D.; Barille, R.; Rivoire, G.

    2000-07-01

    The backward Stimulated Raman scattering (BSRS) is studied in liquid water. We show that BSRS can be produced by small volumes of active materials. Our experimental results and calculations with different geometries and intensities of excitation allow us to choose the best experimental set-up for BSRS efficiencies. The competition with librational scattering is also observed.

  3. Metallic taste from electrical and chemical stimulation.

    PubMed

    Lawless, Harry T; Stevens, David A; Chapman, Kathryn W; Kurtz, Anne

    2005-03-01

    A series of three experiments investigated the nature of metallic taste reports after stimulation with solutions of metal salts and after stimulation with metals and electric currents. To stimulate with electricity, a device was fabricated consisting of a small battery affixed to a plastic handle with the anode side exposed for placement on the tongue or oral tissues. Intensity of taste from metals and batteries was dependent upon the voltage and was more robust in areas dense in fungiform papillae. Metallic taste was reported from stimulation with ferrous sulfate solutions, from metals and from electric stimuli. However, reports of metallic taste were more frequent when the word 'metallic' was presented embedded in a list of choices, as opposed to simple free-choice labeling. Intensity decreased for ferrous sulfate when the nose was occluded, consistent with a decrease in retronasal smell, as previously reported. Intensity of taste evoked by copper metal, bimetallic stimuli (zinc/copper) or small batteries (1.5-3 V) was not affected by nasal occlusion. This difference suggests two distinct mechanisms for evocation of metallic taste reports, one dependent upon retronasal smell and a second mediated by oral chemoreceptors. PMID:15741603

  4. Fidget Blankets: A Sensory Stimulation Outreach Program.

    PubMed

    Kroustos, Kelly Reilly; Trautwein, Heidi; Kerns, Rachel; Sobota, Kristen Finley

    2016-01-01

    Behavioral and Psychological Symptoms of Dementia (BPSD) include behaviors such as aberrant motor behavior, agitation, anxiety, apathy, delusions, depression, disinhibition, elation, hallucinations, irritability, and sleep or appetite changes. A student-led project to provide sensory stimulation in the form of "fidget blankets" developed into a community outreach program. The goal was to decrease the use of antipsychotics used for BPSD. PMID:27250073

  5. Social Early Stimulation of Trisomy-21 Babies

    ERIC Educational Resources Information Center

    Aparicio, Maria Teresa Sanz; Balana, Javier Menendez

    2003-01-01

    This study was initiated with twenty Down's syndrome babies to verify whether subjects undergoing social early stimulation would benefit from this type of treatment. An experimental study was designed with two training groups: visual or written instructions. The analyses of the results established statistically significant differences in the…

  6. Extradural implantation of sacral anterior root stimulators.

    PubMed Central

    Sauerwein, D; Ingunza, W; Fischer, J; Madersbacher, H; Polkey, C E; Brindley, G S; Colombel, P; Teddy, P

    1990-01-01

    A technique for extradural deafferentation of the S2 to S5 segments and extradural implantation of stimulating electrodes is described, and its application to twelve patients with spinal cord lesions is reported. Nine patients use their implants for micturition, and seven are fully continent. The advantages and disadvantages of this technique compared with the more usual intrathecal procedure are discussed. PMID:2213045

  7. STIMULATION TECHNOLOGIES FOR DEEP WELL COMPLETIONS

    SciTech Connect

    Stephen Wolhart

    2003-06-01

    The Department of Energy (DOE) is sponsoring a Deep Trek Program targeted at improving the economics of drilling and completing deep gas wells. Under the DOE program, Pinnacle Technologies is conducting a project to evaluate the stimulation of deep wells. The objective of the project is to assess U.S. deep well drilling & stimulation activity, review rock mechanics & fracture growth in deep, high pressure/temperature wells and evaluate stimulation technology in several key deep plays. Phase 1 was recently completed and consisted of assessing deep gas well drilling activity (1995-2007) and an industry survey on deep gas well stimulation practices by region. Of the 29,000 oil, gas and dry holes drilled in 2002, about 300 were drilled in the deep well; 25% were dry, 50% were high temperature/high pressure completions and 25% were simply deep completions. South Texas has about 30% of these wells, Oklahoma 20%, Gulf of Mexico Shelf 15% and the Gulf Coast about 15%. The Rockies represent only 2% of deep drilling. Of the 60 operators who drill deep and HTHP wells, the top 20 drill almost 80% of the wells. Six operators drill half the U.S. deep wells. Deep drilling peaked at 425 wells in 1998 and fell to 250 in 1999. Drilling is expected to rise through 2004 after which drilling should cycle down as overall drilling declines.

  8. Magnetized stimulated scattering in pulsar winds

    NASA Technical Reports Server (NTRS)

    Sincell, Mark W.; Krolik, Julian H.

    1992-01-01

    The effects of stimulated scattering on a collimated high brightness temperature beam of photons traversing a relativistically streaming magnetized plasma are studied. Under the assumption that the center of the photon beam is parallel to the bulk motion, we calculate the scattering rate as a function of the angular spread of the beam and the Lorentz factor gamma. Magnetization changes the photon recoil, without which stimulated scattering has no effect. It also introduces a strong dependence on frequency and polarization: if the photon frequency matches the electron cyclotron frequency, the scattering rate of photons polarized perpendicular to the magnetic field can be substantially enhanced relative to Thomson, and if the photon frequency is much less than the cyclotron frequency, the scattering is suppressed. Applying these calculations to pulsars, we find that stimulated scattering of the radio beam in the magnetized wind believed to exist outside the light cylinder can substantially alter the spectrum and polarization state of the radio signal. We suggest that the scattering rate is so high in some pulsars that the ability of the radio signal to penetrate the pulsar magnetosphere requires modification of either the conventional model of the magnetosphere or assumptions about the effects of stimulated scattering upon a beam.

  9. Seismic stimulation for enhanced oil recovery

    SciTech Connect

    Pride, S.R.; Flekkoy, E.G.; Aursjo, O.

    2008-07-22

    The pore-scale effects of seismic stimulation on two-phase flow are modeled numerically in random 2D grain0pack geometries. Seismic stimulation aims to enhance oil production by sending seismic waves across a reservoir to liberate immobile patches of oil. For seismic amplitudes above a well-defined (analytically expressed) dimensionless criterion, the force perturbation associated with the waves indeed can liberate oil trapped on capillary barriers and get it flowing again under the background pressure gradient. Subsequent coalescence of the freed oil droplets acts to enhance oil movement further because longer bubbles overcome capillary barriers more efficiently than shorter bubbles do. Poroelasticity theory defines the effective force that a seismic wave adds to the background fluid-pressure gradient. The lattice-Boltzmann model in two dimensions is used to perform pore-scale numerical simulations. Dimensionless numbers (groups of material and force parameters) involved in seismic stimulation are defined carefully so that numerical simulations can be applied to field-scale conditions. Using the analytical criteria defined in the paper, there is a significant range of reservoir conditions over which seismic stimulation can be expected to enhance oil production.

  10. Fidget Blankets: A Sensory Stimulation Outreach Program.

    PubMed

    Kroustos, Kelly Reilly; Trautwein, Heidi; Kerns, Rachel; Sobota, Kristen Finley

    2016-01-01

    Behavioral and Psychological Symptoms of Dementia (BPSD) include behaviors such as aberrant motor behavior, agitation, anxiety, apathy, delusions, depression, disinhibition, elation, hallucinations, irritability, and sleep or appetite changes. A student-led project to provide sensory stimulation in the form of "fidget blankets" developed into a community outreach program. The goal was to decrease the use of antipsychotics used for BPSD.

  11. Fourier transform stimulated emission pumping spectroscopy

    NASA Astrophysics Data System (ADS)

    Felker, P. M.; Henson, B. F.; Corcoran, T. C.; Connell, L. L.; Hartland, G. V.

    1987-12-01

    Theoretical and experimental results that demonstrate a new technique of non-linear interferometry based on stimulated emission pumping spectroscopy (SEPS) are presented. It is shown that splittings between the initial and final states in SEP processes can be measured by the method. Advantages and disadvantages of the technique relative to spectral domain SEPS are discussed.

  12. How Learning Environments Can Stimulate Student Imagination

    ERIC Educational Resources Information Center

    Liang, Chaoyun; Hsu, Yuling; Huang, Yinghsiu; Chen, Sheng-Chih

    2012-01-01

    The purpose of this study was to investigate an array of environmental factors that can stimulate imagination and explore how these factors manifest in different design phases. The participants of this study were students in the field of educational technology from four universities across Taiwan. The instructional design process was divided into…

  13. Stimulation Technologies for Deep Well Completions

    SciTech Connect

    2004-03-31

    The Department of Energy (DOE) is sponsoring the Deep Trek Program targeted at improving the economics of drilling and completing deep gas wells. Under the DOE program, Pinnacle Technologies is conducting a study to evaluate the stimulation of deep wells. The objective of the project is to assess U.S. deep well drilling and stimulation activity, review rock mechanics and fracture growth in deep, high-pressure/temperature wells and evaluate stimulation technology in several key deep plays. An assessment of historical deep gas well drilling activity and forecast of future trends was completed during the first six months of the project; this segment of the project was covered in Technical Progress Report No. 1. During the next six months, efforts were primarily split between summarizing rock mechanics and fracture growth in deep reservoirs and contacting operators about case studies of deep gas well stimulation as documented in Technical Progress Report No. 2. This report details work done with Anadarko and ChevronTexaco in the Table Rock Field in Wyoming.

  14. Aromatase inhibitors in stimulated IVF cycles

    PubMed Central

    2011-01-01

    Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels PMID:21693033

  15. Evaluation of intradural stimulation efficiency and selectivity in a computational model of spinal cord stimulation.

    PubMed

    Howell, Bryan; Lad, Shivanand P; Grill, Warren M

    2014-01-01

    Spinal cord stimulation (SCS) is an alternative or adjunct therapy to treat chronic pain, a prevalent and clinically challenging condition. Although SCS has substantial clinical success, the therapy is still prone to failures, including lead breakage, lead migration, and poor pain relief. The goal of this study was to develop a computational model of SCS and use the model to compare activation of neural elements during intradural and extradural electrode placement. We constructed five patient-specific models of SCS. Stimulation thresholds predicted by the model were compared to stimulation thresholds measured intraoperatively, and we used these models to quantify the efficiency and selectivity of intradural and extradural SCS. Intradural placement dramatically increased stimulation efficiency and reduced the power required to stimulate the dorsal columns by more than 90%. Intradural placement also increased selectivity, allowing activation of a greater proportion of dorsal column fibers before spread of activation to dorsal root fibers, as well as more selective activation of individual dermatomes at different lateral deviations from the midline. Further, the results suggest that current electrode designs used for extradural SCS are not optimal for intradural SCS, and a novel azimuthal tripolar design increased stimulation selectivity, even beyond that achieved with an intradural paddle array. Increased stimulation efficiency is expected to increase the battery life of implantable pulse generators, increase the recharge interval of rechargeable implantable pulse generators, and potentially reduce stimulator volume. The greater selectivity of intradural stimulation may improve the success rate of SCS by mitigating the sensitivity of pain relief to malpositioning of the electrode. The outcome of this effort is a better quantitative understanding of how intradural electrode placement can potentially increase the selectivity and efficiency of SCS, which, in turn

  16. Gender and Injuries Predict Stimulant Medication Use

    PubMed Central

    Leckman, James F.; Nielsen, Helena Skyt; Simonsen, Marianne

    2014-01-01

    Abstract Objective: The purpose of this article was to examine whether injuries in early childhood and gender predict prescriptions of stimulant medication in three groups of children: With attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other psychiatric disorders (OPD). Methods: This was a population-based study with prospective and complete follow-up of children with ADHD (n=11,553), ASD (n=9698), and OPD (n=48,468), of whom 61%, 16%, and 3%, respectively, were treated with stimulants. For all 69,719 individual children data on psychiatric diagnoses, injuries, and drug prescriptions were obtained from national registers and merged. Results: Having sustained an injury before 5 years of age increased the likelihood of later stimulant treatment, in children with ADHD (odds ratio [OR]=1.09; 95% confidence interval [CI]=1.01–1.21), ASD (OR=1.19; 95% CI=1.02–1.40), and OPD (OR=1.24; 95% CI=1.08–1.42), with each injury increasing the likelihood by 3%, 10%, and 7%, respectively. Head injury did not increase the likelihood of later stimulant treatment. Within each of the three groups, ADHD, ASD, and OPD boys were more likely than girls to receive stimulant medication, OR=1.17 (95% CI=1.07–1.28); OR=1.71 (95% CI=1.47–2.01), and OR=2.41 (95% CI=2.16–2.71), respectively. Conclusions: To our knowledge, this is the first prospective study assessing early life predictors of later ADHD medication in children with a psychiatric disorder, taken from a national cohort with complete follow-up of all cases. We found that the number of injuries prior to diagnosis was associated with initiation of stimulant treatment in all three groups of patients. In addition, male gender predicted treatment with ADHD medications. Our results suggest that the number of injuries early in life prior to diagnosis is associated with stimulant treatment, and may serve as a proxy for the level of later severity of ADHD symptoms, as it is universally

  17. Lipopolysaccharide (LPS) stimulation of fungal secondary metabolism

    PubMed Central

    Khalil, Zeinab G.; Kalansuriya, Pabasara; Capon, Robert J.

    2014-01-01

    We report on a preliminary investigation of the use the Gram-negative bacterial cell wall constituent lipopolysaccharide (LPS) as a natural chemical cue to stimulate and alter the expression of fungal secondary metabolism. Integrated high-throughput micro-cultivation and micro-analysis methods determined that 6 of 40 (15%) of fungi tested responded to an optimal exposure to LPS (0.6 ng/mL) by activating, enhancing or accelerating secondary metabolite production. To explore the possible mechanisms behind this effect, we employed light and fluorescent microscopy in conjunction with a nitric oxide (NO)-sensitive fluorescent dye and an NO scavenger to provide evidence that LPS stimulation of fungal secondary metabolism coincided with LPS activation of NO. Several case studies demonstrated that LPS stimulation can be scaled from single microplate well (1.5 mL) to preparative (>400 mL) scale cultures. For example, LPS treatment of Penicillium sp. (ACM-4616) enhanced pseurotin A and activated pseurotin A1 and pseurotin A2 biosynthesis, whereas LPS treatment of Aspergillus sp. (CMB-M81F) substantially accelerated and enhanced the biosynthesis of shornephine A and a series of biosynthetically related ardeemins and activated production of neoasterriquinone. As an indication of broader potential, we provide evidence that cultures of Penicillium sp. (CMB-TF0411), Aspergillus niger (ACM-4993F), Rhizopus oryzae (ACM-165F) and Thanatephorus cucumeris (ACM-194F) were responsive to LPS stimulation, the latter two examples being particular noteworthy as neither are known to produce secondary metabolites. Our results encourage the view that LPS stimulation can be used as a valuable tool to expand the molecular discovery potential of fungal strains that either have been exhaustively studied by or are unresponsive to traditional culture methodology. PMID:25379339

  18. Stimulants and the lung : review of literature.

    PubMed

    Tseng, Will; Sutter, Mark E; Albertson, Timothy E

    2014-02-01

    Illicit stimulants, such as cocaine, amphetamine, and their derivatives (e.g., "ecstasy"), continue to exact heavy toll on health care in both developed and developing countries. The US Department of Health and Human Service reported over one million illicit drug-related emergency department visits in 2010, which was higher than any of the six previous years. Both inhaled and intravenous forms of these substances of abuse can result in a variety of acute and chronic injuries to practically every part of the respiratory tract, leading potentially to permanent morbidities as well as fatal consequences--including but not limited to nasal septum perforation, pulmonary hypertension, pneumothorax, pneumomediastinum, interstitial lung disease, alveolar hemorrhage, reactive airway disease, pulmonary edema, pulmonary granulomatosis, infections, foreign body aspiration, infections, bronchoconstriction, and thermal injuries. Stimulants are all rapidly absorbed substances that can also significantly alter the patient's systemic acid-base balance and central nervous system, thereby leading to further respiratory compromise. Mounting evidence in the past decade has demonstrated that adulterants coinhaled with these substances (e.g., levamisole) and the metabolites of these substances (e.g., cocaethylene) are associated with specific forms of systemic and respiratory complications as well. Recent studies have also demonstrated the effects of stimulants on autoimmune-mediated injuries of the respiratory tract, such as cocaine-induced midline destructive lesions. A persistent challenge to studies involving stimulant-associated respiratory toxidromes is the high prevalence of concomitant usage of various substances by drug abusers, including tobacco smoking. Now more than ever, health care providers must be familiar with the multitude of respiratory toxidromes as well as the diverse pathophysiology related to commonly abused stimulants to provide timely diagnosis and effective

  19. Temporal Prediction in lieu of Periodic Stimulation

    PubMed Central

    Schroeder, Charles E.; Wyart, Valentin

    2016-01-01

    Predicting not only what will happen, but also when it will happen is extremely helpful for optimizing perception and action. Temporal predictions driven by periodic stimulation increase perceptual sensitivity and reduce response latencies. At the neurophysiological level, a single mechanism has been proposed to mediate this twofold behavioral improvement: the rhythmic entrainment of slow cortical oscillations to the stimulation rate. However, temporal regularities can occur in aperiodic contexts, suggesting that temporal predictions per se may be dissociable from entrainment to periodic sensory streams. We investigated this possibility in two behavioral experiments, asking human participants to detect near-threshold auditory tones embedded in streams whose temporal and spectral properties were manipulated. While our findings confirm that periodic stimulation reduces response latencies, in agreement with the hypothesis of a stimulus-driven entrainment of neural excitability, they further reveal that this motor facilitation can be dissociated from the enhancement of auditory sensitivity. Perceptual sensitivity improvement is unaffected by the nature of temporal regularities (periodic vs aperiodic), but contingent on the co-occurrence of a fulfilled spectral prediction. Altogether, the dissociation between predictability and periodicity demonstrates that distinct mechanisms flexibly and synergistically operate to facilitate perception and action. SIGNIFICANCE STATEMENT Temporal predictions are increasingly recognized as fundamental instruments for optimizing performance, enabling mammals to exploit regularities in the world. However, the notion of temporal predictions is often confounded with the idea of entrainment to periodic sensory inputs. At the behavioral level, it is also unclear whether perceptual sensitivity and reaction time improvements benefit the same way from temporal predictions and periodic stimulation. In two behavioral experiments on human

  20. Tissue damage thresholds during therapeutic electrical stimulation

    NASA Astrophysics Data System (ADS)

    Cogan, Stuart F.; Ludwig, Kip A.; Welle, Cristin G.; Takmakov, Pavel

    2016-04-01

    Objective. Recent initiatives in bioelectronic modulation of the nervous system by the NIH (SPARC), DARPA (ElectRx, SUBNETS) and the GlaxoSmithKline Bioelectronic Medicines effort are ushering in a new era of therapeutic electrical stimulation. These novel therapies are prompting a re-evaluation of established electrical thresholds for stimulation-induced tissue damage. Approach. In this review, we explore what is known and unknown in published literature regarding tissue damage from electrical stimulation. Main results. For macroelectrodes, the potential for tissue damage is often assessed by comparing the intensity of stimulation, characterized by the charge density and charge per phase of a stimulus pulse, with a damage threshold identified through histological evidence from in vivo experiments as described by the Shannon equation. While the Shannon equation has proved useful in assessing the likely occurrence of tissue damage, the analysis is limited by the experimental parameters of the original studies. Tissue damage is influenced by factors not explicitly incorporated into the Shannon equation, including pulse frequency, duty cycle, current density, and electrode size. Microelectrodes in particular do not follow the charge per phase and charge density co-dependence reflected in the Shannon equation. The relevance of these factors to tissue damage is framed in the context of available reports from modeling and in vivo studies. Significance. It is apparent that emerging applications, especially with microelectrodes, will require clinical charge densities that exceed traditional damage thresholds. Experimental data show that stimulation at higher charge densities can be achieved without causing tissue damage, suggesting that safety parameters for microelectrodes might be distinct from those defined for macroelectrodes. However, these increased charge densities may need to be justified by bench, non-clinical or clinical testing to provide evidence of device

  1. BQ123 Stimulates Skeletal Muscle Antioxidant Defense via Nrf2 Activation in LPS-Treated Rats

    PubMed Central

    Jeleń, Agnieszka; Żebrowska, Marta; Balcerczak, Ewa; Gorąca, Anna

    2016-01-01

    Little is understood of skeletal muscle tissue in terms of oxidative stress and inflammation. Endothelin-1 is an endogenous, vasoconstrictive peptide which can induce overproduction of reactive oxygen species and proinflammatory cytokines. The aim of this study was to evaluate whether BQ123, an endothelin-A receptor antagonist, influences the level of TNF-α, IL-6, SOD-1, HO-1, Nrf2 mRNA, and NF-κB subunit RelA/p65 mRNA in the femoral muscle obtained from endotoxemic rats. Male Wistar rats were divided into 4 groups (n = 6) and received iv (1) saline (control), (2) LPS (15 mg/kg), (3) BQ123 (1 mg/kg), (4) BQ123 (1 mg/kg), and LPS (15 mg/kg, resp.) 30 min later. Injection of LPS led to significant increase in levels of RelA/p65 mRNA, TNF-α, and IL-6, while content of SOD-1, HO-1, and Nrf2 mRNA was unchanged. Administration of BQ123 prior to LPS challenge resulted in a significant reduction in RelA/p65 mRNA, TNF-α, and IL-6 levels, as well as markedly elevated concentrations of SOD-1, HO-1, and Nrf2 mRNA. BQ123 appears to enhance antioxidant defense and prevent production of TNF-α and IL-6 in skeletal muscle of LPS-treated rat. In conclusion, endothelin-A receptor antagonism exerts significant impact on the skeletal muscle favouring anti-inflammatory effects and protection against oxidative stress. PMID:26823945

  2. Comparison of quadriceps inactivation between nerve and muscle stimulation.

    PubMed

    Place, Nicolas; Casartelli, Nicola; Glatthorn, Julia F; Maffiuletti, Nicola A

    2010-12-01

    We evaluated the use of direct muscle stimulation for quantifying quadriceps inactivation at different contraction levels as opposed to conventional twitch interpolation using nerve stimulation. Fourteen healthy volunteers were tested. Paired stimuli were delivered to the femoral nerve or to the quadriceps muscle belly during voluntary contractions ranging from 20% to 100% of maximum, and the amplitude of the superimposed doublet was quantified to investigate inactivation. Superimposed doublet for muscle and nerve stimulation, respectively between the range of 60% to 100% of maximum (e.g., at 100%, muscle stimulation was 14 ± 5 Nm and nerve stimulation was 15 ± 6 Nm). Despite higher current doses, muscle stimulation was associated with less discomfort than nerve stimulation (P < 0.05). Collectively, our data suggest that direct muscle stimulation could be used to assess quadriceps inactivation at maximal and quasi-maximal contraction levels as a valid alternative to motor nerve stimulation.

  3. Electrical Stimulation for Drug-Resistant Epilepsy

    PubMed Central

    Chambers, A; Bowen, JM

    2013-01-01

    Objective The objective of this analysis was to evaluate the effectiveness of deep brain stimulation (DBS) and vagus nerve stimulation (VNS) for the treatment of drug-resistant epilepsy in adults and children. Data Sources A literature search was performed using MEDLINE, EMBASE, the Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published from January 2007 until December 2012. Review Methods Systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies (in the absence of RCTs) of adults or children were included. DBS studies were included if they specified that the anterior nucleus of thalamus was the area of the brain stimulated. Outcomes of interest were seizure frequency, health resource utilization, and safety. A cost analysis was also performed. Results The search identified 6 studies that assessed changes in seizure frequency after electrical stimulation: 1 RCT on DBS in adults, 4 RCTs on VNS in adults, and 1 RCT on VNS in children. The studies of DBS and VNS in adults found significantly improved rates of seizure frequency, but the study of VNS in children did not find a significant difference in seizure frequency between the high and low stimulation groups. Significant reductions in hospitalizations and emergency department visits were found for adults and children who received VNS. No studies addressed the use of health resources for patients undergoing DBS. Five studies reported on adverse events, which ranged from serious to transient for both procedures in adults and were mostly transient in the 1 study of VNS in children. Limitations We found no evidence on DBS in children or on health care use related to DBS. The measurement of seizure frequency is self-reported and is therefore subject to bias and issues of compliance. Conclusions Based on evidence of low to moderate quality, both DBS and VNS seemed to reduce seizure frequency in adults. In children, VNS did not appear to be as

  4. Mechanisms of osteocyte stimulation in osteoporosis.

    PubMed

    Verbruggen, Stefaan W; Vaughan, Ted J; McNamara, Laoise M

    2016-09-01

    Experimental studies have shown that primary osteoporosis caused by oestrogen-deficiency results in localised alterations in bone tissue properties and mineral composition. Additionally, changes to the lacunar-canalicular architecture surrounding the mechanosensitive osteocyte have been observed in animal models of the disease. Recently, it has also been demonstrated that the mechanical stimulation sensed by osteocytes changes significantly during osteoporosis. Specifically, it was shown that osteoporotic bone cells experience higher maximum strains than healthy bone cells after short durations of oestrogen deficiency. However, in long-term oestrogen deficiency there was no significant difference between bone cells in healthy and normal bone. The mechanisms by which these changes arise are unknown. In this study, we test the hypothesis that complex changes in tissue composition and lacunar-canalicular architecture during osteoporosis alter the mechanical stimulation of the osteocyte. The objective of this research is to employ computational methods to investigate the relationship between changes in bone tissue composition and microstructure and the mechanical stimulation of osteocytes during osteoporosis. By simulating physiological loading, it was observed that an initial decrease in tissue stiffness (of 0.425GPa) and mineral content (of 0.66wt% Ca) relative to controls could explain the mechanical stimulation observed at the early stages of oestrogen deficiency (5 weeks post-OVX) during in situ bone cell loading in an oestrogen-deficient rat model of post-menopausal osteoporosis (Verbruggen et al., 2015). Moreover, it was found that a later increase in stiffness (of 1.175GPa) and mineral content (of 1.64wt% Ca) during long-term osteoporosis (34 weeks post-OVX), could explain the mechanical stimuli previously observed at a later time point due to the progression of osteoporosis. Furthermore, changes in canalicular tortuosity arising during osteoporosis were shown

  5. Computational electromagnetic methods for transcranial magnetic stimulation

    NASA Astrophysics Data System (ADS)

    Gomez, Luis J.

    Transcranial magnetic stimulation (TMS) is a noninvasive technique used both as a research tool for cognitive neuroscience and as a FDA approved treatment for depression. During TMS, coils positioned near the scalp generate electric fields and activate targeted brain regions. In this thesis, several computational electromagnetics methods that improve the analysis, design, and uncertainty quantification of TMS systems were developed. Analysis: A new fast direct technique for solving the large and sparse linear system of equations (LSEs) arising from the finite difference (FD) discretization of Maxwell's quasi-static equations was developed. Following a factorization step, the solver permits computation of TMS fields inside realistic brain models in seconds, allowing for patient-specific real-time usage during TMS. The solver is an alternative to iterative methods for solving FD LSEs, often requiring run-times of minutes. A new integral equation (IE) method for analyzing TMS fields was developed. The human head is highly-heterogeneous and characterized by high-relative permittivities (107). IE techniques for analyzing electromagnetic interactions with such media suffer from high-contrast and low-frequency breakdowns. The novel high-permittivity and low-frequency stable internally combined volume-surface IE method developed. The method not only applies to the analysis of high-permittivity objects, but it is also the first IE tool that is stable when analyzing highly-inhomogeneous negative permittivity plasmas. Design: TMS applications call for electric fields to be sharply focused on regions that lie deep inside the brain. Unfortunately, fields generated by present-day Figure-8 coils stimulate relatively large regions near the brain surface. An optimization method for designing single feed TMS coil-arrays capable of producing more localized and deeper stimulation was developed. Results show that the coil-arrays stimulate 2.4 cm into the head while stimulating 3

  6. Monitoring changes in hemodynamics following optogenetic stimulation

    NASA Astrophysics Data System (ADS)

    Frye, Seth

    The brain is composed of billions of neurons, all of which connected through a vast network. After years of study and applications of different technologies and techniques, there are still more questions than answers when it comes to the fundamental functions of the brain. This project aims to provide a new tool which can be used to gain a better understanding of the fundamental mechanisms that govern neurological processes inside the brain. In order for neural networks to operate, blood has to be supplied through neighboring blood vessels. As such, the increase or decrease in the blood supply has been used as an indicator of neural activity. The neural activity and blood supply relationship is known as neural vasculature coupling. Monitoring the hemodynamics is used as an indicator of neurological activity, but the causal relationship is an area of current research. Gaining a better understanding of the coupling of neural activity and the surrounding vasculature provides a more accurate methodology to evaluate regional neural activity. The new optical technology applied in this project provides a set of tools to both stimulate and monitor this coupling relationship. Optogenetics provides the capability of stimulating neural activity using specific wavelengths of light. Essentially this tool allows for the direct stimulation of networks of neurons by simply shining one color of light onto the brain. Optical Coherence Tomography (OCT), another new optical technology applied in this project, can record volumetric images of blood vessels and flow using only infrared light. The combination of the two optical technologies is then capable of stimulating neural activity and monitoring the hemodynamic response inside the brain using only light. As a result of this project we have successfully demonstrated the capability of both stimulating and imaging the brain using new optical technologies. The optical stimulation of neural activity has evoked a direct hemodynamic effect

  7. Unconventional physical mechanisms between stimulated Brillouin scattering and backward stimulated Raman scattering in liquid water

    NASA Astrophysics Data System (ADS)

    Shi, Jiulin; Liu, Juan; Li, Shujing; Xia, Jian; Liu, Jian'an; Fang, Wei; Yang, Kecheng; He, Xingdao

    2011-07-01

    In this paper, the stimulated Brillouin scattering (SBS) and the backward stimulated Raman scattering (BSRS) excited by a focused Gaussian laser in liquid water with different attenuation coefficients are investigated experimentally. Experimental results indicate that the relationships between SBS and BSRS are not merely competitive; the former has an obvious amplifying effect on the latter. Also, two different physical mechanisms were discussed in order to explain these phenomena.

  8. Amplifier design for EMG recording from stimulation electrodes during functional electrical stimulation leg cycling ergometry.

    PubMed

    Shalaby, Raafat; Schauer, Thomas; Liedecke, Wolfgang; Raisch, Jörg

    2011-02-01

    Functional electrical stimulation leg cycle ergometry (FES-LCE), which is often used as exercise for people with spinal cord injury (SCI), has recently been applied in the motor rehabilitation of stroke patients. Recently completed studies show controversial results, but with a tendency to positive training effects. Current technology is identical to that used in FES-LCE for SCI, whereas the pathology of stroke differs strongly. Most stroke patients with hemiparesis are able to drive an ergometer independently. Depending on the degree of spasticity, the paretic leg will partially support or hinder movements. Electrical stimulation increases muscle force and endurance and both are prerequisites for restoring gait. However, the effect of FES-LCE on improving impaired motor coordination is unclear. To measure motor coordination during FES-LCE, an EMG-amplifier design has been investigated which suppresses stimulation artifacts and allows detection of volitional or reflex induced muscle activity. Direct measurement of EMG from stimulation electrodes between stimulation pulses is an important asset of this amplifier. Photo-MOS switches in front of the preamplifier are utilized to achieve this. The technology presented here can be used to monitor the effects of FES-LCE to adapt the stimulation strategy or to realize EMG-biofeedback training. PMID:21162696

  9. A fully implanted programmable stimulator based on wireless communication for epidural spinal cord stimulation in rats.

    PubMed

    Zhou, Hui; Xu, Qi; He, Jiping; Ren, Hangkong; Zhou, Houlun; Zheng, Kejia

    2012-03-15

    Clinical research indicates that the epidural spinal cord stimulation (ESCS) has shown potential in promoting locomotor recovery in patients with incomplete spinal cord injury (ISCI). This paper presents the development of a fully implantable voltage-regulated stimulator with bi-directional wireless communication for investigating underlying neural mechanisms of ESCS facilitating motor function improvement. The stimulation system consists of a computer, an external controller, an implantable pulse generator (IPG), a magnet, the extension leads and a stimulation electrode. The telemetry transmission between the IPG and the external controller is achieved by a commercially available transceiver chip with 2.4GHz carrier band. The magnet is used to activate the IPG only when necessary to minimize the power consumption. The encapsulated IPG measures 33mm×24mm×8mm, with a total mass of ∼12.6g. Feasibility experiments are conducted in three Sprague-Dawley rats to validate the function of the stimulator, and to investigate the relationship between lumbar-sacral ESCS and hindlimb electromyography (EMG) responses. The results show that the stimulation system provides an effective tool for investigation of ESCS application in motor function recovery in small animals. PMID:22085835

  10. Can the human lumbar posterior columns be stimulated by transcutaneous spinal cord stimulation? A modeling study.

    PubMed

    Danner, Simon M; Hofstoetter, Ursula S; Ladenbauer, Josef; Rattay, Frank; Minassian, Karen

    2011-03-01

    Stimulation of different spinal cord segments in humans is a widely developed clinical practice for modification of pain, altered sensation, and movement. The human lumbar cord has become a target for modification of motor control by epidural and, more recently, by transcutaneous spinal cord stimulation. Posterior columns of the lumbar spinal cord represent a vertical system of axons and when activated can add other inputs to the motor control of the spinal cord than stimulated posterior roots. We used a detailed three-dimensional volume conductor model of the torso and the McIntyre-Richard-Grill axon model to calculate the thresholds of axons within the posterior columns in response to transcutaneous lumbar spinal cord stimulation. Superficially located large-diameter posterior column fibers with multiple collaterals have a threshold of 45.4 V, three times higher than posterior root fibers (14.1 V). With the stimulation strength needed to activate posterior column axons, posterior root fibers of large and small diameters as well as anterior root fibers are coactivated. The reported results inform on these threshold differences, when stimulation is applied to the posterior structures of the lumbar cord at intensities above the threshold of large-diameter posterior root fibers. PMID:21401670

  11. Cisplatin stimulates protein tyrosine phosphorylation in macrophages.

    PubMed

    Kumar, R; Shrivastava, A; Sodhi, A

    1995-03-01

    Cisplatin [cis-dichlorodiamine platinum (II)], a potent anti-tumor compound, stimulates immune responses by activating monocyte-macrophages and other cells of the immune system. The mechanism by which cisplatin activates these cells is poorly characterized. Since protein tyrosine phosphorylation appears to be a major intracellular signalling event that mediates cellular responses, we examined whether cisplatin alters tyrosine phosphorylation in macrophages. We found that cisplatin increased tyrosine phosphorylation of several proteins in peritoneal macrophages and in P388D1 and IC-21 macrophage cell lines. Treatment of macrophages with tyrosine kinase inhibitors, genestein and lavendustin A, inhibited cisplatin-stimulated protein tyrosine phosphorylation in macrophages. Macrophages treated with cisplatin also exhibit increased fluorescence with anti-phosphotyrosine-FITC antibody. These data indicate that protein tyrosine phosphorylation plays a role in cisplatin-induced activation of macrophages. PMID:7539662

  12. Neutron dosimetry using optically stimulated luminescence

    NASA Astrophysics Data System (ADS)

    Miller, S. D.; Eschbach, P. A.

    1991-06-01

    The addition of thermoluminescent (TL) materials within hydrogenous matrices to detect neutron induced proton recoils for radiation dosimetry is a well known concept. Previous attempts to implement this technique have met with limited success, primarily due to the high temperatures required for TL readout and the low melting temperatures of hydrogen-rich plastics. Research in recent years PNL has produced a new Optically Stimulated Luminescence (OSL) technique known as the Cooled Optically Stimulated Luminescence (COSL) that offers, for the first time, the capability of performing extremely sensitive radiation dosimetry at low temperatures. In addition to its extreme sensitivity, the COSL technique offers multiple readout capability, limited fading in a one year period, and the capability of analyzing single grains within a hydrogenous matrix.

  13. Smoothened regulation in response to Hedgehog stimulation

    PubMed Central

    Jiang, Kai; Jia, Jianhang

    2016-01-01

    The Hedgehog (Hh) signaling pathway play critical roles in embryonic development and adult tissue homeostasis. A critical step in Hh signal transduction is how Hh receptor Patched (Ptc) inhibits the atypical G protein-coupled receptor Smoothened (Smo) in the absence of Hh and how this inhibition is release by Hh stimulation. It is unlikely that Ptc inhibits Smo by direct interaction. Here we discuss how Hh regulates the phosphorylation and ubiquitination of Smo, leading to cell surface and ciliary accumulation of Smo in Drosophila and vertebrate cells, respectively. In addition, we discuss how PI(4)P phospholipid acts in between Ptc and Smo to regulate Smo phosphorylation and activation in response to Hh stimulation. PMID:26973699

  14. Neutron dosimetry using optically stimulated luminescence

    SciTech Connect

    Miller, S.D.; Eschbach, P.A.

    1991-06-01

    The addition of thermoluminescent (TL) materials within hydrogenous matrices to detect neutron-induced proton recoils for radiation dosimetry is a well-known concept. Previous attempts to implement this technique have met with limited success, primarily due to the high temperatures required for TL readout and the low melting temperatures of hydrogen-rich plastics. Research in recent years at Pacific Northwest laboratories (PNL) has produced a new Optically Stimulated Luminescence (OSL) technique known as the Cooled Optically Stimulated Luminescence (COSL) that offers, for the first time, the capability of performing extremely sensitive radiation dosimetry at low temperatures. In addition to its extreme sensitivity, the COSL technique offers multiple readout capability, limited fading in a one-year period, and the capability of analyzing single grains within a hydrogenous matrix. 4 refs., 10 figs.

  15. Stimulated recall interviews for describing pragmatic epistemology

    NASA Astrophysics Data System (ADS)

    Shubert, Christopher W.; Meredith, Dawn C.

    2015-12-01

    Students' epistemologies affect how and what they learn: do they believe physics is a list of equations, or a coherent and sensible description of the physical world? In order to study these epistemologies as part of curricular assessment, we adopt the resources framework, which posits that students have many productive epistemological resources that can be brought to bear as they learn physics. In previous studies, these epistemologies have been either inferred from behavior in learning contexts or probed through surveys or interviews outside of the learning context. We argue that stimulated recall interviews provide a contextually and interpretively valid method to access students' epistemologies that complement existing methods. We develop a stimulated recall interview methodology to assess a curricular intervention and find evidence that epistemological resources aptly describe student epistemologies.

  16. Spinal Cord Stimulation for Chronic Limb Ischemia

    PubMed Central

    Naoum, Joseph J.; Arbid, Elias J.

    2013-01-01

    The treatment of chronic limb ischemia involves the restoration of pulsatile blood flow to the distal extremity. Some patients cannot be treated with endovascular means or with open surgery; some may have medical comorbidities that render them unfit for surgery, while others may have persistent ischemia or pain even in the face of previous attempts at reperfusion. In spinal cord stimulation (SCS), a device with electrodes is implanted in the epidural space to stimulate sensory fibers. This activates cell-signaling molecules that in turn cause the release of vasodilatory molecules, a decrease in vascular resistance, and relaxation of smooth muscle cells. SCS also suppresses sympathetic vasoconstriction and pain transmission. When patient selection is based on microcirculatory parameters, SCS therapy can significantly improve pain relief, halt the progression of ulcers, and potentially achieve limb salvage. PMID:23805343

  17. Growth rebound after termination of stimulant drugs.

    PubMed

    Safer, D J; Allen, R P; Barr, E

    1975-01-01

    To explore further the report of an accelerated weight gain following termination of treatment with a stimulant drug, 66 biannual growth measurements were obtained from 1970 to 1973 on hyperactive schoolchildren who were receiving medication. All received either dextroamphetamine or methylphenidate during the school year; some also received it during the summer. The data revealed that those whose stimulant medication was terminated at the start of summer subsequently grew in weight and height at a significantly greater rate than those who continued to receive medication from June to September. In fact, discontinuance of the medication resulted in a growth rebound for this period which was 15-68% above the age-expected increment.

  18. Ionospheric Stimulation By High Power Radio Waves

    NASA Astrophysics Data System (ADS)

    Minami, S.; Nishino, M.; Suzuki, Y.; Sato, S.; Tanikawa, T.; Nakamura, Y.; Wong, A. Y.

    1999-01-01

    We have performed an experiment to artificially stimulate the ionosphere using higher power radio waves at the HIPAS (High Power Auroral Stimulation) facility in Alaska. A radio transmission of 2.85 MHz was made at 80 MW (ERP). Diagnostics were made at the other site located 35 km from the transmission site. The results of cross-correlating the excited HF wave and observed with an 8 channel, 30 MHz scanning cosmic radio noise absorption records revealed the excited height of 90 km. Also atmospheric pressure waves observed on the ground show evident propagation of pressure waves which are generated in the ionosphere by the high-power HF wave. The results determine the excitation height of 90 km in the ionosphere and show evidence of the pressure wave coupling between the ionosphere and the lower atmosphere for periods of 10 min

  19. Image formation using stimulated raman scattering gain

    NASA Astrophysics Data System (ADS)

    Bespalov, V. G.; Makarov, E. A.; Stasel'ko, D. I.

    2016-07-01

    Theoretical analysis of the spatial, noise, and energy characteristics of an amplifier has been performed in the mode of spectral and time selection using subnanosecond stimulated Raman Scattering gain of weak echo signals in crystalline active media that are known for high (up to 10-1 cm/MW) gain coefficients. The possibility to reach high gain values has been demonstrated for weak signals from objects at acceptable angular sizes of the field of vision of an amplifier. To provide a signal-to-noise ratio that exceeds unity over the entire field of vision, the number of photons at the input to an amplifier that is required has to exceed the number of its resolution elements. Accurate determination of the possibilities of recording of weak echo signals and quality of images of targets that are obtained using amplifiers under stimulated Raman Scattering requires additional special experiments.

  20. Stimulated neutrino transformation with sinusoidal density profiles

    DOE PAGES

    Kneller, J. P.; McLaughlin, G. C.; Patton, K. M.

    2013-03-28

    Large amplitude oscillations between the states of a quantum system can be stimulated by sinusoidal external potentials with frequencies that are similar to the energy level splitting of the states or a fraction thereof. Situations where the applied frequency is equal to an integer fraction of the energy level splittings are known as parametric resonances. We investigate this effect for neutrinos both analytically and numerically for the case of arbitrary numbers of neutrino flavors. We look for environments where the effect may be observed and find that supernovae are the one realistic possibility due to the necessity of both largemore » densities and large amplitude fluctuations. In conclusion, the comparison of numerical and analytical results of neutrino propagation through a model supernova reveals that it is possible to predict the locations and strengths of the stimulated transitions that occur.« less

  1. Stimulated neutrino transformation with sinusoidal density profiles

    SciTech Connect

    Kneller, J. P.; McLaughlin, G. C.; Patton, K. M.

    2013-03-28

    Large amplitude oscillations between the states of a quantum system can be stimulated by sinusoidal external potentials with frequencies that are similar to the energy level splitting of the states or a fraction thereof. Situations where the applied frequency is equal to an integer fraction of the energy level splittings are known as parametric resonances. We investigate this effect for neutrinos both analytically and numerically for the case of arbitrary numbers of neutrino flavors. We look for environments where the effect may be observed and find that supernovae are the one realistic possibility due to the necessity of both large densities and large amplitude fluctuations. In conclusion, the comparison of numerical and analytical results of neutrino propagation through a model supernova reveals that it is possible to predict the locations and strengths of the stimulated transitions that occur.

  2. Bubble nonlinear dynamics and stimulated scattering process

    NASA Astrophysics Data System (ADS)

    Jie, Shi; De-Sen, Yang; Sheng-Guo, Shi; Bo, Hu; Hao-Yang, Zhang; Shi-Yong, Hu

    2016-02-01

    A complete understanding of the bubble dynamics is deemed necessary in order to achieve their full potential applications in industry and medicine. For this purpose it is first needed to expand our knowledge of a single bubble behavior under different possible conditions including the frequency and pressure variations of the sound field. In addition, stimulated scattering of sound on a bubble is a special effect in sound field, and its characteristics are associated with bubble oscillation mode. A bubble in liquid can be considered as a representative example of nonlinear dynamical system theory with its resonance, and its dynamics characteristics can be described by the Keller-Miksis equation. The nonlinear dynamics of an acoustically excited gas bubble in water is investigated by using theoretical and numerical analysis methods. Our results show its strongly nonlinear behavior with respect to the pressure amplitude and excitation frequency as the control parameters, and give an intuitive insight into stimulated sound scattering on a bubble. It is seen that the stimulated sound scattering is different from common dynamical behaviors, such as bifurcation and chaos, which is the result of the nonlinear resonance of a bubble under the excitation of a high amplitude acoustic sound wave essentially. The numerical analysis results show that the threshold of stimulated sound scattering is smaller than those of bifurcation and chaos in the common condition. Project supported by the Program for Changjiang Scholars and Innovative Research Team in University, China (Grant No. IRT1228) and the Young Scientists Fund of the National Natural Science Foundation of China (Grant Nos. 11204050 and 11204049).

  3. [A community program to stimulate smoking cessation].

    PubMed

    Villalbí, J R; Ballestín, M; Surós, C; de Miguel-Blondel, E; Cabello, R

    1992-01-01

    A community program to stimulate smoking cessation developed on the 1988 World No-smoking Day in the city of Barcelona (Spain) is presented. Participants in this program could make a written commitment to quit, and received support materials by mail. The results are evaluated in a sample of participants: 69% declare having quit on the specified date, and 29% do not smoke after one year.

  4. Magnetically stimulated diffusion of Rydberg gases.

    PubMed

    Dumin, Yurii V

    2013-01-18

    The specific kind of diffusion stimulated (rather than suppressed) by the external magnetic field, which was predicted for the first time by Schmelcher and Cederbaum in 1992, is considered here for the case of high-angular-momentum (i.e., approximately "circular") Rydberg atoms. The coefficient of such diffusion was calculated by a purely analytical approach and was found to be very relevant to the experiments on antihydrogen formation.

  5. Ultrabroad stimulated emission from quantum well laser

    SciTech Connect

    Wang, Huolei; Zhou, Xuliang; Yu, Hongyan; Mi, Junping; Wang, Jiaqi; Bian, Jing; Wang, Wei; Pan, Jiaoqing; Ding, Ying; Chen, Weixi

    2014-06-23

    Observation of ultrabroad stimulated emission from a simplex quantum well based laser at the center wavelength of 1.06 μm is reported. With increased injection current, spectrum as broad as 38 nm and a pulsed output power of ∼50 mW have been measured. The experiments show evidence of an unexplored broad emission regime in the InGaAs/GaAs quantum well material system, which still needs theoretical modeling and further analysis.

  6. Prescription stimulant use is associated with earlier onset of psychosis.

    PubMed

    Moran, Lauren V; Masters, Grace A; Pingali, Samira; Cohen, Bruce M; Liebson, Elizabeth; Rajarethinam, R P; Ongur, Dost

    2015-12-01

    A childhood history of attention deficit hyperactivity disorder (ADHD) is common in psychotic disorders, yet prescription stimulants may interact adversely with the physiology of these disorders. Specifically, exposure to stimulants leads to long-term increases in dopamine release. We therefore hypothesized that individuals with psychotic disorders previously exposed to prescription stimulants will have an earlier onset of psychosis. Age of onset of psychosis (AOP) was compared in individuals with and without prior exposure to prescription stimulants while controlling for potential confounding factors. In a sample of 205 patients recruited from an inpatient psychiatric unit, 40% (n = 82) reported use of stimulants prior to the onset of psychosis. Most participants were prescribed stimulants during childhood or adolescence for a diagnosis of ADHD. AOP was significantly earlier in those exposed to stimulants (20.5 vs. 24.6 years stimulants vs. no stimulants, p < 0.001). After controlling for gender, IQ, educational attainment, lifetime history of a cannabis use disorder or other drugs of abuse, and family history of a first-degree relative with psychosis, the association between stimulant exposure and earlier AOP remained significant. There was a significant gender × stimulant interaction with a greater reduction in AOP for females, whereas the smaller effect of stimulant use on AOP in males did not reach statistical significance. In conclusion, individuals with psychotic disorders exposed to prescription stimulants had an earlier onset of psychosis, and this relationship did not appear to be mediated by IQ or cannabis. PMID:26522870

  7. Caloric vestibular stimulation modulates nociceptive evoked potentials.

    PubMed

    Ferrè, Elisa Raffaella; Haggard, Patrick; Bottini, Gabriella; Iannetti, Gian Domenico

    2015-12-01

    Vestibular stimulation has been reported to alleviate central pain. Clinical and physiological studies confirm pervasive interactions between vestibular signals and somatosensory circuits, including nociception. However, the neural mechanisms underlying vestibular-induced analgesia remain unclear, and previous clinical studies cannot rule out explanations based on alternative, non-specific effects such as distraction or placebo. To investigate how vestibular inputs influence nociception, we combined caloric vestibular stimulation (CVS) with psychophysical and electrocortical responses elicited by nociceptive-specific laser stimulation in humans (laser-evoked potentials, LEPs). Cold water CVS applied to the left ear resulted in significantly lower subjective pain intensity for experimental laser pain to the left hand immediately after CVS, relative both to before CVS and to 1 h after CVS. This transient reduction in pain perception was associated with reduced amplitude of all LEP components, including the early N1 wave reflecting the first arrival of nociceptive input to primary somatosensory cortex. We conclude that cold left ear CVS elicits a modulation of both nociceptive processing and pain perception. The analgesic effect induced by CVS could be mediated either by subcortical gating of the ascending nociceptive input, or by direct modulation of the primary somatosensory cortex.

  8. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus

    PubMed Central

    Varela-Nallar, Lorena; Arredondo, Sebastian B.; Tapia-Rojas, Cheril; Hancke, Juan; Inestrosa, Nibaldo C.

    2015-01-01

    Andrographolide (ANDRO) is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected. PMID:26798521

  9. Mechanical stimulation enhances endothelin-1 hyperalgesia.

    PubMed

    Joseph, E K; Gear, R W; Levine, J D

    2011-03-31

    When comparing a cumulative dose-response curve for endothelin-1 (ET-1)-induced mechanical hyperalgesia to the effect of individual doses (1 ng, 10 ng, 100 ng, and 1 μg) administered in separate groups of rats, a marked difference was observed in the peak magnitude of hyperalgesia. Hyperalgesia was measured as decrease in the threshold for mechanically-induced withdrawal of the hind paw. The cumulative dosing protocol produced markedly greater maximum hyperalgesia. To determine whether this was due to the cumulative dosing protocol or to the repeated exposure to the mechanical test stimulus, we evaluated the impact of repeated testing on ET-1-induced mechanical hyperalgesia. While ET-1-induced mechanical hyperalgesia was dose- and time-dependent, repeated testing of nociceptive threshold, at 5 min intervals, following a single dose of ET-1, produced further decrease in nociceptive threshold. This mechanical stimulation-induced enhancement of ET-1 hyperalgesia lasted only 3-4 h, while the hyperalgesia lasted in excess of 5 days. The stimulation-enhanced hyperalgesia also occurred after a second injection of ET-1, administered 24 h after the initial dose. That this phenomenon is unique to ET-1 is suggested by the observation that while five additional, direct-acting hyperalgesic agents-prostaglandin E2 (PGE2), nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα)-induced robust mechanical hyperalgesia, none produced mechanical stimulation-enhanced hyperalgesia.

  10. Auricular electrical stimulation and dental pain threshold.

    PubMed Central

    Simmons, M. S.; Oleson, T. D.

    1993-01-01

    A modified double-blind evaluation of naloxone reversibility of dental analgesia produced by auricular electrical stimulation (AES) was examined in 40 subjects assigned randomly to one of four groups: AES followed by saline (AS), AES followed by naloxone (AN), placebo AES followed by saline (PS), and placebo AES followed by naloxone (PN). Dental pain threshold was tested using a hand-held dental pulp tester. A second investigator administered the true or placebo AES using an electrical stimulator. A third investigator injected intravenously saline or naloxone. The subjects and investigators 1 and 3 were blind to all treatment conditions. A repeated measures analysis of variance revealed a significant difference among the four groups. The AES groups exhibited a statistically significant 18% elevation of pain threshold, whereas the two placebo stimulation groups (PS and PN) remained essentially unchanged. The mean pain threshold increased to more than 23% for group AS, but fell to less than 12% for the subjects in group AN, who were given naloxone. These findings indicate a small but significant elevation of pain threshold by AES, an effect partially blocked by naloxone, suggesting an endogenous opioid system as one mechanism for AES analgesia. Images Figure 1 Figure 2 PMID:8185085

  11. Improved Microseismicity Detection During Newberry EGS Stimulations

    DOE Data Explorer

    Templeton, Dennise

    2013-11-01

    Effective enhanced geothermal systems (EGS) require optimal fracture networks for efficient heat transfer between hot rock and fluid. Microseismic mapping is a key tool used to infer the subsurface fracture geometry. Traditional earthquake detection and location techniques are often employed to identify microearthquakes in geothermal regions. However, most commonly used algorithms may miss events if the seismic signal of an earthquake is small relative to the background noise level or if a microearthquake occurs within the coda of a larger event. Consequently, we have developed a set of algorithms that provide improved microearthquake detection. Our objective is to investigate the microseismicity at the DOE Newberry EGS site to better image the active regions of the underground fracture network during and immediately after the EGS stimulation. Detection of more microearthquakes during EGS stimulations will allow for better seismic delineation of the active regions of the underground fracture system. This improved knowledge of the reservoir network will improve our understanding of subsurface conditions, and allow improvement of the stimulation strategy that will optimize heat extraction and maximize economic return.

  12. Improved Microseismicity Detection During Newberry EGS Stimulations

    DOE Data Explorer

    Templeton, Dennise

    2013-10-01

    Effective enhanced geothermal systems (EGS) require optimal fracture networks for efficient heat transfer between hot rock and fluid. Microseismic mapping is a key tool used to infer the subsurface fracture geometry. Traditional earthquake detection and location techniques are often employed to identify microearthquakes in geothermal regions. However, most commonly used algorithms may miss events if the seismic signal of an earthquake is small relative to the background noise level or if a microearthquake occurs within the coda of a larger event. Consequently, we have developed a set of algorithms that provide improved microearthquake detection. Our objective is to investigate the microseismicity at the DOE Newberry EGS site to better image the active regions of the underground fracture network during and immediately after the EGS stimulation. Detection of more microearthquakes during EGS stimulations will allow for better seismic delineation of the active regions of the underground fracture system. This improved knowledge of the reservoir network will improve our understanding of subsurface conditions, and allow improvement of the stimulation strategy that will optimize heat extraction and maximize economic return.

  13. The ethics of deep brain stimulation (DBS).

    PubMed

    Unterrainer, Marcus; Oduncu, Fuat S

    2015-11-01

    Deep brain stimulation (DBS) is an invasive technique designed to stimulate certain deep brain regions for therapeutic purposes and is currently used mainly in patients with neurodegenerative disorders, such as Parkinson's disease. However, DBS is also used increasingly for other experimental applications, such as the treatment of psychiatric disorders (e.g. severe depression), weight reduction. Apart from its therapeutic potential, DBS can cause severe adverse effects, some that might also have a significant impact on the patient's personality and autonomy by the external stimulation of DBS which effects lie beyond the individual's control and free will. The article's purpose is to outline the procedures of DBS currently used in therapeutic and experimental applications and to discuss the ethical concerns regarding this procedure. It will address the clinical benefit-risk-ratio, the particular ethics of research in this field, and the ethical issues raised by affecting a patient's or an individual's personality and autonomous behaviour. Moreover, a potential ethical guideline, the Ulysses contract is discussed for the field of clinical application as well as the question of responsibility. PMID:25597042

  14. Temporal Prediction in lieu of Periodic Stimulation.

    PubMed

    Morillon, Benjamin; Schroeder, Charles E; Wyart, Valentin; Arnal, Luc H

    2016-02-24

    Predicting not only what will happen, but also when it will happen is extremely helpful for optimizing perception and action. Temporal predictions driven by periodic stimulation increase perceptual sensitivity and reduce response latencies. At the neurophysiological level, a single mechanism has been proposed to mediate this twofold behavioral improvement: the rhythmic entrainment of slow cortical oscillations to the stimulation rate. However, temporal regularities can occur in aperiodic contexts, suggesting that temporal predictions per se may be dissociable from entrainment to periodic sensory streams. We investigated this possibility in two behavioral experiments, asking human participants to detect near-threshold auditory tones embedded in streams whose temporal and spectral properties were manipulated. While our findings confirm that periodic stimulation reduces response latencies, in agreement with the hypothesis of a stimulus-driven entrainment of neural excitability, they further reveal that this motor facilitation can be dissociated from the enhancement of auditory sensitivity. Perceptual sensitivity improvement is unaffected by the nature of temporal regularities (periodic vs aperiodic), but contingent on the co-occurrence of a fulfilled spectral prediction. Altogether, the dissociation between predictability and periodicity demonstrates that distinct mechanisms flexibly and synergistically operate to facilitate perception and action. PMID:26911682

  15. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus.

    PubMed

    Varela-Nallar, Lorena; Arredondo, Sebastian B; Tapia-Rojas, Cheril; Hancke, Juan; Inestrosa, Nibaldo C

    2015-01-01

    Andrographolide (ANDRO) is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected. PMID:26798521

  16. A continuum model of retinal electrical stimulation

    NASA Astrophysics Data System (ADS)

    Joarder, Saiful A.; Abramian, Miganoosh; Suaning, Gregg J.; Lovell, Nigel H.; Dokos, Socrates

    2011-10-01

    A continuum mathematical model of retinal electrical stimulation is described. The model is represented by a passive vitreous domain, a thin layer of active retinal ganglion cell (RGC) tissue adjacent to deeper passive neural layers of the retina, the retinal pigmented epithelium (RPE) and choroid thus ending at the sclera. To validate the model, in vitro epiretinal responses to stimuli from 50 µm disk electrodes, arranged in a hexagonal mosaic, were recorded from rabbit retinas. 100 µs/phase anodic-first biphasic current pulses were delivered to the retinal surface in both the mathematical model and experiments. RGC responses were simulated and recorded using extracellular microelectrodes. The model's epiretinal thresholds compared favorably with the in vitro data. In addition, simulations showed that single-return bipolar electrodes recruited a larger area of the retina than twin-return or six-return electrodes arranged in a hexagonal layout in which a central stimulating electrode is surrounded by six, eqi-spaced returns. Simulations were also undertaken to investigate the patterns of RGC activation in an anatomically-accurate model of the retina, as well as RGC activation patterns for subretinal and suprachoroidal bipolar stimulation. This paper was originally submitted for the special issue containing contributions from the Sixth Biennial Research Congress of The Eye and the Chip.

  17. Origin and Evolution of Deep Brain Stimulation

    PubMed Central

    Sironi, Vittorio A.

    2011-01-01

    This paper briefly describes how the electrical stimulation, used since antiquity to modulate the nervous system, has been a fundamental tool of neurophysiologic investigation in the second half of the eighteenth century and was subsequently used by the early twentieth century, even for therapeutic purposes. In mid-twentieth century the advent of stereotactic procedures has allowed the drift from lesional to stimulating technique of deep nuclei of the brain for therapeutic purposes. In this way, deep brain stimulation (DBS) was born, that, over the last two decades, has led to positive results for the treatment of medically refractory Parkinson’s disease, essential tremor, and dystonia. In recent years, the indications for therapeutic use of DBS have been extended to epilepsy, Tourette’s syndrome, psychiatric diseases (depression, obsessive–compulsive disorder), some kinds of headache, eating disorders, and the minimally conscious state. The potentials of the DBS for therapeutic use are fascinating, but there are still many unresolved technical and ethical problems, concerning the identification of the targets for each disease, the selection of the patients and the evaluation of the results. PMID:21887135

  18. Newberry Volcano EGS Demonstration Stimulation Modeling

    SciTech Connect

    Trenton T. Cladouhos, Matthew Clyne, Maisie Nichols,; Susan Petty, William L. Osborn, Laura Nofziger

    2011-10-23

    As a part of Phase I of the Newberry Volcano EGS Demonstration project, several data sets were collected to characterize the rock volume around the well. Fracture, fault, stress, and seismicity data has been collected by borehole televiewer, LiDAR elevation maps, and microseismic monitoring. Well logs and cuttings from the target well (NWG 55-29) and core from a nearby core hole (USGS N-2) have been analyzed to develop geothermal, geochemical, mineralogical and strength models of the rock matrix, altered zones, and fracture fillings (see Osborn et al., this volume). These characterization data sets provide inputs to models used to plan and predict EGS reservoir creation and productivity. One model used is AltaStim, a stochastic fracture and flow software model developed by AltaRock. The software's purpose is to model and visualize EGS stimulation scenarios and provide guidance for final planning. The process of creating an AltaStim model requires synthesis of geologic observations at the well, the modeled stress conditions, and the stimulation plan. Any geomechanical model of an EGS stimulation will require many assumptions and unknowns; thus, the model developed here should not be considered a definitive prediction, but a plausible outcome given reasonable assumptions. AltaStim is a tool for understanding the effect of known constraints, assumptions, and conceptual models on plausible outcomes.

  19. Vestibular stimulation leads to distinct hemodynamic patterning

    NASA Technical Reports Server (NTRS)

    Kerman, I. A.; Emanuel, B. A.; Yates, B. J.

    2000-01-01

    Previous studies demonstrated that responses of a particular sympathetic nerve to vestibular stimulation depend on the type of tissue the nerve innervates as well as its anatomic location. In the present study, we sought to determine whether such precise patterning of vestibulosympathetic reflexes could lead to specific hemodynamic alterations in response to vestibular afferent activation. We simultaneously measured changes in systemic blood pressure and blood flow (with the use of Doppler flowmetry) to the hindlimb (femoral artery), forelimb (brachial artery), and kidney (renal artery) in chloralose-urethane-anesthetized, baroreceptor-denervated cats. Electrical vestibular stimulation led to depressor responses, 8 +/- 2 mmHg (mean +/- SE) in magnitude, that were accompanied by decreases in femoral vasoconstriction (23 +/- 4% decrease in vascular resistance or 36 +/- 7% increase in vascular conductance) and increases in brachial vascular tone (resistance increase of 10 +/- 6% and conductance decrease of 11 +/- 4%). Relatively small changes (<5%) in renal vascular tone were observed. In contrast, electrical stimulation of muscle and cutaneous afferents produced pressor responses (20 +/- 6 mmHg) that were accompanied by vasoconstriction in all three beds. These data suggest that vestibular inputs lead to a complex pattern of cardiovascular changes that is distinct from that which occurs in response to activation of other types of somatic afferents.

  20. Knee cartilage defect: marrow stimulating techniques.

    PubMed

    Mirza, M Zain; Swenson, Richard D; Lynch, Scott A

    2015-12-01

    Painful chondral defects of the knee are very difficult problems. The incidence of these lesions in the general population is not known since there is likely a high rate of asymptomatic lesions. The rate of lesions found during arthroscopic exam is highly variable, with reports ranging from 11 to 72 % Aroen (Aroen Am J Sports Med 32: 211-5, 2004); Curl(Arthroscopy13: 456-60, 1997); Figueroa(Arthroscopy 23(3):312-5, 2007;); Hjelle(Arthroscopy 18: 730-4, 2002). Examples of current attempts at cartilage restoration include marrow stimulating techniques, ostochondral autografts, osteochondral allografts, and autologous chondrocyte transplantation. Current research in marrow stimulating techniques has been focused on enhancing and guiding the biology of microfracture and other traditional techniques. Modern advances in stem cell biology and biotechnology have provided many avenues for exploration. The purpose of this work is to review current techniques in marrow stimulating techniques as it relates to chondral damage of the knee. PMID:26411978

  1. Deep brain stimulation for movement disorders.

    PubMed

    Larson, Paul S

    2014-07-01

    Deep brain stimulation (DBS) is an implanted electrical device that modulates specific targets in the brain resulting in symptomatic improvement in a particular neurologic disease, most commonly a movement disorder. It is preferred over previously used lesioning procedures due to its reversibility, adjustability, and ability to be used bilaterally with a good safety profile. Risks of DBS include intracranial bleeding, infection, malposition, and hardware issues, such migration, disconnection, or malfunction, but the risk of each of these complications is low--generally ≤ 5% at experienced, large-volume centers. It has been used widely in essential tremor, Parkinson's disease, and dystonia when medical treatment becomes ineffective, intolerable owing to side effects, or causes motor complications. Brain targets implanted include the thalamus (most commonly for essential tremor), subthalamic nucleus (most commonly for Parkinson's disease), and globus pallidus (Parkinson's disease and dystonia), although new targets are currently being explored. Future developments include brain electrodes that can steer current directionally and systems capable of "closed loop" stimulation, with systems that can record and interpret regional brain activity and modify stimulation parameters in a clinically meaningful way. New, image-guided implantation techniques may have advantages over traditional DBS surgery. PMID:24833244

  2. The ethics of deep brain stimulation (DBS).

    PubMed

    Unterrainer, Marcus; Oduncu, Fuat S

    2015-11-01

    Deep brain stimulation (DBS) is an invasive technique designed to stimulate certain deep brain regions for therapeutic purposes and is currently used mainly in patients with neurodegenerative disorders, such as Parkinson's disease. However, DBS is also used increasingly for other experimental applications, such as the treatment of psychiatric disorders (e.g. severe depression), weight reduction. Apart from its therapeutic potential, DBS can cause severe adverse effects, some that might also have a significant impact on the patient's personality and autonomy by the external stimulation of DBS which effects lie beyond the individual's control and free will. The article's purpose is to outline the procedures of DBS currently used in therapeutic and experimental applications and to discuss the ethical concerns regarding this procedure. It will address the clinical benefit-risk-ratio, the particular ethics of research in this field, and the ethical issues raised by affecting a patient's or an individual's personality and autonomous behaviour. Moreover, a potential ethical guideline, the Ulysses contract is discussed for the field of clinical application as well as the question of responsibility.

  3. Herbicide Phosphinothricin Causes Direct Stimulation Hormesis

    PubMed Central

    Dragićević, Milan; Platiša, Jelena; Nikolić, Radomirka; Todorović, Slađana; Bogdanović, Milica; Mitić, Nevena; Simonović, Ana

    2013-01-01

    Herbicide phosphinothricin (PPT) inhibits glutamine synthetase (GS), a key enzyme in nitrogen assimilation, thus causing ammonia accumulation, glutamine depletion and eventually plant death. However, the growth response of Lotus corniculatus L. plants immersed in solutions with a broad range of PPT concentrations is biphasic, with pronounced stimulating effect on biomass production at concentrations ≤ 50 μM and growth inhibition at higher concentrations. The growth stimulation at low PPT concentrations is a result of activation of chloroplastic isoform GS2, while the growth suppression is caused by inhibition of both cytosolic GS1 and GS2 at higher PPT concentrations. Since the results are obtained in cell-free system (e.g. protein extracts), to which the principles of homeostasis are not applicable, this PPT effect is an unambiguous example of direct stimulation hormesis. A detailed molecular mechanism of concentration-dependent interaction of both PPT and a related GS inhibitor, methionine sulfoximine, with GS holoenzymes is proposed. The mechanism is in concurrence with all experimental and literature data. PMID:23983663

  4. Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

    PubMed

    Mwenge, Gimbada B; Rombaux, Philippe; Lengele, Benoit; Rodenstein, Daniel

    2015-01-01

    Obstructive sleep apnea (OSA) is a very frequent affliction that affects about 1-5% of the adult population in its severe form. Continuous positive airway pressure (CPAP) is the most commonly used treatment and is highly effective, but its use is limited by low long-term adherence rates and overall poor acceptance among the patients. Therefore, there is a need for developing alternative approaches to OSA treatment, including a more 'natural' concept of maintaining an open airway through neuromodulation. Here we review the concept, scientific rationale, and technical details of hypoglossal nerve stimulation. We also review results of published clinical studies with several hypoglossal stimulation devices that are being investigated today. Hypoglossal nerve stimulation appears to be a very promising treatment for patients with moderate-to-severe OSA. If its efficacy is confirmed, it will probably be complementary with CPAP therapy and initially aimed at patients unable or unwilling to use CPAP. Once it becomes a standard therapy, its advantages might prove sufficient to challenge CPAP as the first-line therapy.

  5. Deep brain stimulation for movement disorders.

    PubMed

    Larson, Paul S

    2014-07-01

    Deep brain stimulation (DBS) is an implanted electrical device that modulates specific targets in the brain resulting in symptomatic improvement in a particular neurologic disease, most commonly a movement disorder. It is preferred over previously used lesioning procedures due to its reversibility, adjustability, and ability to be used bilaterally with a good safety profile. Risks of DBS include intracranial bleeding, infection, malposition, and hardware issues, such migration, disconnection, or malfunction, but the risk of each of these complications is low--generally ≤ 5% at experienced, large-volume centers. It has been used widely in essential tremor, Parkinson's disease, and dystonia when medical treatment becomes ineffective, intolerable owing to side effects, or causes motor complications. Brain targets implanted include the thalamus (most commonly for essential tremor), subthalamic nucleus (most commonly for Parkinson's disease), and globus pallidus (Parkinson's disease and dystonia), although new targets are currently being explored. Future developments include brain electrodes that can steer current directionally and systems capable of "closed loop" stimulation, with systems that can record and interpret regional brain activity and modify stimulation parameters in a clinically meaningful way. New, image-guided implantation techniques may have advantages over traditional DBS surgery.

  6. Physical properties of stimulated and unstimulated tears.

    PubMed

    Pandit, J C; Nagyová, B; Bron, A J; Tiffany, J M

    1999-02-01

    It has long been assumed that unstimulated tears are more thoroughly equilibrated with epithelial secretions than stimulated tears, since they are in contact with tarsal, bulbar and corneal surfaces for longer. It was also believed from results with model solutions that soluble mucin is responsible for the observed surface tension and viscosity of tears. If longer contact means more mucin is dissolved in the aqueous tears, then the surface activity (surface tension lowered by mucin) and viscosity (raised by mucin) of tears should therefore be enhanced in unstimulated over stimulated tears. Pools of stimulated and minimally-stimulated tears were collected from a group of healthy adult volunteers by glass capillary. Viscosities were measured in the Contraves Low Shear 30 rheometer over the range of shear rates 0-130 sec-1. Surface tension was measured in the collection capillaries by a micro-technique, before and after refrigerated storage. Both surface tension and viscosity were determined for a variety of tear proteins and mucins. No significant difference was found between the viscosity/shear rate plots of stimulated and unstimulated tear samples. The viscosities of solutions of individual tear proteins were low, except for the combination of lysozyme and secretory IgA. Surface tensions were also similar in both cases, and unchanged by storage at room temperature or refrigeration, indicating no significant loss of surface-active material by adsorption on the capillary walls. Results with model mucin solutions gave a variety of results indicating either little surface activity or losses due to wall adsorption. Tear proteins, individually or in combination, did not lower surface tension to the level of tears. Tear viscosity seems not to depend on the level of dissolved mucins. This suggests either that a constant level of these is picked up even by short-term contact with ocular surfaces, or that viscosity arises from currently unknown materials which vary little

  7. Effects of stimulation parameters and electrode location on thresholds for epidural stimulation of cat motor cortex

    NASA Astrophysics Data System (ADS)

    Wongsarnpigoon, Amorn; Grill, Warren M.

    2011-12-01

    Epidural electrical stimulation (ECS) of the motor cortex is a developing therapy for neurological disorders. Both placement and programming of ECS systems may affect the therapeutic outcome, but the treatment parameters that will maximize therapeutic outcomes and minimize side effects are not known. We delivered ECS to the motor cortex of anesthetized cats and investigated the effects of electrode placement and stimulation parameters on thresholds for evoking motor responses in the contralateral forelimb. Thresholds were inversely related to stimulation frequency and the number of pulses per stimulus train. Thresholds were lower over the forelimb representation in motor cortex (primary site) than surrounding sites (secondary sites), and thresholds at sites <4 mm away from the primary site were significantly lower than at sites >4 mm away. Electrode location and montage influenced the effects of polarity on thresholds: monopolar anodic and cathodic thresholds were not significantly different over the primary site, cathodic thresholds were significantly lower than anodic thresholds over secondary sites and bipolar thresholds were significantly lower with the anode over the primary site than with the cathode over the primary site. A majority of bipolar thresholds were either between or equal to the respective monopolar thresholds, but several bipolar thresholds were greater than or less than the monopolar thresholds of both the anode and cathode. During bipolar stimulation, thresholds were influenced by both electric field superposition and indirect, synaptically mediated interactions. These results demonstrate the influence of stimulation parameters and electrode location during cortical stimulation, and these effects should be considered during the programming of systems for therapeutic cortical stimulation.

  8. Selective Activation of Neuronal Targets With Sinusoidal Electric Stimulation

    PubMed Central

    Freeman, Daniel K.; Eddington, Donald K.; Rizzo, Joseph F.

    2010-01-01

    Electric stimulation of the CNS is being evaluated as a treatment modality for a variety of neurological, psychiatric, and sensory disorders. Despite considerable success in some applications, existing stimulation techniques offer little control over which cell types or neuronal substructures are activated by stimulation. The ability to more precisely control neuronal activation would likely improve the clinical outcomes associated with these applications. Here, we show that specific frequencies of sinusoidal stimulation can be used to preferentially activate certain retinal cell types: photoreceptors are activated at 5 Hz, bipolar cells at 25 Hz, and ganglion cells at 100 Hz. In addition, low-frequency stimulation (≤25 Hz) did not activate passing axons but still elicited robust synaptically mediated responses in ganglion cells; therefore, elicited neural activity is confined to within a focal region around the stimulating electrode. Our results suggest that sinusoidal stimulation provides significantly improved control over elicited neural activity relative to conventional pulsatile stimulation. PMID:20810683

  9. ADHD Common Among College Students Who Misuse Stimulant Drugs

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_160405.html ADHD Common Among College Students Who Misuse Stimulant Drugs ... misuse stimulant drugs are more likely to have attention-deficit hyperactivity disorder (ADHD) or other psychiatric problems, a new study ...

  10. 21 CFR 882.5860 - Implanted neuromuscular stimulator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... electrical stimulation to a patient's peroneal or femoral nerve to cause muscles in the leg to contract, thus improving the gait in a patient with a paralyzed leg. The stimulator consists of an implanted receiver...

  11. 21 CFR 882.5860 - Implanted neuromuscular stimulator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... electrical stimulation to a patient's peroneal or femoral nerve to cause muscles in the leg to contract, thus improving the gait in a patient with a paralyzed leg. The stimulator consists of an implanted receiver...

  12. 21 CFR 874.1820 - Surgical nerve stimulator/locator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Diagnostic Devices § 874.1820 Surgical nerve stimulator/locator. (a) Identification. A surgical nerve stimulator/locator is a device that is intended...

  13. 21 CFR 874.1820 - Surgical nerve stimulator/locator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Diagnostic Devices § 874.1820 Surgical nerve stimulator/locator. (a) Identification. A surgical nerve stimulator/locator is a device that is intended...

  14. Transcranial direct current stimulation modulates efficiency of reading processes.

    PubMed

    Thomson, Jennifer M; Doruk, Deniz; Mascio, Bryan; Fregni, Felipe; Cerruti, Carlo

    2015-01-01

    Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that offers promise as an investigative method for understanding complex cognitive operations such as reading. This study explores the ability of a single session of tDCS to modulate reading efficiency and phonological processing performance within a group of healthy adults. Half the group received anodal or cathodal stimulation, on two separate days, of the left temporo-parietal junction while the other half received anodal or cathodal stimulation of the right homologue area. Pre- and post-stimulation assessment of reading efficiency and phonological processing was carried out. A larger pre-post difference in reading efficiency was found for participants who received right anodal stimulation compared to participants who received left anodal stimulation. Further, there was a significant post-stimulation increase in phonological processing speed following right hemisphere anodal stimulation. Implications for models of reading and reading impairment are discussed.

  15. Subthreshold Dynamics in Periodically Stimulated Squid Giant Axons

    NASA Astrophysics Data System (ADS)

    Kaplan, Daniel T.; Clay, John R.; Manning, Timothy; Glass, Leon; Guevara, Michael R.; Shrier, Alvin

    1996-05-01

    Action potentials resulting from periodic stimulation of nerve axons occur at intervals that are irregular at moderate stimulation frequencies. Histograms of the intervals are multimodal, as seen in stochastic resonance. At higher stimulation frequencies, the action potentials are suppressed entirely, leaving only subthresh