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Sample records for 15d-pgj2 stimulates ho-1

  1. Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ2-mediated cell death.

    PubMed

    Koyani, Chintan N; Kitz, Kerstin; Rossmann, Christine; Bernhart, Eva; Huber, Evelyn; Trummer, Christopher; Windischhofer, Werner; Sattler, Wolfgang; Malle, Ernst

    2016-03-15

    Despite considerable efforts to improve treatment modalities for osteosarcoma (OS), patient survival remains poor mainly due to pro-survival pathways in OS cells. Among others, prostaglandins (PGs) are the potent regulators of bone homoeostasis and OS pathophysiology. Therefore, the present study aimed to elucidate the impact of 15-deoxy-Δ(12,14)-PGJ2 (15d-PGJ2, a stable PGD2 degradation product) on cell death/cell survival pathways in p53-deficient MG-63 OS cells. Our findings show that 15d-PGJ2 induces generation of reactive oxygen species that promote p38 MAPK activation and subsequent Akt phosphorylation. This pathway induced nuclear expression of Nrf2 and Egr1, and increased transcription of haem oxygenase-1 (HO-1) and the catalytic subunit of glutamate cysteine ligase (GCLc), catalysing the first step in GSH synthesis. Silencing of Nrf2, Egr1 and HO-1 significantly elevated 15d-PGJ2-mediated reduction of cellular metabolic activity. Activation of cell survival genes including HO-1 and GCLc inhibited 15d-PGJ2-induced cleavage of pro-caspase-3 and PARP. Annexin V/propidium iodide staining showed an increase in early/late apoptotic cells in response to 15d-PGJ2. The observed 15d-PGJ2-mediated signalling events are independent of PGD2 receptors (DP1 and DP2) and PPARγ. In addition, the electrophilic carbon atom C9 is a prerequisite for the observed activity of 15d-PGJ2. The present data show that the intracellular redox imbalance acted as a node and triggered both death and survival pathways in response to 15d-PGJ2. Pharmacological or genetic interference of the pro-survival pathway, the p38 MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis, sensitizes MG-63 cells towards 15d-PGJ2-mediated apoptosis. PMID:26801686

  2. Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ2-mediated cell death

    PubMed Central

    Koyani, Chintan N.; Kitz, Kerstin; Rossmann, Christine; Bernhart, Eva; Huber, Evelyn; Trummer, Christopher; Windischhofer, Werner; Sattler, Wolfgang; Malle, Ernst

    2016-01-01

    Despite considerable efforts to improve treatment modalities for osteosarcoma (OS), patient survival remains poor mainly due to pro-survival pathways in OS cells. Among others, prostaglandins (PGs) are the potent regulators of bone homoeostasis and OS pathophysiology. Therefore, the present study aimed to elucidate the impact of 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2, a stable PGD2 degradation product) on cell death/cell survival pathways in p53-deficient MG-63 OS cells. Our findings show that 15d-PGJ2 induces generation of reactive oxygen species that promote p38 MAPK activation and subsequent Akt phosphorylation. This pathway induced nuclear expression of Nrf2 and Egr1, and increased transcription of haem oxygenase-1 (HO-1) and the catalytic subunit of glutamate cysteine ligase (GCLc), catalysing the first step in GSH synthesis. Silencing of Nrf2, Egr1 and HO-1 significantly elevated 15d-PGJ2-mediated reduction of cellular metabolic activity. Activation of cell survival genes including HO-1 and GCLc inhibited 15d-PGJ2-induced cleavage of pro-caspase-3 and PARP. Annexin V/propidium iodide staining showed an increase in early/late apoptotic cells in response to 15d-PGJ2. The observed 15d-PGJ2-mediated signalling events are independent of PGD2 receptors (DP1 and DP2) and PPARγ. In addition, the electrophilic carbon atom C9 is a prerequisite for the observed activity of 15d-PGJ2. The present data show that the intracellular redox imbalance acted as a node and triggered both death and survival pathways in response to 15d-PGJ2. Pharmacological or genetic interference of the pro-survival pathway, the p38 MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis, sensitizes MG-63 cells towards 15d-PGJ2-mediated apoptosis. PMID:26801686

  3. 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

  4. 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.

  5. The cyclopentenone prostaglandin 15d-PGJ2 inhibits the NLRP1 and NLRP3 inflammasomes

    PubMed Central

    Maier, Nolan K.; Leppla, Stephen H.; Moayeri, Mahtab

    2015-01-01

    Inflammasomes are cytosolic protein complexes that respond to diverse danger signals by activating caspase-1. The sensor components of the inflammasome, often proteins of the nucleotide-binding oligomerization domain-like receptor (NLR) family, detect stress, danger stimuli, and pathogen-associated molecular patterns. We report that the eicosanoid 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and related cyclopentenone prostaglandins inhibit caspase-1 activation by the NLRP1 and NLRP3 inflammasomes. This inhibition was independent of 15d-PGJ2’s well characterized role as a peroxisome proliferator receptor-γ agonist, its activation of NRF2, or its anti-inflammatory function as an inhibitor of NF-κB. Instead, 15d-PGJ2 prevents the autoproteolytic activation of caspase-1 and the maturation of IL-1β through induction of a cellular state inhibitory to caspase-1 proteolytic function. The eicosanoid does not directly modify or inactivate the caspase-1 enzyme. Rather, inhibition is dependent on de novo protein synthesis. In a mouse peritonitis model of gout, using monosodium urate crystals to activate NLRP3,15d-PGJ2 caused a significant inhibition of cell recruitment and associated IL-1β release. Furthermore, in a murine anthrax infection model, 15d-PGJ2 reversed anthrax lethal toxin-mediated NLRP1-dependent resistance. The findings reported in this work suggest a novel mechanism for the anti-inflammatory properties of the cyclopentenone prostaglandins through inhibition of caspase-1 and the inflammasome. PMID:25681332

  6. The cyclopentenone prostaglandin 15d-PGJ2 inhibits the NLRP1 and NLRP3 inflammasomes.

    PubMed

    Maier, Nolan K; Leppla, Stephen H; Moayeri, Mahtab

    2015-03-15

    Inflammasomes are cytosolic protein complexes that respond to diverse danger signals by activating caspase-1. The sensor components of the inflammasome, often proteins of the nucleotide-binding oligomerization domain-like receptor (NLR) family, detect stress, danger stimuli, and pathogen-associated molecular patterns. We report that the eicosanoid 15-deoxy-Δ(12,14)-PGJ2 (15d-PGJ2) and related cyclopentenone PGs inhibit caspase-1 activation by the NLR family leucine-rich repeat protein (NLRP)1 and NLRP3 inflammasomes. This inhibition was independent of the well-characterized role of 15d-PGJ2 as a peroxisome proliferator receptor-γ agonist, its activation of NF erythroid 2-related factor 2, or its anti-inflammatory function as an inhibitor of NF-κB. Instead, 15d-PGJ2 prevents the autoproteolytic activation of caspase-1 and the maturation of IL-1β through induction of a cellular state inhibitory to caspase-1 proteolytic function. The eicosanoid does not directly modify or inactivate the caspase-1 enzyme. Rather, inhibition is dependent on de novo protein synthesis. In a mouse peritonitis model of gout, using monosodium urate crystals to activate NLRP3, 15d-PGJ2 caused a significant inhibition of cell recruitment and associated IL-1β release. Furthermore, in a murine anthrax infection model, 15d-PGJ2 reversed anthrax lethal toxin-mediated NLRP1-dependent resistance. The findings reported in this study suggest a novel mechanism for the anti-inflammatory properties of the cyclopentenone PGs through inhibition of caspase-1 and the inflammasome. PMID:25681332

  7. 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

  8. 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

  9. 15-Deoxy-{delta}{sup 12,14}-prostaglandin J2 (15d-PGJ2) mediates repression of TNF-{alpha} by decreasing levels of acetylated histone H3 and H4 at its promoter

    SciTech Connect

    Engdahl, Ryan . E-mail: rengdahl@temple.edu; Monroy, M. Alexandra; Daly, John M.

    2007-07-20

    Prostaglandin metabolite 15-Deoxy-{delta}{sup 12,14}-prostaglandin J2 (15d-PGJ2) is known to inhibit a number of pro-inflammatory cytokines as well as being a ligand for nuclear receptor PPAR{gamma}. We investigated the ability of 15d-PGJ2 to inhibit TNF-{alpha} gene expression through mechanisms that involve histone modification. Pretreatment with 15d-PGJ2 (10 {mu}M) inhibited LPS-stimulated TNF-{alpha} mRNA in THP-1 monocytes or PMA-differentiated cells to nearly basal levels. A specific PPAR{gamma} ligand, GW1929, failed to inhibit LPS-induced TNF-{alpha} mRNA expression nor did a PPAR{gamma} antagonist, GW9662, alter the repression of TNF-{alpha} mRNA in LPS-stimulated cells pretreated with 15d-PGJ2 suggesting a PPAR{gamma}-independent inhibition of TNF-{alpha} mRNA in THP-1 cells. Transfection studies with a reporter construct and subsequent treatment with 15d-PGJ2 demonstrated a dose-dependent inhibition of the TNF-{alpha} promoter. Additional studies demonstrated that inhibition of histone deacetylases with trichostatin A (TSA) or overexpression of histone acetyltransferase CBP could overcome 15d-PGJ2-mediated repression of the TNF-{alpha} promoter, suggesting that an important mechanism whereby 15d-PGJ2 suppresses a cytokine is through factors that regulate histone modifications. To examine the endogenous TNF-{alpha} promoter, chromatin immunoprecipitations (ChIP) were performed. ChIP assays demonstrated that LPS stimulation induced an increase in histone H3 and H4 acetylation at the TNF-{alpha} promoter, which was reduced in cells pretreated with 15d-PGJ2. These results highlight the ability of acetylation and deacetylation factors to affect the TNF-{alpha} promoter and demonstrate that an additional important mechanism whereby 15d-PGJ2 mediates TNF-{alpha} transcriptional repression by altering levels of acetylated histone H3 and H4 at its promoter.

  10. 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

  11. Autocrine secretion of 15d-PGJ2 mediates simvastatin-induced apoptotic burst in human metastatic melanoma cells

    PubMed Central

    Wasinger, Christine; Künzl, Martin; Minichsdorfer, Christoph; Höller, Christoph; Zellner, Maria; Hohenegger, Martin

    2014-01-01

    Background and Purpose Despite new therapeutic approaches, metastatic melanomas still have a poor prognosis. Statins reduce low-density lipoprotein cholesterol and exert anti-inflammatory and anti-proliferative actions. We have recently shown that simvastatin triggers an apoptotic burst in human metastatic melanoma cells by the synthesis of an autocrine factor. Experimental Approach The current in vitro study was performed in human metastatic melanoma cell lines (A375, 518a2) and primary human melanocytes and melanoma cells. The secretome of simvastatin-stressed cells was analysed with two-dimensional difference gel electrophoresis and MS. The signalling pathways involved were analysed at the protein and mRNA level using pharmacological approaches and siRNA technology. Key Results Simvastatin was shown to activate a stress cascade, leading to the synthesis of 15-deoxy-12,14-PGJ2 (15d-PGJ2), in a p38- and COX-2-dependent manner. Significant concentrations of 15d-PGJ2 were reached in the medium of melanoma cells, which were sufficient to activate caspase 8 and the mitochondrial pathway of apoptosis. Inhibition of lipocalin-type PGD synthase, a key enzyme for 15d-PGJ2 synthesis, abolished the apoptotic effect of simvastatin. Moreover, 15d-PGJ2 was shown to bind to the fatty acid-binding protein 5 (FABP5), which was up-regulated and predominantly detected in the secretome of simvastatin-stressed cells. Knockdown of FABP5 abolished simvastatin-induced activation of PPAR-γ and amplified the apoptotic response. Conclusions and Implications We characterized simvastatin-induced activation of the 15d-PGJ2/FABP5 signalling cascades, which triggered an apoptotic burst in melanoma cells but did not affect primary human melanocytes. These data support the rationale for the pharmacological targeting of 15d-PGJ2 in metastatic melanoma. PMID:25091578

  12. 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

  13. Proteome Analysis Identified the PPARγ Ligand 15d-PGJ2 as a Novel Drug Inhibiting Melanoma Progression and Interfering with Tumor-Stroma Interaction

    PubMed Central

    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 G2/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

  14. The anti-inflammatory prostaglandin 15d-PGJ2 and its nuclear receptor PPARgamma are decreased in schizophrenia.

    PubMed

    Martínez-Gras, Isabel; Pérez-Nievas, Beatriz G; García-Bueno, Borja; Madrigal, José L M; Andrés-Esteban, Eva; Rodríguez-Jiménez, Roberto; Hoenicka, Janet; Palomo, Tomás; Rubio, Gabriel; Leza, Juan C

    2011-05-01

    A number of findings suggest that inflammation plays a role in the pathophysiology of schizophrenia. Taking into account a physiological balance between pro- and anti-inflammatory mediators, we measured the plasma levels of cyclooxygenase-derived mediators and other key pro- and anti-inflammatory transcription factors in peripheral blood mononuclear cells (PBMC). Forty healthy subjects and 46 treated chronic schizophrenic patients with an acutely exacerbated condition who met DSM-IV criteria were included. COX by-products prostaglandin E2 (PGE2) and 15d-prostaglandin J2 (15d-PGJ2) plasma levels were measured by EIA. Peroxisome proliferator-activated receptor gamma (PPARγ) as well as nuclear factor kappaB (NFκB) activity in nuclear extracts from PBMC and expression of its inhibitory subunit IκBα in cytosolic extracts were determined using ELISA-based kits. Schizophrenic patients showed higher plasma levels of pro-inflammatory PGE2 than age-matched controls (p=0.043). On the contrary, levels of anti-inflammatory 15-d-PGJ2 were lower (p=0.004), correlating with a lower expression of its nuclear target, PPARγ in nuclear extracts from PBMC (p=0.001). Although no changes in NFκB activity were observed between patients and healthy controls, the expression of its inhibitory protein IκBα was lower in the patients compared to the controls (p=0.027). These findings suggest that schizophrenia is associated with a systemic imbalance in the plasma levels of pro-inflammatory/anti-inflammatory prostaglandins in favor of the former. Furthermore, the expression and activity of anti-inflammatory PPARγ are diminished in PBMC, which indicates a state of inflammation and blunted anti-inflammatory counterbalancing mechanisms at systemic level in these patients. PMID:21334179

  15. 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. PMID:26301727

  16. 15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia.

    PubMed

    Park, Eun Jung; Park, Soo Young; Joe, Eun-hye; Jou, Ilo

    2003-04-25

    Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are now emerging as therapeutic drugs for various inflammatory diseases. However, their molecular mechanism of action remains to be elucidated. Here we report a novel mechanism that underlies the PPAR-gamma agonist-mediated suppression of brain inflammation. We show that 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) and rosiglitazone reduce the phosphorylation of STAT1 and STAT3 as well as Janus kinase 1 (JAK1) and JAK2 in activated astrocytes and microglia. The PPAR-gamma agonist-mediated reduction in phosphorylation leads to the suppression of JAK-STAT-dependent inflammatory responses. The effects of 15d-PGJ(2) and rosiglitazone are not mediated by activation of PPAR-gamma. 15d-PGJ(2) and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling (SOCS) 1 and 3, which in turn inhibit JAK activity in activated glial cells. In addition, Src homology 2 domain-containing protein phosphatase 2 (SHP2), another negative regulator of JAK activity, is also involved in their anti-inflammatory action. Our data suggest that 15d-PGJ(2) and rosiglitazone suppress the initiation of JAK-STAT inflammatory signaling independently of PPAR-gamma, thus attenuating brain inflammation. PMID:12584205

  17. 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

  18. Electroacupuncture Ameliorates Acute Renal Injury in Lipopolysaccharide-Stimulated Rabbits via Induction of HO-1 through the PI3K/Akt/Nrf2 Pathways

    PubMed Central

    Gong, Li-rong; Dong, Shu-an; Cao, Xin-shun; Wu, Li-li; Wu, Li-na

    2015-01-01

    Electroacupuncture at select acupoints have been verified to protect against organ dysfunctions during endotoxic shock. And, heme oxygenase (HO)-1 as a phase II enzyme and antioxidant contributed to the protection of kidney in septic shock rats. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway mediated the activation of NF-E2 related factor-2 (Nrf2), which was involved in HO-1 induction. To understand the efficacy of electroacupuncture stimulation in ameliorating acute kidney injury (AKI) through the PI3K/Akt/Nrf2 pathway and subsequent HO-1 upregulation, a dose of LPS 5mg/kg was administered intravenously to replicate the rabbit model of AKI induced by endotoxic shock. Electroacupuncture pretreatment was handled bilaterally at Zusanli and Neiguan acupoints for five consecutive days while sham electroacupuncture at non-acupoints as control. Results displayed that electroacupuncture stimulation significantly alleviated the morphologic renal damage, attenuated renal tubular apoptosis, suppressed the elevated biochemical indicators of AKI caused by LPS, enhanced the expressions of phospho-Akt, HO-1protein, Nrf2 total and nucleoprotein, and highlighted the proportions of Nrf2 nucleoprotein as a parallel. Furthermore, partial protective effects of elecroacupuncture were counteracted by preconditioning with wortmannin (the selective PI3K inhibitor), indicating a direct involvement of PI3K/Akt pathway. Inconsistently, wortmannin pretreatment made little difference to the expressions of HO-1, Nrf2 nucleoprotein and total protein, which indicated that PI3K/Akt may be not the only pathway responsible for electroacupuncture-afforded protection against LPS-induced AKI. These findings provide new insights into the potential future clinical applications of electroacupuncture for AKI induced by endotoxic shock instead of traditional remedies. PMID:26524181

  19. Pistacia chinensis inhibits NO production and upregulates HO-1 induction via PI-3K/Akt pathway in LPS stimulated macrophage cells.

    PubMed

    Yayeh, Taddesse; Hong, Mei; Jia, Qi; Lee, Young-Chul; Kim, Hyun-Jin; Hyun, Eujin; Kim, Tae-Wan; Rhee, Man Hee

    2012-01-01

    Pistacia chinensis has been used for various purposes in China including as an understock for grafting Pistacia vera. However, little attention was given to its health promoting effects. Therefore, in this study, we investigated the effect of Pistacia chinensis methanolic extract (PCME) containing resorcinol class of phenolic lipids on pro-inflammatory mediators and heme oxygenase-1(HO-1) in lipopolysaccharide stimulated RAW264.7 cells. While PCME (2.5-10 μg/ml) inhibited mRNA expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interleukin (IL)-6, it up-regulated HO-1 expression. Likewise, PCME inhibited iNOS protein expression, but not COX-2, and reduced nitric oxide (NO) release. Moreover, Phosphorylated c-Jun N-terminal Kinase (JNK) was attenuated dose-dependently in PCME pre-treated RAW264.7 cells. In addition, PCME up-regulated HO-1 protein expression was diminished by pre-treatment of PI-3K inhibitor. Furthermore, nuclear factor erythroid 2 related factor 2 (Nrf2) repressor was attenuated time-dependently during PCME treatment. Taken together, our study showed (for the first time) that PCME inhibited NO production and up-regulated HO-1 induction via PI-3K/Akt pathway, suggesting the role of Pistacia chinensis as potential sources of anti-inflammatory and antioxidant natural compounds. PMID:22928837

  20. Forsythiaside A Exhibits Anti-inflammatory Effects in LPS-Stimulated BV2 Microglia Cells Through Activation of Nrf2/HO-1 Signaling Pathway.

    PubMed

    Wang, Yue; Zhao, Hongfei; Lin, Chuangxin; Ren, Jie; Zhang, Shizhong

    2016-04-01

    Inflammation and oxidative stress have been reported to play critical roles in the pathogenesis of neurodegenerative disease. Forsythiaside A, a phenylethanoside product isolated from air-dried fruits of Forsythia suspensa, has been reported to have anti-inflammatory and antioxidant effects. In this study, the anti-inflammatory effects of forsythiaside A on LPS-stimulated BV2 microglia cells and primary microglia cells were investigated. The production of inflammatory mediators TNF-α, IL-1β, NO and PGE2 were detected in this study. NF-κB, nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) expression were detected by western blot analysis. Our results showed that forsythiaside A significantly inhibited LPS-induced inflammatory mediators TNF-α, IL-1β, NO and PGE2 production. LPS-induced NF-κB activation was suppressed by forsythiaside A. Furthermore, forsythiaside A was found to up-regulate the expression of Nrf2 and HO-1. In conclusion, this study demonstrates that forsythiaside A inhibits LPS-induced inflammatory responses in BV2 microglia cells and primary microglia cells through inhibition of NF-κB activation and activation of Nrf2/HO-1 signaling pathway. PMID:26498935

  1. 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.

  2. 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

  3. 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. PMID:27131287

  4. Downregulation of NO and PGE2 in LPS-stimulated BV2 microglial cells by trans-isoferulic acid via suppression of PI3K/Akt-dependent NF-κB and activation of Nrf2-mediated HO-1.

    PubMed

    Dilshara, Matharage Gayani; Lee, Kyoung-Tae; Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Kang, Chang-Hee; Park, Sang Rul; Choi, Yung Hyun; Choi, Il-Whan; Hyun, Jin-Won; Chang, Weon-Young; Kim, Yeon-Su; Lee, Hak-Ju; Kim, Gi-Young

    2014-01-01

    Little is known about whether trans-isoferulic acid (TIA) regulates the production of lipopolysaccharide (LPS)-induced proinflammatory mediators. Therefore, we examined the effect of TIA isolated from Clematis mandshurica on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in BV2 microglial cells. We found that TIA inhibited the production of LPS-induced NO and PGE2 without accompanying cytotoxicity in BV2 microglial cells. TIA also downregulated the expression levels of specific regulatory genes such as inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) by suppressing LPS-induced NF-κB activity via dephosphorylation of PI3K/Akt. In addition, we demonstrated that a specific NF-κB inhibitor PDTC and a selective PI3K/Akt inhibitor, LY294002 effectively attenuated the expression of LPS-stimulated iNOS and COX-2 mRNA, while LY294002 suppressed LPS-induced NF-κB activity, suggesting that TIA attenuates the expression of these proinflammatory genes by suppressing PI3K/Akt-mediated NF-κB activity. Our results showed that TIA suppressed NO and PGE2 production through the induction of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent heme oxygenase-1 (HO-1). Taken together, our data indicate that TIA suppresses the production of proinflammatory mediators such as NO and PGE2, as well as their regulatory genes, in LPS-stimulated BV2 microglial cells, by inhibiting PI3K/Akt-dependent NF-κB activity and enhancing Nrf2-mediated HO-1 expression. PMID:24291391

  5. 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. PMID:18692581

  6. 15d-prostaglandin J2 enhancement of nerve growth factor-induced neurite outgrowth is blocked by the chemoattractant receptor- homologous molecule expressed on T-helper type 2 cells (CRTH2) antagonist CAY10471 in PC12 cells.

    PubMed

    Hatanaka, Michiyoshi; Shibata, Norihiro; Shintani, Norihito; Haba, Ryota; Hayata, Atsuko; Hashimoto, Hitoshi; Baba, Akemichi

    2010-01-01

    The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is the most recently identified prostaglandin (PG) receptor for both PGD(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). We examined the mechanism by which 15d-PGJ(2) enhances nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. CAY10471 (CRTH2 antagonist) inhibited both the neurite-promotion and p38 mitogen-activated protein (MAP) kinase phosphorylation induced by 15d-PGJ(2). In contrast, 13,14-dihydro-15-keto-PGD(2 )(DK-PGD(2)) (selective CRTH2 agonist) stimulated its phosphorylation but failed to produce neurite-promoting effects. These suggest, for the first time, the action of 15d-PGJ(2) is mediated by CRTH2, although the CRTH2 activation alone is insufficient for the underlying action. PMID:20424389

  7. The Role of Cyclooxygenase-2, Interleukin-1β and Fibroblast Growth Factor-2 in the Activation of Matrix Metalloproteinase-1 in Sheared-Chondrocytes and Articular Cartilage

    PubMed Central

    Guan, Pei-Pei; Guo, Jing-Wen; Yu, Xin; Wang, Yue; Wang, Tao; Konstantopoulos, Konstantinos; Wang, Zhan-You; Wang, Pu

    2015-01-01

    MMP-1 expression is detected in fluid shear stress (20 dyn/cm2)-activated and osteoarthritic human chondrocytes, however, the precise mechanisms underlying shear-induced MMP-1 synthesis remain unknown. Using primary chondrocytes and T/C-28a2 chondrocytic cells as model systems, we report that prolonged application of high fluid shear to human chondrocytes induced the synthesis of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and fibroblast growth factor-2 (FGF-2), which led to a marked increase in MMP-1 expression. IL-1β, COX-2-dependent PGE2 activated the PI3-K/AKT and p38 signaling pathways, which were in turn responsible for MMP-1 synthesis via NF-κB- and c-Jun-transactivating pathways. Prolonged shear stress exposure (>12 h) induced 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) synthesis. Although 15d-PGJ2 suppressed PI3-K/AKT and p38 signaling pathways, it stimulated MMP-1 expression via activating heme oxygenase 1 (HO-1). The critical role of COX-2 in regulating MMP-1 expression in articular cartilage in vivo was demonstrated using COX-2+/− transgenic mice in the absence or presence of rofecoxib oral administration. These findings provide novel insights for developing therapeutic strategies to combat OA. PMID:25992485

  8. Presence of an HO-1 expression threshold in renal glomeruli.

    PubMed

    Detsika, Maria G; Atsaves, Vassileios; Papalois, Apostolos; Lianos, Elias A

    2015-12-01

    This article reports data describing HO-1 expression patterns of heme oxygenase (HO)-1 in isolated rat glomeruli and in cultured glomerular epithelial cells (GEC) in response to its natural substrate heme. Qualitative and quantitative data are presented to support presence of a HO-1 expression threshold in glomeruli but not in GEC. Interpretation of our data and further insight into HO-1 expression pattern in glomeruli may be found in 'HO-1 expression control in the rat glomerulus' [1]. PMID:26702422

  9. Induction of proliferation by 15-deoxy-delta12,14-prostaglandin J2 and the precursors in monocytic leukemia U937.

    PubMed

    Azuma, Yasutaka; Watanabe, Kyoko; Date, Masataka; Daito, Michiharu; Ohura, Kiyoshi

    2004-08-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in several human tumors including gastric, lung, colon, prostate and breast. However, the role of PPARgamma signals in leukemia is still unclear. The aim of this study is to evaluate the ability of 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2), that is a ligand for PPARgamma, on proliferation of human leukemia cell line U937. 15dPGJ2 at 5 micromol/l stimulated the proliferation. In contrast, 15dPGJ2 at concentrations of >10 micromol/l inhibited the proliferation through the induction of apoptosis. PGD2, PGJ2 and Delta12-PGJ2 (DeltaPGJ2), those are precursors of 15dPGJ2, had similarly proliferative effects, whereas they showed antiproliferative effects at high concentrations. FACScan analysis revealed that PGD2 at 5 micromol/l, PGJ2 at 1 micromol/l, DeltaPGJ2 at 1 micromol/l and 15dPGJ2 at 5 micromol/l, all accelerated cell cycle progression. Immunoblotting analysis revealed that PGD2 at 5 micromol/l and 15dPGJ2 at 5 micromol/l inhibited the expression of phospho-p38, phospho-MKK3/MKK6 and phospho-ATF-2, and the expression of Cdk inhibitors including p18, p27. In contrast, PGJ2 at 1 micromol/l and DeltaPGJ2 at 1 micromol/l did not affect the expression of them. These results suggest that 15dPGJ2 and PGD2 may, through inactivation of the p38 MAPK pathway, inhibit the expression of Cdk inhibitors, leading to acceleration of proliferation. PMID:15240994

  10. Presence of an HO-1 expression threshold in renal glomeruli

    PubMed Central

    Detsika, Maria G; Atsaves, Vassileios; Papalois, Apostolos; Lianos, Elias A.

    2015-01-01

    This article reports data describing HO-1 expression patterns of heme oxygenase (HO)-1 in isolated rat glomeruli and in cultured glomerular epithelial cells (GEC) in response to its natural substrate heme. Qualitative and quantitative data are presented to support presence of a HO-1 expression threshold in glomeruli but not in GEC. Interpretation of our data and further insight into HO-1 expression pattern in glomeruli may be found in ‘HO-1 expression control in the rat glomerulus’ [1]. PMID:26702422

  11. 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. PMID:27185495

  12. HO-1/CO system in tumor growth, angiogenesis and metabolism - Targeting HO-1 as an anti-tumor therapy.

    PubMed

    Loboda, Agnieszka; Jozkowicz, Alicja; Dulak, Jozef

    2015-11-01

    Heme oxygenase-1 (HO-1, hmox-1) catalyzes the rate-limiting step in the heme degradation processes. Out of three by-products of HO-1 activity, biliverdin, iron ions and carbon monoxide (CO), the latter was mostly shown to mediate many beneficial HO-1 effects, including protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. Mounting evidence suggests that HO-1/CO systemmay be of special benefit in protection inmany pathological conditions, like atherosclerosis or myocardial infarction. By contrast, the augmented expression of HO-1 in tumor tissues may have detrimental effect as HO-1 accelerates the formation of tumor neovasculature and provides the selective advantage for tumor cells to overcome the increased oxidative stress during tumorigenesis and during treatment. The inhibition of HO-1 has been proposed as an anti-cancer therapy, however, because of non-specific effects of known HO-1 inhibitors, the discovery of ideal drug lowering HO-1 expression/activity is still an open question. Importantly, in several types of cancer HO-1/CO system exerts opposite activities, making the possible treatment more complicated. All together indicates the complex role for HO-1/CO in various in vitro and in vivo conditions. PMID:26392237

  13. Modulation of mammary cancer cell migration by 15-deoxy-Δ12,14-prostaglandin J2: implications for anti-metastatic therapy

    PubMed Central

    Diers, Anne R.; Dranka, Brian P.; Ricart, Karina C.; Oh, Joo Yeun; Johnson, Michelle S.; Zhou, Fen; Pallero, Manuel A.; Bodenstine, Thomas M.; Murphy-Ullrich, Joanne E.; Welch, Danny R.; Aimee, Landar

    2010-01-01

    SYNOPSIS Recently, a number of steps in the progression of metastatic disease have been shown to be regulated by redox signaling. Electrophilic lipids affect redox signaling through the post-translational modification of critical cysteine residues in proteins. However, the therapeutic potential as well as the precise mechanisms of action of electrophilic lipids in cancer cells is poorly understood. In this study, we investigate the effect of the electrophilic prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) on metastatic properties of breast cancer cells. 15d-PGJ2 was shown to decrease migration, stimulate focal adhesion disassembly and cause extensive F-actin reorganization at low concentrations (0.03-0.3 μM). Importantly, these effects seem to be independent of PPARγ and modification of actin or Keap1, which are known protein targets of 15d-PGJ2 at higher concentrations. Interestingly, the p38 inhibitor SB203580 was able to prevent both 15d-PGJ2-induced F-actin reorganization and focal adhesion disassembly. Taken together, our results suggest that electrophiles such as 15d-PGJ2 are potential anti-metastatic agents which exhibit specificity for migration and adhesion pathways at low concentrations where there are no observed effects on Keap1 or cytotoxicity. PMID:20536428

  14. Possible involvement of p38 in mechanisms underlying acceleration of proliferation by 15-deoxy-Delta(12,14)-prostaglandin J2 and the precursors in leukemia cell line THP-1.

    PubMed

    Azuma, Yasutaka; Watanabe, Kyoko; Date, Masataka; Daito, Michiharu; Ohura, Kiyoshi

    2004-03-01

    15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ2), which is a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), induced apoptosis of several human tumors including gastric, lung, colon, prostate, and breast. However, the role of PPARgamma signals in other types of cancer cells (e.g., leukemia) except solid cancer cells is still unclear. The aim of this study is to evaluate the ability of 15dPGJ2 to modify the proliferation of the human leukemia cell line THP-1. 15dPGJ2 at 5 microM stimulated the proliferation in THP-1 at 24 to 72 h after incubation. In contrast, 15dPGJ2 at concentrations above 10 microM inhibited the proliferation through the induction of apoptosis. PGD2, PGJ2, and Delta12-PGJ2 (DeltaPGJ2), precursors of 15dPGJ2, had similar proliferative effects at lower concentrations, whereas they induced apoptosis at high concentrations. 15dPGJ2 and three precursors failed to induce the differentiation in THP-1 as assessed by using the differentiation marker CD11b. FACScan analysis revealed that PGD2 at 5 microM, PGJ2 at 1 microM, DeltaPGJ2 at 1 microM and 15dPGJ2 at 5 microM all accelerated cell cycle progression in THP-1. Immunoblotting analysis revealed that PGD2 at 5 microM and 15dPGJ2 at 5 microM inhibited the expression of phospho-p38, phospho-MKK3/MKK6, and phospho-ATF-2, and the expression of Cdk inhibitors including p18, p21, and p27 in THP-1. In contrast, PGJ2 at 1 microM and DeltaPGJ2 at 1 microM did not affect their expressions. These results suggest that 15dPGJ2 and PGD2 may, through inactivation of the p38 mitogen-activated protein kinase pathway, inhibit the expression of Cdk inhibitors, leading to acceleration of the THP-1 proliferation. PMID:15037811

  15. 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.

  16. 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. PMID:7703255

  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. PMID:12376366

  18. 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. PMID:25870947

  19. Salvianolic acid A protects RPE cells against oxidative stress through activation of Nrf2/HO-1 signaling.

    PubMed

    Zhang, Hui; Liu, Yuan-yuan; Jiang, Qin; Li, Ke-ran; Zhao, Yu-xia; Cao, Cong; Yao, Jin

    2014-04-01

    Reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelial (RPE) cells, which is known as one major cause of age-related macular degeneration. Salvianolic acid A (Sal A) is the main effective aqueous extract of Salvia miltiorrhiza. The aim of this study was to test the potential role of Sal A against oxidative stress in cultured RPE cells and to investigate the underlying mechanistic signaling pathways. We observed that Sal A significantly inhibited hydrogen peroxide (H2O2)-induced primary and transformed RPE cell death and apoptosis. H2O2-stimulated mitogen-activated protein kinase activation, ROS production, and subsequent proapoptotic AMP-activated protein kinase activation were largely inhibited by Sal A. Further, Sal A stimulation resulted in a fast and dramatic activation of Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, followed by phosphorylation, accumulation, and nuclear translocation of the NF-E2-related factor 2 (Nrf2), along with increased expression of the antioxidant-response element-dependent gene heme oxygenase-1 (HO-1). Both Nrf2 and HO-1 were required for Sal A-mediated cytoprotective effect, as Nrf2/HO-1 inhibition abolished Sal A-induced beneficial effects against H2O2. Meanwhile, the PI3K/Akt/mTORC1 chemical inhibitors not only suppressed Sal A-induced Nrf2/HO-1 activation, but also eliminated its cytoprotective effect in RPE cells. These observations suggest that Sal A activates the Nrf2/HO-1 axis in RPE cells and protects against oxidative stress via activation of Akt/mTORC1 signaling. PMID:24486344

  20. 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.

  1. HtrA3 is regulated by 15-deoxy-{Delta}12,14-prostaglandin J2 independently of PPAR{gamma} in clear cell renal cell carcinomas

    SciTech Connect

    Theoleyre, Sandrine; Mottier, Stephanie; Masson, Damien; Denis, Marc G.

    2010-04-09

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) ligands have been shown to possess anti-proliferative effects in many types of cancer. In clear cell renal cell carcinoma (CCRCC), the targets involved in these effects are not known. In this study, we demonstrated that, in CCRCC cell lines, the endogenous PPAR{gamma} ligand 15-deoxy-{Delta}12,14-prostaglandin J2 (15dPGJ2) induces the expression, both at the mRNA and the protein levels, of the HtrA3 gene. This gene belongs to the High-Temperature Requirement Factor A family of serine proteases that repress signaling by TGF-{beta} family members and inhibit cell migration. Rosiglitazone or ciglitazone, synthetic PPAR{gamma} agonists, did not induce HtrA3 expression, and the PPAR{gamma} antagonist GW9662 did not prevent 15dPGJ2 induction, suggesting that the up-regulation of HtrA3 by 15dPGJ2 is independent of PPAR{gamma}. The MEK/ERK inhibitor PD98059 dramatically repressed HtrA3 induction. Altogether, these data indicate that 15dPGJ2 is able to stimulate the expression of HtrA3 through an indirect mechanism involving the MEK/ERK pathway but independent of PPAR{gamma}. Our results provide a better understanding of the mechanisms involved in the regulation of HtrA3, a potential tumor suppressor gene.

  2. P8 deficiency increases cellular ROS and induces HO-1.

    PubMed

    Weis, Sebastian; Bielow, Tobias; Sommerer, Ines; Iovanna, Juan; Malicet, Cédric; Mössner, Joachim; Hoffmeister, Albrecht

    2015-01-01

    The gene p8 encodes for a small cytoprotective protein with no apparent enzymatic activity being proposed to act as co-transcription factor whose expression is increased during inflammation. Recent data from astrocytes demonstrates that p8 suppression leads to induction of heme oxygenase 1 (HO-1). Here, we assessed the cross-talk between p8 and HO-1 in mouse embryonic fibroblasts (MEF) observing an increased expression of HO-1 in p8-deficient (p8(-/-)) MEFs in non-treated and treated conditions. This effect was independent of the cell cycle. Our findings revealed that generation of reactive oxygen species (ROS) was higher in p8(-/-) MEFs. Mitochondria and NADPH oxidases were not the origin of ROS. This observation was not restricted to MEF as suppression of p8 gene transcription in MiaPaCa-2 cells also led to increased intracellular ROS. Additionally, p8 deficiency did not affect the Rac1 dependant NADPH oxidase complex. Our data shows that p8 deficiency increases ROS and subsequently the expression of anti-oxidative enzymes, such as HO-1, suggesting an involvement in the anti-oxidative defense. Moreover, we suggest that the severity of AP observed in p8(-/-) mice is induced by an impaired anti oxidative capacity of the pancreas, which is caused by increased generation of ROS. PMID:25475530

  3. 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...

  4. NSAIDs inhibit neovascularization of choroid through HO-1-dependent pathway.

    PubMed

    Yoshinaga, Narimasa; Arimura, Noboru; Otsuka, Hiroki; Kawahara, Ko-Ichi; Hashiguchi, Teruto; Maruyama, Ikuro; Sakamoto, Taiji

    2011-09-01

    Intraocular neovascularization is the leading cause of severe visual loss and anti-vascular endothelial growth factor (VEGF) therapy is currently performed for choroidal neovascularization (CNV). Despite its potent anti-angiogenic effect, there are concerns about its long-term safety. Non-steroidal anti-inflammatory drugs (NSAIDs) are common therapeutic agents used for treating inflammatory diseases, and their anti-stress effects are attracting attention now. We studied the effects of topical NSAIDs on CNV, focusing on anti-stress proteins. Cultured retinal pigment epithelium (RPE) cells were treated with NSAIDs: bromfenac, indomethacin, or vehicle control. Transcription factor NF-E2-related factor 2 (Nrf2) and its downstream anti-oxidant protein heme oxygenase (HO)-1 were assessed using western blot and immunohistochemistry. As a result, NSAIDs induced translocation of Nrf2 into the nucleus and the robust expression of HO-1 in a dose- and time-dependent manner. Flow cytometric analysis revealed that bromfenac inhibited H(2)O(2)-induced apoptosis in cultured RPE cells. Next, we studied the effects of topical bromfenac on laser-induced CNV model in rat. The expressions of Nrf2 and HO-1, infiltrations of ED-1-positive macrophages at CNV lesions and size were analyzed. VEGF in the ocular fluid of these rats was also measured using enzyme-linked immunosorbent assay. Rats administered an inhibitor of HO-1 stannic mesoporphyrin (SnMP) were also studied. The results showed that topical bromfenac led to translocation of Nrf2 and induction of HO-1 in CNV lesions and that the number of infiltrating macrophages at the CNV lesion decreased. The sizes of CNV lesions were significantly smaller in bromfenac-treated rats than control CNV, and the effects were diminished by SnMP. VEGF increased in the ocular fluid after laser treatment and was inhibited by bromfenac and SnMP canceling these effects. NSAIDs inhibit CNV through the novel anti-stress protein HO-1-dependent pathway

  5. 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

  6. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity.

    PubMed

    Di Biase, Stefano; Lee, Changhan; Brandhorst, Sebastian; Manes, Brianna; Buono, Roberta; Cheng, Chia-Wei; Cacciottolo, Mafalda; Martin-Montalvo, Alejandro; de Cabo, Rafael; Wei, Min; Morgan, Todd E; Longo, Valter D

    2016-07-11

    Immune-based interventions are promising strategies to achieve long-term cancer-free survival. Fasting was previously shown to differentially sensitize tumors to chemotherapy while protecting normal cells, including hematopoietic stem and immune cells, from its toxic side effects. Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8(+) tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8(+)-dependent tumor cytotoxicity. PMID:27411588

  7. Punicalagin Induces Nrf2/HO-1 Expression via Upregulation of PI3K/AKT Pathway and Inhibits LPS-Induced Oxidative Stress in RAW264.7 Macrophages.

    PubMed

    Xu, Xiaolong; Li, Hongquan; Hou, Xiaolin; Li, Deyin; He, Shasha; Wan, Changrong; Yin, Peng; Liu, Mingjiang; Liu, Fenghua; Xu, Jianqin

    2015-01-01

    Reactive oxygen species (ROS) and oxidative stress are thought to play a central role in potentiating macrophage activation, causing excessive inflammation, tissue damage, and sepsis. Recently, we have shown that punicalagin (PUN) exhibits anti-inflammatory activity in LPS-stimulated macrophages. However, the potential antioxidant effects of PUN in macrophages remain unclear. Revealing these effects will help understand the mechanism underlying its ability to inhibit excessive macrophage activation. Hemeoxygenase-1 (HO-1) exhibits antioxidant activity in macrophages. Therefore, we hypothesized that HO-1 is a potential target of PUN and tried to reveal its antioxidant mechanism. Here, PUN treatment increased HO-1 expression together with its upstream mediator nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). However, specific inhibition of Nrf2 by brusatol (a specific Nrf2 inhibitor) dramatically blocked PUN-induced HO-1 expression. Previous research has demonstrated that the PI3K/Akt pathway plays a critical role in modulating Nrf2/HO-1 protein expression as an upstream signaling molecule. Here, LY294002, a specific PI3K/Akt inhibitor, suppressed PUN-induced HO-1 expression and led to ROS accumulation in macrophages. Furthermore, PUN inhibited LPS-induced oxidative stress in macrophages by reducing ROS and NO generation and increasing superoxide dismutase (SOD) 1 mRNA expression. These findings provide new perspectives for novel therapeutic approaches using antioxidant medicines and compounds against oxidative stress and excessive inflammatory diseases including tissue damage, sepsis, and endotoxemic shock. PMID:25969626

  8. Punicalagin Induces Nrf2/HO-1 Expression via Upregulation of PI3K/AKT Pathway and Inhibits LPS-Induced Oxidative Stress in RAW264.7 Macrophages

    PubMed Central

    Xu, Xiaolong; Li, Hongquan; Hou, Xiaolin; Li, Deyin; He, Shasha; Wan, Changrong; Liu, Mingjiang; Liu, Fenghua

    2015-01-01

    Reactive oxygen species (ROS) and oxidative stress are thought to play a central role in potentiating macrophage activation, causing excessive inflammation, tissue damage, and sepsis. Recently, we have shown that punicalagin (PUN) exhibits anti-inflammatory activity in LPS-stimulated macrophages. However, the potential antioxidant effects of PUN in macrophages remain unclear. Revealing these effects will help understand the mechanism underlying its ability to inhibit excessive macrophage activation. Hemeoxygenase-1 (HO-1) exhibits antioxidant activity in macrophages. Therefore, we hypothesized that HO-1 is a potential target of PUN and tried to reveal its antioxidant mechanism. Here, PUN treatment increased HO-1 expression together with its upstream mediator nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). However, specific inhibition of Nrf2 by brusatol (a specific Nrf2 inhibitor) dramatically blocked PUN-induced HO-1 expression. Previous research has demonstrated that the PI3K/Akt pathway plays a critical role in modulating Nrf2/HO-1 protein expression as an upstream signaling molecule. Here, LY294002, a specific PI3K/Akt inhibitor, suppressed PUN-induced HO-1 expression and led to ROS accumulation in macrophages. Furthermore, PUN inhibited LPS-induced oxidative stress in macrophages by reducing ROS and NO generation and increasing superoxide dismutase (SOD) 1 mRNA expression. These findings provide new perspectives for novel therapeutic approaches using antioxidant medicines and compounds against oxidative stress and excessive inflammatory diseases including tissue damage, sepsis, and endotoxemic shock. PMID:25969626

  9. 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

  10. [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. PMID:15636365

  11. 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

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

    2016-05-01

    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

  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. Micro-RNA-155-mediated control of heme oxygenase 1 (HO-1) is required for restoring adaptively tolerant CD4+ T-cell function in rodents.

    PubMed

    Zhang, Jinyu; Vandevenne, Patricia; Hamdi, Haifa; Van Puyvelde, Merry; Zucchi, Alessandro; Bettonville, Marie; Weatherly, Kathleen; Braun, Michel Y

    2015-03-01

    T cells chronically stimulated by a persistent antigen often become dysfunctional and lose effector functions and proliferative capacity. To identify the importance of micro-RNA-155 (miR-155) in this phenomenon, we analyzed mouse miR-155-deficient CD4(+) T cells in a model where the chronic exposure to a systemic antigen led to T-cell functional unresponsiveness. We found that miR-155 was required for restoring function of T cells after programmed death receptor 1 blockade. Heme oxygenase 1 (HO-1) was identified as a specific target of miR-155 and inhibition of HO-1 activity restored the expansion and tissue migration capacity of miR-155(-/-) CD4(+) T cells. Moreover, miR-155-mediated control of HO-1 expression in CD4(+) T cells was shown to sustain in vivo antigen-specific expansion and IL-2 production. Thus, our data identify HO-1 regulation as a mechanism by which miR-155 promotes T-cell-driven inflammation. PMID:25641586

  14. 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

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

    PubMed

    Halin Bergström, Sofia; Nilsson, Maria; 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

  16. Lentivirus mediated HO-1 gene transfer enhances myogenic precursor cell survival after autologous transplantation in pig.

    PubMed

    Laumonier, Thomas; Yang, Sheng; Konig, Stephane; Chauveau, Christine; Anegon, Ignacio; Hoffmeyer, Pierre; Menetrey, Jacques

    2008-02-01

    Cell therapy for Duchenne muscular dystrophy and other muscle diseases is limited by a massive early cell death following injections. In this study, we explored the potential benefit of heme oxygenase-1 (HO-1) expression in the survival of porcine myogenic precursor cells (MPCs) transplanted in pig skeletal muscle. Increased HO-1 expression was assessed either by transient hyperthermia or by HO-1 lentiviral infection. One day after the thermic shock, we observed a fourfold and a threefold increase in HSP70/72 and HO-1 levels, respectively. This treatment protected 30% of cells from staurosporine-induced apoptosis in vitro. When porcine MPC were heat-shocked prior to grafting, we improved cell survival by threefold at 5 days after autologous transplantation (26.3 +/- 5.5% surviving cells). After HO-1 lentiviral transduction, almost 60% of cells expressed the transgene and kept their myogenic properties to proliferate and fuse in vitro. Apoptosis of HO-1 transduced cells was reduced by 50% in vitro after staurosporine induction. Finally, a fivefold enhancement in cell survival was observed after transplantation of HO-1-group (47.5 +/- 9.1% surviving cells) as compared to the nls-LacZ-group or control group. These results identify HO-1 as a protective gene against early MPC death post-transplantation. PMID:18026170

  17. 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. PMID:19250338

  18. EET agonist prevents adiposity and vascular dysfunction in rats fed a high fat diet via a decrease in Bach 1 and an increase in HO-1 levels.

    PubMed

    Sodhi, Komal; Puri, Nitin; Inoue, Kazuyoshi; Falck, John R; Schwartzman, Michal L; Abraham, Nader G

    2012-08-01

    Recent reports have shown interplay between EETs (epoxides) and the heme oxygenase (HO) system in attenuating adipogenesis in cell culture models; prompting an examination of the effectiveness of EET agonist on obesity and associated cardio-metabolic dysfunction. Patho-physiological effects of an EET agonist (NUDSA) were contrasted in the absence and in the presence of stannous mesoporphyrin (an HO inhibitor) in SD rats fed a high fat (58%, HF) for 16 weeks. Animals on HF diet exhibited enhanced oxidative stress, increased levels of inflammatory cytokines and decreased levels of adiponectin along with reduced vascular and adipose tissue levels of EETs, HO-1; as compared to control rats (11% dietary fat). Treatment with NUDSA not only reversed serum adiponectin and vascular and adipose tissue levels of EETs and HO-1, but also, decreased blood pressure, subcutaneous and visceral fat content and serum TNFα and IL-6 levels in rats on HF diet. Aortic endothelial function, peNOS expression and adipose tissue markers of energy homeostasis i.e. pAMPK, Sirt1 and FAS, impaired in rats fed a HF diet, were restored in animals treated with this EET agonist. That NUDSA enhanced HO-1 expression, was accompanied by increase in p-GSK-3β and pAKT levels along with attenuation of adipose tissue levels of Bach 1--the transcriptional suppresser of HO-1 expression. Prevention of these beneficial effects of NUDSA, in animals on HF diet and concurrently exposed to NUDSA and SnMP, supports the role of EET-HO interaction in mediating such effects. Taken together, our findings suggest that the EETs stimulate HO-1 expression via suppression of Bach 1 and interplay of these two systems affords vascular and metabolic protection in diet induced obesity. PMID:22209722

  19. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function.

    PubMed

    Liu, Xiaoli; Pachori, Alok S; Ward, Christopher A; Davis, J Paul; Gnecchi, Massimiliano; Kong, Deling; Zhang, Lunan; Murduck, Jared; Yet, Shaw-Fang; Perrella, Mark A; Pratt, Richard E; Dzau, Victor J; Melo, Luis G

    2006-02-01

    We reported previously that predelivery of the anti-oxidant gene heme oxygenase-1 (HO-1) to the heart by adeno associated virus (AAV) markedly reduces injury after acute myocardial infarction (MI). However, the effect of HO-1 gene delivery on postinfarction recovery has not been investigated. In the current study, we assessed the effect of HO-1 gene delivery on post-MI left ventricle (LV) remodeling and function using echocardiographic imaging and histomorphometric approaches. Two groups of Sprague-Dawley rats were injected with 4 x 10(11) particles of AAV-LacZ (control) or AAV-hHO-1 in the LV wall. Eight wk after gene transfer, the animals were subjected to 30 min of ischemia by ligation of left anterior descending artery (LAD) followed by reperfusion. Echocardiographic measurements were obtained in a blinded fashion prior and at 1.5 and 3 months after I/R. Ejection fraction (EF) was reduced by 13% and 40% in the HO-1 and LacZ groups, respectively at 1.5 months after MI. Three months after MI, EF recovered fully in the HO-1, but only partially in the LacZ-treated animals. Post-MI LV dimensions were markedly increased and the anterior wall was markedly thinned in the LacZ-treated animals compared with the HO-1-treated animals. Significant myocardial scarring and fibrosis were observed in the LacZ-group in association with elevated levels of interstitial collagen I and III and MMP-2 activity. Post-MI myofibroblast accumulation was reduced in the HO-1-treated animals, and retroviral overexpression of HO-1 reduced proliferation of isolated cardiac fibroblasts. Our data indicate that rAAV-HO-1 gene transfer markedly reduces fibrosis and ventricular remodeling and restores LV function and chamber dimensions after myocardial infarction. PMID:16449792

  20. Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals.

    PubMed

    Kim, So Ra; Ha, Yu Mi; Kim, Young Min; Park, Eun Jung; Kim, Jung Whan; Park, Sang Won; Kim, Hye Jung; Chung, Hun Taeg; Chang, Ki Churl

    2015-06-15

    High mobility group box 1 (HMGB1) is now recognized as a late mediator of sepsis. We tested hypothesis that ascorbic acid (AscA) induces heme oxygenase (HO)-1 which inhibits HMGB1 release in lipopolysaccharide (LPS)-stimulated cells and increases survival of septic mice. AscA increased HO-1 protein expression in a concentration- and time-dependent manner via Nrf2 activation in RAW 264.7 cells. HO-1 induction by AscA was significantly reduced by Nrf2 siRNA-transfected cells. Mutation of cysteine to serine of keap-1 proteins (C151S, C273S, and C288S) lost the ability of HO-1 induction by AscA, due to failure of translocation of Nrf-2 to nucleus. The PI3 kinase inhibitor, LY294002, inhibited HO-1 induction by AscA. Oxyhemoglobin (HbO2), LY294002, and ZnPPIX (HO-1 enzyme inhibitor) reversed effect of AscA on HMGB1 release. Most importantly, administration of AscA (200mg/kg, i.p.) significantly increased survival in LPS-induced endotoxemic mice. In cecal ligation and puncture (CLP)-induced septic mice, AscA reduced hepatic injury and serum HMGB1 and plasminogen activator inhibitor (PAI)-1 in a ZnPPIX-sensitive manner. In addition, AscA failed to increase survival in Nrf2 knockout mice by LPS. Thus, we concluded that high dose of AscA may be useful in the treatment of sepsis, at least, by activation of Nrf2/HO-1 signals. PMID:25896849

  1. 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

  2. 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

  3. 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

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

    PubMed Central

    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

  5. 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

  6. Hydrangenol inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-mediated HO-1 pathway.

    PubMed

    Kim, Hee-Ju; Kang, Chang-Hee; Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Dilshara, Matharage Gayani; Lee, Seungheon; Choi, Yung Hyun; Seo, Yong Taek; Kim, Gi-Young

    2016-06-01

    We previously demonstrated the anti-inflammatory effect of water extract of Hydrangea macrophylla in lipopolysaccharide (LPS)-stimulated macrophage cells. Here, we investigated whether hydrangenol, a bioactive component of H. macrophylla, attenuates the expression of nitric oxide (NO) and its associated gene, inducible NO synthase (iNOS), in LPS-stimulated BV2 microglial cells. Our data showed that low dosages of hydrangenol inhibited LPS-stimulated NO release and iNOS expression without any accompanying cytotoxicity. Hydrangenol also suppressed LPS-induced nuclear translocation of nuclear factor-κB (NF-κB) subunits, consequently inhibiting DNA-binding activity of NF-κB. Additionally, the NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC) and PS-1145, significantly attenuated LPS-induced iNOS expression, indicating that hydrangenol-induced NF-κB inhibition might be a key regulator of iNOS expression. Furthermore, our data showed that hydrangenol suppresses NO production by inducing heme oxygenase-1 (HO-1). The presence of cobalt protoporphyrin, a specific HO-1 inducer, potently suppressed LPS-induced NO production. Hydrangenol also promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequently increased its binding activity at the specific antioxidant response element sites. Additionally, transient knockdown of Nrf2 significantly downregulated hydrangenol-induced HO-1 expression, indicating that hydrangenol-induced Nrf2 is an upstream regulator of HO-1. Taken together, these data suggest that hydrangenol attenuates NO production and iNOS expression in LPS-stimulated BV2 microglial cells by inhibiting NF-κB activation and by stimulating the Nrf2-mediated HO-1 signaling pathway. Therefore, hydrangenol is a promising therapeutic agent for treatment of LPS-mediated inflammatory diseases. PMID:27032067

  7. Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron.

    PubMed

    Suttner, D M; Dennery, P A

    1999-10-01

    It is often postulated that the cytoprotective nature of heme oxygenase (HO-1) explains the inducible nature of this enzyme. However, the mechanisms by which protection occurs are not verified by systematic evaluation of the physiological effects of HO. To explain how induction of HO-1 results in protection against oxygen toxicity, hamster fibroblasts (HA-1) were stably transfected with a tetracycline response plasmid containing the full-length rat HO-1 cDNA construct to allow for regulation of gene expression by varying concentrations of doxycycline (Dox). Transfected cells were exposed to hyperoxia (95% O(2)/5% CO2) for 24 h and several markers of oxidative injury were measured. With varying concentrations of Dox, HO activity was regulated between 3- and 17-fold. Despite cytoprotection with low (less than fivefold) HO activity, high levels of HO-1 expression (greater than 15-fold) were associated with significant oxygen cytotoxicity. Levels of non-heme reactive iron correlated with cellular injury in hyperoxia whereas lower levels of heme were associated with cytoprotection. Cellular levels of cyclic GMP and bilirubin were not significantly altered by modification of HO activity, precluding a substantial role for activation of guanylate cyclase by carbon monoxide or for accumulation of bile pigments in the physiological consequences of HO-1 overexpression. Inhibition of HO activity or chelation of cellular iron prior to hyperoxic exposure decreased reactive iron levels in the samples and significantly reduced oxygen toxicity. We conclude that there is a beneficial threshold of HO-1 overexpression related to the accumulation of reactive iron released in the degradation of heme. Therefore, despite the ready induction of HO-1 in oxidant stress, accumulation of reactive iron formed makes it unlikely that exaggerated expression of HO-1 is a cytoprotective response. PMID:10506583

  8. GEC-targeted HO-1 expression reduces proteinuria in glomerular immune injury.

    PubMed

    Duann, Pu; Lianos, Elias A

    2009-09-01

    Induction of heme oxygenase (HO)-1 is a key defense mechanism against oxidative stress. Compared with tubules, glomeruli are refractory to HO-1 upregulation in response to injury. This can be a disadvantage as it may be associated with insufficient production of cytoprotective heme-degradation metabolites. We, therefore, explored whether 1) targeted HO-1 expression can be achieved in glomeruli without altering their physiological integrity and 2) this expression reduces proteinuria in immune injury induced by an anti-glomerular basement membrane (GBM) antibody (Ab). We employed a 4.125-kb fragment of a mouse nephrin promoter downstream to which a FLAG-tagged hHO-1 cDNA sequence was inserted and subsequently generated transgenic mice from the FVB/N parental strain. There was a 16-fold higher transgene expression in the kidney than nonspecific background (liver) while the transprotein immunolocalized in glomerular epithelial cells (GEC). There was no change in urinary protein excretion, indicating that GEC-targeted HO-1 expression had no effect on glomerular protein permeability. Urinary protein excretion in transgenic mice with anti-GBM Ab injury (days 3 and 6) was significantly lower compared with wild-type controls. There was no significant change in renal expression levels of profibrotic (TGF-beta1) or anti-inflammatory (IL-10) cytokines in transgenic mice with anti-GBM Ab injury. These observations indicate that GEC-targeted HO-1 expression does not alter glomerular physiological integrity and reduces proteinuria in glomerular immune injury. PMID:19587144

  9. Higenamine promotes M2 macrophage activation and reduces Hmgb1 production through HO-1 induction in a murine model of spinal cord injury.

    PubMed

    Zhang, Zhenyu; Li, Mingchao; Wang, Yan; Wu, Jian; Li, Jiaping

    2014-12-01

    Spinal cord injury (SCI) is considered to be primarily associated with loss of motor function and leads to the activation of diverse cellular mechanisms in the central nervous system to attempt to repair the damaged spinal cord tissue. Higenamine (HG) (1-[(4-hydroxyphenyl) methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol), an active ingredient of Aconiti Lateralis Radix Praeparata, has been traditionally used as a heart stimulant and anti-inflammatory agent in oriental countries. However, the function and related mechanism of HG on SCI have never been investigated. In our current study, HG treatment displayed increased myelin sparring and enhanced spinal cord repair process. The numbers of CD4(+) T cells, CD8(+) T cells, Ly6G(+) neutrophils and CD11b(+) macrophages were all significantly lower in the HG-treated group than that in the control group after SCI. HG administration increased the expression of IL-4 and IL-10 and promoted M2 macrophage activation. Significantly reduced Hmgb1 expression was also observed in HG-treated mice with SCI. Furthermore, HG treatment promoted HO-1 production. The increased number of M2 macrophages, decreased expression of Hmgb1 and promoted locomotor recovery induced by HG were all reversed with additional HO-1 inhibitor treatment. In conclusion, HG promotes M2 macrophage activation and reduces Hmgb1 expression dependent on HO-1 induction and then promotes locomotor function after SCI. PMID:25445960

  10. 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

  11. Nrf2-Mediated HO-1 Induction Coupled with the ERK Signaling Pathway Contributes to Indirect Antioxidant Capacity of Caffeic Acid Phenethyl Ester in HepG2 Cells

    PubMed Central

    Kim, Jin-Kyoung; Jang, Hae-Dong

    2014-01-01

    The objective of this study is to investigate the contributing effect of the nuclear transcription factor-erythroid 2-related factor 2 (Nrf2)-mediated signaling pathway on the indirect antioxidant capacity of caffeic acid phenethyl ester (CAPE) against oxidative stress in HepG2 cells. The result of an antioxidant response element (ARE)-luciferase assay showed that CAPE stimulated ARE promoter activity resulting in increased transcriptional and translational activities of heme oxygenase-1 (HO-1). In addition, CAPE treatment enhanced Nrf2 accumulation in the nucleus and the post-translational phosphorylation level of extracellular signal-regulated kinase (ERK) among several protein kinases tested. Treatment with ERK inhibitor U126 completely suppressed CAPE-induced ERK phosphorylation and HO-1 expression, but it only partly inhibited CAPE-induced Nrf2 accumulation and ARE promoter. Using the 2',7'-dichlorofluorescein-diacetate (DCFH-DA) method, the cellular antioxidant capacity of CAPE against 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH)- or H2O2-induced oxidative stress also was shown to be partially suppressed by the ERK inhibitor. From the overall results it is proposed that the indirect antioxidant activity of CAPE against oxidative stress in HepG2 cells is partially attributed to induction of HO-1, which is regulated by Kelch-like erythroid-cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1)-independent Nrf2 activation relying on post-translational phosphorylation of ERK. PMID:25007817

  12. Butylated Hydroxyanisole Stimulates Heme Oxygenase-1 Gene Expression and Inhibits Neointima Formation in Rat Arteries

    PubMed Central

    Liu, Xiao-ming; Azam, Mohammed A.; Peyton, Kelly J.; Ensenat, Diana; Keswani, Amit N.; Wang, Hong; Durante, William

    2007-01-01

    Objective Butylated hydroxyanisole (BHA) is a synthetic phenolic compound that is a potent inducer of phase II genes. Since heme oxygenase-1 (HO-1) is a vasoprotective protein that is upregulated by phase II inducers, the present study examined the effects of BHA on HO-1 gene expression and vascular smooth muscle cell proliferation. Methods The regulation of HO-1 gene expression and vascular cell growth by BHA was studied in cultured rat aortic smooth muscle cells and in balloon injured rat carotid arteries. Results Treatment of cultured smooth muscle cells with BHA stimulated the expression of HO-1 protein, mRNA and promoter activity in a time- and concentration-dependent manner. BHA-mediated HO-1 expression was dependent on the activation of NF-E2-related factor-2 by p38 mitogen-activated protein kinase. BHA also inhibited cell cycle progression and DNA synthesis in a HO-1-dependent manner. In addition, the local perivascular delivery of BHA immediately after arterial injury of rat carotid arteries induced HO-1 protein expression and markedly attenuated neointima formation. Conclusions These studies demonstrate that BHA stimulates HO-1 gene expression in vascular smooth muscle cells, and that the induction of HO-1 contributes to the antiproliferative actions of this phenolic antioxidant. BHA represents a potentially novel therapeutic agent in treating or preventing vasculoproliferative disease. PMID:17320844

  13. 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

  14. 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

  15. 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.

  16. 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

  17. 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

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

    PubMed

    Jeong, Yun Hee; Oh, You-Chang; Cho, Won-Kyung; Yim, Nam-Hui; Ma, Jin Yeul

    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

  19. Magnetic properties of (Ho 1-cGd c) Co 2 compounds

    NASA Astrophysics Data System (ADS)

    Tari, A.; Keith, V.; Hwang, J. S.

    1994-02-01

    E.S.R., magnetisation and susceptibility measurements have been carried out on the series (Ho 1-cGd c)Co 2. In compounds with c≤ 0.40 we find evidence of spin reorientation. In the three most dilute compounds a g-value of about four is obtained which increases with increasing Gd content.

  20. 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

  1. Mechanisms of HO-1 mediated attenuation of renal immune injury: a gene profiling study.

    PubMed

    Duann, Pu; Lianos, Elias A

    2011-10-01

    Using a mouse model of immune injury directed against the renal glomerular vasculature and resembling human forms of glomerulonephritis (GN), we assessed the effect of targeted expression of the cytoprotective enzyme heme oxygenase (HO)-1. A human (h) HO-1 complementary DNAN (cDNA) sequence was targeted to glomerular epithelial cells (GECs) using a GEC-specific murine nephrin promoter. Injury by administration of antibody against the glomerular basement membrane (anti-GBM) to transgenic (TG) mice with GEC-targeted hHO-1 was attenuated compared with wild-type (WT) controls. To explore changes in the expression of genes that could mediate this salutary effect, we performed gene expression profiling using a microarray analysis of RNA isolated from the renal cortex of WT or TG mice with or without anti-GBM antibody-induced injury. Significant increases in expression were detected in 9 major histocompatibility complex (MHC)-class II genes, 2 interferon-γ (IFN-γ)-inducible guanosine triphosphate (GTP)ases, and 3 genes of the ubiquitin-proteasome system. The increase in MHC-class II and proteasome gene expression in TG mice with injury was validated by real-time polymerase chain reaction (PCR) or Western blot analysis. The observations point to novel mechanisms underlying the cytoprotective effect of HO-1 in renal immune injury. PMID:21925121

  2. Bone-marrow-derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats.

    PubMed

    Zhou, Jing; Jiang, Liyan; Long, Xuan; Fu, Cuiping; Wang, Xiangdong; Wu, Xiaodan; Liu, Zilong; Zhu, Fen; Shi, Jindong; Li, Shanqun

    2016-09-01

    Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP(+) ) or EGFP(-) BMSCs or 15d-PGJ2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-α and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of p-p65 and increased the levels of interleukin-10 and 15d-PGJ2 and the expression of peroxisome proliferator-activated receptor (PPAR)-γ in the lung tissue in CASP-induced rats. Tumour necrosis factor-α stimulated BMSCs to secrete 15d-PGJ2 . A tracking experiment showed that EGFP(+) BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ2 activation of the PPAR-γ receptor, reducing the production of

  3. In vitro evaluation of mitochondrial-chloroplast subcellular localization of heme oxygenase1 (HO1) in Glycine max.

    PubMed

    Dixit, Shubham; Verma, Khushbu; Shekhawat, Gyan Singh

    2014-05-01

    Heme oxygenase1 (HO1) catalyzes the degradation of heme in to biliverdin, carbon monoxide, and ferrous ions. Its role in higher plants has been found as an antioxidant and precursor of phytochrome synthesis. The present study focuses on subcellular localization of HO1 in leaves of soybean has been investigated. Most activity appeared to be located within chloroplast due to its role in phytochrome synthesis but mitochondria also share its localization. Mitochondrial location of HO1 might be on its inner membranous space due to its role in the synthesis of electron donor species which facilitates HO1 catalyzed reaction. Study reports the co-localization of HO1 in both chloroplast and mitochondria. PMID:24158377

  4. 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

    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

  5. 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

  6. Heme Oxygenase-1 (HO-1) Expression in Prostate Cancer Cells Modulates the Oxidative Response in Bone Cells

    PubMed Central

    Ferrando, Mercedes; Wan, Xinhai; Meiss, Roberto; Yang, Jun; De Siervi, Adriana; Navone, Nora; Vazquez, Elba

    2013-01-01

    Prostate cancer (PCa) is a leading cause of death among males. It is currently estimated that inflammatory responses are linked to 15-20% of all deaths from cancer worldwide. PCa is dominated by complications arising from metastasis to the bone where the tumor cells interact with the bone microenvironment impairing the balance between bone formation and degradation. However, the molecular nature of this interaction is not completely understood. Heme oxygenase-1 (HO-1) counteracts oxidative damage and inflammation. Previous studies from our laboratory showed that HO-1 is implicated in PCa, demonstrating that endogenous HO-1 inhibits bone derived-prostate cancer cells proliferation, invasion and migration and decreases tumor growth and angiogenesis in vivo. The aim of this work was to analyze the impact of HO-1 modulated PCa cells on osteoblasts proliferation in vitro and on bone remodeling in vivo. Using a co-culture system of PC3 cells with primary mice osteoblasts (PMOs), we demonstrated that HO-1 pharmacological induction (hemin treatment) abrogated the diminution of PMOs proliferation induced by PCa cells and decreased the expression of osteoclast-modulating factors in osteoblasts. No changes were detected in the expression of genes involved in osteoblasts differentiation. However, co-culture of hemin pre-treated PC3 cells (PC3 Hem) with PMOs provoked an oxidative status and activated FoxO signaling in osteoblasts. The percentage of active osteoblasts positive for HO-1 increased in calvarias explants co-cultured with PC3 Hem cells. Nuclear HO-1 expression was detected in tumors generated by in vivo bone injection of HO-1 stable transfected PC3 (PC3HO-1) cells in the femur of SCID mice. These results suggest that HO-1 has the potential to modify the bone microenvironment impacting on PCa bone metastasis. PMID:24224047

  7. Silencing HO-1 sensitizes SKM-1 cells to apoptosis induced by low concentration 5-azacytidine through enhancing p16 demethylation.

    PubMed

    Wang, Ping; Ma, Dan; Wang, Jishi; Fang, Qin; Gao, Rui; Wu, Weibing; Lu, Tangsheng; Cao, Lu

    2015-03-01

    Heme oxygenase-1 was reported previously as a resistance target on acute myelocytic leukemia (AML). We found that HO-1 was resistant to 5-azacytidine (AZA) treatment of myelodysplastic syndrome (MDS), and explored further the relative mechanisms. Patient bone marrow mononuclear cells (n=48) diagnosed as different levels of MDS were collected. Cell growth was evaluated by MTT assay; cell cycle and apoptosis were detected by flow cytometry; mRNA expression was assessed by real-time PCR, protein expression was analyzed through western blotting. Methylation was assessed by MSP. The survival time, and weight of mice were recorded. HO-1 overexpression was observed in SKM-1 cells after AZA treatment comparing to other cell lines. The HO-1 expression in MDS patients with high-risk was higher than in low-risk patients. After HO-1 was silenced by lentivirus-mediated siRNA, the proliferation of SKM-1 cells was effectively inhibited by low concentration AZA, and the cell cycle was arrested in the G0/G1 phase. Upregulation of p16 and changing of p16-relative cell cycle protein was observed after silencing HO-1 in AZA treated SKM-1 cells. In addition, DNMT1 was downregulated following the decrease of HO-1 expression. In vivo, silencing HO-1 inhibited SKM-1 cell growth induced by AZA in a NOD/SCID mouse model. Silencing HO-1 sensitized SKM-1 cells toward AZA, which may be attributed to the influence of HO-1 on AZA-induced p16 demethylation. HO-1 may be one of the targets that enhance the therapeutic effects of AZA on MDS malignant transformation inspiring new treatment methods for high-risk and very high-risk MDS patients in clinical practice. PMID:25585641

  8. Protein assay for heme oxygenase-1 (HO-1) induced by chemicals in HepG2 cells.

    PubMed

    Miyamoto, Yohei; Ohshida, Keiyu; Sasago, Kaori

    2009-12-01

    Levels of heme oxygenase-1 (HO-1), a stress response protein, were measured to examine oxidative stress induced by several chemicals in HepG2 cells with and without S9mix using an ELISA. CdCl(2), heme, and diclofenac sodium salt (diclofenac) were used as inducers of HO-1. Acetaminophen (AAP) and cyclophosphamide (CP) were used as oxidative stress inducers. Stannic mesoporphyrin (SnMP) was used as an inhibitor of HO activity. Cytotoxicity was determined, and HO-1 levels were measured in HepG2 cells exposed to chemicals other than CP with non-metabolic activation without S9mix, and to diclofenac, AAP and CP with metabolic activation with S9mix. HO-1 levels were increased by CdCl(2) (7.5 microM), heme (10, 100 microM), and stannic mesoporphyrin (SnMP) (10 microM), but were not changed by AAP, and were decreased by diclofenac. HO-1 levels were increased by diclofenac (300 microM), and CP (36 microM), but were unaffected by AAP because of low sensitivity in HepG2 cells. The induction of HO-1 expression was first observed in cultured HepG2 cells treated with CP under conditions involving metabolic activation. These results showed the measurement of HO-1 protein levels in this system is useful when assessing oxidative stress as a tool for detecting drug toxicity. PMID:19952508

  9. Increased HO-1 Levels Ameliorate Fatty Liver Development Through a Reduction of Heme and Recruitment of FGF21

    PubMed Central

    Hinds, Terry D.; Sodhi, Komal; Meadows, Charles; Fedorova, Larisa; Puri, Nitin; Kim, Dong Hyun; Peterson, Stephen J.; Shapiro, Joseph; Abraham, Nader G.; Kappas, Attallah

    2013-01-01

    Objective Obese leptin deficient (ob/ob) mice are a model of adiposity that displays increased levels of fat, glucose and liver lipids. Our hypothesis is that HO-1 overexpression ameliorates fatty liver development. Design and Methods Obese mice were administered cobalt protoporphyrin (CoPP) and stannic mesoporphyrin (SnMP) for 6 weeks. Heme, HO-1, HO activity, PGC1α, FGF21, glycogen content and lipogenesis were assessed. Results CoPP administration increased hepatic HO-1 protein levels and HO activity, decreased hepatic heme, body weight gain, glucose levels and resulted in decreased steatosis. Increased levels of HO-1 produced a decrease in lipid droplet size, FAS levels involving recruitment of FGF21, PPARα and Glut 1. These beneficial effects were reversed by inhibition of HO activity. Conclusion Increased levels of HO-1 and HO activity reduced the levels of obesity by reducing hepatic heme and lipid accumulation. These changes were manifested by decreases in cellular heme, increases in FGF21, glycogen content and fatty liver. The beneficial effect of HO-1 induction results from an increase in PPARα and FGF21 levels and a decrease in PGC1α, levels they were reversed by SnMP. Low levels of HO-1 and HO activity are responsible for fatty liver. PMID:23839791

  10. 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

  11. 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.

  12. Delayed cutaneous wound closure in HO-2 deficient mice despite normal HO-1 expression

    PubMed Central

    Lundvig, Ditte M S; Scharstuhl, Alwin; Cremers, Niels A J; Pennings, Sebastiaan W C; te Paske, Jeroen; van Rheden, René; van Run-van Breda, Coby; Regan, Raymond F; Russel, Frans G M; Carels, Carine E; Maltha, Jaap C; Wagener, Frank A D T G

    2014-01-01

    Impaired wound healing can lead to scarring, and aesthetical and functional problems. The cytoprotective haem oxygenase (HO) enzymes degrade haem into iron, biliverdin and carbon monoxide. HO-1 deficient mice suffer from chronic inflammatory stress and delayed cutaneous wound healing, while corneal wound healing in HO-2 deficient mice is impaired with exorbitant inflammation and absence of HO-1 expression. This study addresses the role of HO-2 in cutaneous excisional wound healing using HO-2 knockout (KO) mice. Here, we show that HO-2 deficiency also delays cutaneous wound closure compared to WT controls. In addition, we detected reduced collagen deposition and vessel density in the wounds of HO-2 KO mice compared to WT controls. Surprisingly, wound closure in HO-2 KO mice was accompanied by an inflammatory response comparable to WT mice. HO-1 induction in HO-2 deficient skin was also similar to WT controls and may explain this protection against exaggerated cutaneous inflammation but not the delayed wound closure. Proliferation and myofibroblast differentiation were similar in both two genotypes. Next, we screened for candidate genes to explain the observed delayed wound closure, and detected delayed gene and protein expression profiles of the chemokine (C-X-C) ligand-11 (CXCL-11) in wounds of HO-2 KO mice. Abnormal regulation of CXCL-11 has been linked to delayed wound healing and disturbed angiogenesis. However, whether aberrant CXCL-11 expression in HO-2 KO mice is caused by or is causing delayed wound healing needs to be further investigated. PMID:25224969

  13. Transport properties of Ho1- x Lu x B12 solid solutions

    NASA Astrophysics Data System (ADS)

    Gabáni, S.; Bat'ko, I.; Bat'ková, M.; Flachbart, K.; Gaz̆o, E.; Pristás̆, G.; Takác̆ová, I.; Bogach, A. V.; Sluchanko, N. E.; Shitsevalova, N. Yu.

    2013-05-01

    Our studies of Ho1- x Lu x B12 solid solutions have shown that the temperature of antiferromagnetic (AF) order in geometrically frustrated system of HoB12 ( T N = 7.4 K) is linearly suppressed to zero temperature, i.e. T N → 0, as lutetium concentration increases to x→ x c ≈ 0.9. In this contribution, we present original results of electrical resistivity measurements on Ho1- x Lu x B12 single crystalline samples with x = 0, 0.2, 0.5, 0.7, 0.9, 1 in the temperature range 0.06-300 K and in magnetic fields ( B) up to 8 T. Complex B vs T N phase diagrams were received from precise temperature ρ( T) and field ρ( B) dependences of resistivity with several AF phases for x ≤ 0.5 pointing to a possibility of quantum critical point at x c ≈ 0.9. The scattering of conduction electrons in the AF phase and in the paramagnetic phase as well as Hall effect results are analyzed and discussed for various concentrations x, when magnetic dilution increases with the increasing content of nonmagnetic Lu ions in the Ho1- x Lu x B12 system.

  14. 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

  15. Polaprezinc (Zinc L-carnosine) is a potent inducer of anti-oxidative stress enzyme, heme oxygenase (HO)-1 - a new mechanism of gastric mucosal protection.

    PubMed

    Ueda, Kazuki; Ueyama, Takashi; Oka, Masashi; Ito, Takao; Tsuruo, Yoshihiro; Ichinose, Masao

    2009-07-01

    Heme oxygenase (HO)-1 is implicated in cytoprotection in various organs. We tested a possibility that polaprezinc (PZ), an anti-ulcer drug, could induce HO-1 in the gastric mucosa. Male 6-week-old Wistar rats were intragastrically administered PZ. Gastric expression of HO-1 was assessed by real time RT-PCR and western blotting, and localization of HO-1 was observed by in situ hybridization and immunohistochemistry. The levels of HO-1 mRNA were increased in a dose-dependent manner. The levels of HO-1 mRNA were increased 4-fold by PZ at the dose of 200 mg/kg at 3 h as compared with control levels. The levels of immunoreactive HO-1 were increased 3-fold at 6 h. Signals for HO-1 mRNA and immunoreactivity were detected strongly in the surface gastric mucosal cells and moderately in the gastric macrophages. Treatment with an HO-1 inhibitor, stannous mesoporphyrin (SnMP) significantly worsened the HCl-induced acute gastric mucosal lesions and increased the apoptosis of mucosal cells. Mucosal lesions were decreased by pretreatment with PZ, while they were increased by co-administration with SnMP. These data indicate for the first time that PZ is an effective inducer of HO-1 in the stomach. PZ-induced HO-1 functions as a part of the mucosal protective effects of PZ. PMID:19542683

  16. 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

  17. Anti-Inflammatory Effects of Melandrii Herba Ethanol Extract via Inhibition of NF-κB and MAPK Signaling Pathways and Induction of HO-1 in RAW 264.7 Cells and Mouse Primary Macrophages.

    PubMed

    Jeong, Yun Hee; Oh, You-Chang; Cho, Won-Kyung; Lee, Bohyoung; Ma, Jin Yeul

    2016-01-01

    Melandrii Herba (MH) is a traditional Asian medicinal herb used to treat breast cancer, anuria, and diseases of lactation. However, its biological properties and molecular mechanisms have not been fully elucidated. The purpose of this study was to investigate the anti-inflammatory activity and underlying molecular mechanism of MH ethanol extract (MHE) on the lipopolysaccharide (LPS)-mediated inflammatory response in macrophages. MHE cytotoxicity was determined using a cell counting kit (CCK) assay. The effects of MHE on the production of NO, inflammatory cytokines, and related proteins and mRNAs were determined using the Griess test, ELISA, Western blotting, and real-time RT-PCR, respectively. In addition, intracellular signaling pathways, such as NF-κB, MAPK, and HO-1, were analyzed using Western blotting. Our results revealed that MHE treatment significantly inhibited the secretion of NO and inflammatory cytokines, including TNF-α, IL-6, and IL-1β in macrophages, at sub-cytotoxic concentrations. Furthermore, MHE treatment inhibited iNOS expression and induced HO-1 expression. Finally, the transcriptional activities of NF-κB and MAPK activation were significantly suppressed by MHE in LPS-stimulated macrophages. The results indicate that MHE exerts anti-inflammatory effects by suppressing inflammatory mediator production via NF-κB and MAPK signaling pathways inhibition and induction of HO-1 expression in macrophages. Therefore, our results suggest the potential value of MHE as an inflammatory therapeutic agent developed from a natural substance. PMID:27338335

  18. Inhibitory Effects of Palmultang on Inflammatory Mediator Production Related to Suppression of NF-κB and MAPK Pathways and Induction of HO-1 Expression in Macrophages

    PubMed Central

    Oh, You-Chang; Jeong, Yun Hee; Cho, Won-Kyung; Gu, Min-Jung; Ma, Jin Yeul

    2014-01-01

    Palmultang (PM) is an herbal decoction that has been used to treat anorexia, anemia, general prostration, and weakness due to chronic illness since medieval times in Korea, China, and Japan. The present study focused on the inhibitory effects of PM on the production of inflammatory factors and on the activation of mechanisms in murine macrophages. PM suppressed the expression of nitric oxide (NO), inflammatory cytokines and inflammatory proteins by inhibiting nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways and by inducing heme oxygenase (HO)-1 expression. Collectively, our results explain the anti-inflammatory effect and inhibitory mechanism of PM in macrophages stimulated with lipopolysaccharide (LPS). PMID:24828204

  19. 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.

  20. 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.

  1. Vanadium(III)-L-cysteine protects cisplatin-induced nephropathy through activation of Nrf2/HO-1 pathway.

    PubMed

    Basu, Abhishek; Singha Roy, Somnath; Bhattacharjee, Arin; Bhuniya, Avishek; Baral, Rathindranath; Biswas, Jaydip; Bhattacharya, Sudin

    2016-01-01

    Cisplatin (CDDP) is one of the first-line anticancer drugs; however, the major limitation of CDDP therapy is development of nephrotoxicity (25-35% cases), whose precise mechanism mainly involves oxidative stress, inflammation and cell death. Therefore, in search of a potential chemoprotectant, an organovanadium complex, viz., vanadium(III)-L-cysteine (VC-III) was evaluated against CDDP-induced nephropathy in mice. CDDP was administered intraperitoneally (5 mg/kg b.w.) and VC-III was given by oral gavage (1 mg/kg b.w.) in concomitant and pre-treatment schedule. The results showed that VC-III administration reduced (p < 0.001) serum creatinine and blood urea nitrogen levels, suggesting amelioration of renal dysfunction. VC-III treatment also significantly (p < 0.001) prevented CDDP-induced generation of reactive oxygen species, reactive nitrogen species, and onset of lipid peroxidation in kidney tissues of the experimental mice. In addition, VC-III also substantially (p < 0.001) restored CDDP-induced depleted activities of the renal antioxidant enzymes such as, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glutathione (reduced) level. Furthermore, histopathological study also confirmed the renoprotective efficacy of VC-III. Western blotting analysis appended by immunohistochemical data showed that VC-III treatment quite effectively reduced the expression of proinflammatory mediators such as, NFκβ, COX-2 and IL-6. VC-III administration also stimulated Nrf2-mediated antioxidant defense system by promotion of downstream antioxidant enzymes, such as HO-1. Moreover, treatment with VC-III significantly (p < 0.001) enhanced CDDP-mediated cytotoxicity in MCF-7 and NCI-H520 human cancer cell lines. Thus, VC-III can serve as a suitable chemoprotectant and increase the therapeutic window of CDDP in cancer patients. PMID:26573721

  2. Totarol prevents neuronal injury in vitro and ameliorates brain ischemic stroke: Potential roles of Akt activation and HO-1 induction.

    PubMed

    Gao, Yuanxue; Xu, Xiaojun; Chang, Sai; Wang, Yunjie; Xu, Yazhou; Ran, Siqi; Huang, Zhangjian; Li, Ping; Li, Jia; Zhang, Luyong; Saavedra, Juan M; Liao, Hong; Pang, Tao

    2015-12-01

    The natural product totarol, a phenolic diterpenoid and a major constituent isolated from the sap of Podocarpus totara, has been reported to have a potent antimicrobial activity. In this study, we determined whether totarol possessed an additional neuroprotective activity in vitro and in vivo. We found that totarol prevented glutamate- and oxygen and glucose deprivation-induced neuronal death in primary rat cerebellar granule neuronal cells and cerebral cortical neurons. Totarol increased Akt and GSK-3β phosphorylation, Nrf2 and heme oxygenase-1 (HO-1) protein expressions and suppressed oxidative stress by increasing GSH and SOD activities. The PI3K/Akt inhibitor LY294002 prevented totarol neuroprotective effect by suppressing the totarol-induced changes in HO-1 expression and the activities of GSH and SOD. The HO-1 inhibitor ZnPPIX also prevented totarol-increased GSH and SOD activities. In a model of acute cerebral ischemic injury in Sprague-Dawley rats, produced by occlusion of the middle cerebral artery for 2h followed by 22 h or 46 h of reperfusion, totarol significantly reduced infarct volume and improved the neurological deficit. In this model, totarol increased HO-1 expression and the activities of GSH and SOD. These observations suggest that totarol may be a novel activator of the Akt/HO-1 pathway protecting against ischemic stroke through reduction of oxidative stress. PMID:26440581

  3. 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

  4. Growth of Acinetobacter sp. strain HO1-N on n-hexadecanol: physiological and ultrastructural characteristics

    SciTech Connect

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

    1985-04-01

    The growth of Acinetobacter sp. strain HO1-N on hexadecanol results in the formation of intracytoplasmic membranes and intracellular rectangular inclusions containing one of the end products of hexadecanol metabolism, hexadecyl palmitate. The intracellular inclusions were purified and characterized as wax ester inclusions consisting of 85.6% hexadecyl palmitate, 4.8% hexadecanol, and 9.6% phospholipid, with a phospholipid-to-protein ratio of 0.42 ..mu..mol of lipid phosphate per mg of inclusion protein. The cellular lipids consisted of 69.8% hexadecyl palmitate, 22.8% phospholipid, 1.9% triglyceride, 4.7% mono- and diglyceride, 0.1% free fatty acid, and 0.8% hexadecanol, as compared with 98% hexadecyl palmitate and 1.9% triglyceride, which comprised the extracellular lipids. Cell-associated hexadecanol represented 0.05% of the exogenously supplied hexadecanol, with hexadecyl palmitate accounting for 14.7% of the total cellular dry weight. Acinetobacter sp. strain HO1-N possesses a mechanism for the intracellular packaging of hexadecyl palmitate in wax ester inclusions, which differ in structure and chemical composition from hydrocarbon inclusions isolated from hexadecane-grown cells.

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

    PubMed Central

    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

  6. Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression

    PubMed Central

    2011-01-01

    Background There is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications. Toll-like receptor 4 (TLR-4) has a regulatory role in the brain's response to stress. Psychological stress may compromise the intestinal barrier, and increased gastrointestinal permeability with translocation of lipopolysaccharide (LPS) from Gram-negative bacteria may play a role in the pathophysiology of major depression. Methods Adult male Sprague-Dawley rats were subjected to chronic mild stress (CMS) or CMS+intestinal antibiotic decontamination (CMS+ATB) protocols. Levels of components of the TLR-4 signaling pathway, of LPS and of different inflammatory, oxidative/nitrosative and anti-inflammatory mediators were measured by RT-PCR, western blot and/or ELISA in brain prefrontal cortex. Behavioral despair was studied using Porsolt's test. Results CMS increased levels of TLR-4 and its co-receptor MD-2 in brain as well as LPS and LPS-binding protein in plasma. In addition, CMS also increased interleukin (IL)-1β, COX-2, PGE2 and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ2 in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ2, however this did not affect depressive-like behavior induced by CMS. Conclusions Our results suggest that LPS from bacterial translocation is responsible, at least in part, for the TLR-4 activation found in brain after CMS, which leads to release of inflammatory mediators in the CNS. The use of Gram-negative antibiotics offers a potential therapeutic approach for the adjuvant treatment of depression. PMID:22053929

  7. Ectopic over-expression of BoHO1, a cabbage heme oxygenase gene, improved salt tolerance in Arabidopsis: A case study on proteomic analysis.

    PubMed

    Duan, Xingliang; Dai, Chen; Li, Zhiwei; Zhou, Heng; Xiao, Tianyu; Xie, Yanjie; Shen, Wenbiao

    2016-06-01

    Plant heme oxygenase (HO) catalyzes the oxygenation of heme to biliverdin, carbon monoxide, and free iron, and is regarded as a stress-responsive protein. Here, a cabbage HO1 gene (named as BoHO1) was isolated and characterized. BoHO1 shares a high degree homology with Arabidopsis AtHO1, and could locate in Arabidopsis chloroplast. BoHO1 mRNA was ubiquitously expressed in cabbage tissues, and was responsive to several stimuli and chemicals. Genetic evidence illustrated that over-expression of BoHO1 in transgenic Arabidopsis plants (35S:BoHO1-1 and 35S:BoHO1-2) significantly alleviated salinity stress-inhibited seedling growth, which were accompanied with the re-establishment of reactive oxygen species and ion homeostasis. Comparative proteomic analysis was subsequently performed. Results revealed that protein abundance related to light reactions was greatly suppressed by NaCl stress in wild-type, whereas was partially recovered in 35S:BoHO1-1. Salinity stress also strongly activated stress-related metabolic processes in wild-type, i.e. carbon and energy metabolism, ammonium detoxification, and protein turnover, and these induced tendencies were more intensive in 35S:BoHO1-1. Particularly, proteins related to glutathione metabolism and ion homeostasis were specifically enriched in NaCl-stressed 35S:BoHO1-1. On the basis of above results, we propose that BoHO1 could activate multiple stress-responsive pathways to help Arabidopsis regain cellular homeostasis, thus presenting enhanced adaptation to salinity stress. PMID:27016873

  8. 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

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

    PubMed

    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

  10. 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

  11. 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

  12. 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.

  13. 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

  14. Magnetic properties of Ho1- x Lu x B12 solid solutions

    NASA Astrophysics Data System (ADS)

    Gabáni, S.; Gaz̆o, E.; Pristás̆, G.; Takác̆ová, I.; Flachbart, K.; Shitsevalova, N.; Siemensmeyer, K.; Sluchanko, N.

    2013-05-01

    Magnetic properties of the geometrically frustrated antiferromagnet HoB12 (with T N = 7.4 K) modified by substitution of magnetic Ho atoms through non-magnetic Lu ones are presented and discussed. In this case, in Ho1- x Lu x B12 solid solutions, both chemical pressure resulting from different Lu3+ and Ho3+ radii and magnetic dilution take place with increasing Lu content ( x) that change properties of the system. The received results show strong indication for the existence of a quantum critical point near x = 0.9, which separates the region of magnetic order (starting with HoB12 for x = 0) and the nonmagnetic region (ending with superconducting LuB12 for x = 1).

  15. Effect of Crystal Fields in Ho1 - xDyxNi2B2 C

    NASA Astrophysics Data System (ADS)

    Lee, W. C.

    2013-03-01

    From the anisotropy and the temperature dependence of magnetic susceptibilities of Ho1 - x Dyx Ni2B2 C system with magnetic field H perpendicular or parallel to c-axis, the crystalline electric field (CEF) effect has been studied and the magnetic exchange interaction constant Jex of rare-earth ions perpendicular to the c-axis estimated for 0 <=x <=1. The crystalline electric field parameter, B02, the first Steven parameter and the most dominant term in this system, are determined from the high-temperature-limit anisotropic Weiss temperatures of the magnetic susceptibilities and there is a broad minimum around x ~ 0.3, where superconducting transition temperature, TC, and Néel temperature, TN, are almost same.

  16. Preconditioning with Ginkgo biloba (EGb 761®) provides neuroprotection through HO1 and CRMP2

    PubMed Central

    Nada, Shadia E.; Shah, Zahoor A.

    2012-01-01

    Ginkgo biloba/EGb 761® (EGb 761) is a popular and standardized natural extract used worldwide for the treatment of many ailments. Although EGb 761 is purported to have a plethora of benefits, here, we were interested to study the neuroprotective properties of EGb 761 and its components and determine whether nuclear factor E2 (Nrf2)/heme oxygenase 1 (HO1) induction of the collapsin response mediator protein 2 (CRMP2) pathway contributes to neuroprotection. Mice were pretreated with EGb 761 or one of its constituents (bilobalide, ginkgolide A, ginkgolide B, and terpene free material [TFM]) for 7 days and then subjected to transient middle cerebral artery occlusion (tMCAO) and 48 h of reperfusion. All components except TFM significantly reduced infarct volumes and neurologic deficits. Next, we examined the antioxidant and neuritogenic properties of EGb 761 in primary neurons. Compared with vehicle-treated cells, pretreatment with EGb 761 significantly enhanced the survival of neurons exposed to tertiary butylhydroperoxide (t-BuOOH), hydrogen peroxide (H2O2), and N-methyl-D-aspartate (NMDA). Bilobalide and ginkgolide A also protected cells against NMDA-induced excitotoxicity. Immunofluorescence and Western blot analysis showed that EGb 761 pretreatment significantly increased the protein expression levels of Nrf2, HO1, GAPDH, β-actin, CRMP2, and histone H3 during t-BuOOH-induced oxidative stress. These findings suggest that EGb 761 not only has antioxidant activity but also neuritogenic potential. Demonstrating such effects for possible drug discovery may prove beneficial in stroke and ischemic brain injury. PMID:22297164

  17. Eicosapentaenoic acid suppression of systemic inflammatory responses and inverse up-regulation of 15-deoxyΔ12,14 Prostaglandin J2 production

    PubMed Central

    Davidson, Jillian; Higgs, Warren; Rotondo, Dino

    2013-01-01

    Background and Purpose Eicosapentaenoic acid (EPA) has been shown to suppress immune cell responses, such as cytokine production and downstream PG production in vitro. Studies in vivo, however, have used EPA as a minor constituent of fish oil with variable results. We investigated the effects of EPA on systemic inflammatory responses as pure EPA has not been evaluated on immune/inflammatory responses in vivo. Experimental Approach Rabbits were administered polyinosinic: polycytidylic acid (poly I:C) i.v. before and after oral treatment with EPA for 42 days (given daily). The responses to IL-1β and TNF-α were also studied. Immediately following administration of poly I:C, body temperature was continuously monitored and blood samples were taken. Plasma levels of IL-1β, PGE2 (PGE2), and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) were measured by enzyme immunoassay. Key Results Following EPA treatment, the fever response to poly I:C was markedly suppressed compared with pretreatment responses. This was accompanied by a parallel reduction in the poly I:C-stimulated elevation in plasma levels of IL-1β and PGE2. Paradoxically, the levels of 15d-PGJ2 were higher following EPA treatment. EPA treatment did not significantly alter the fever response or plasma levels of PGE2 in response to either IL-1β or TNF-α. Conclusion and Implications Oral treatment with EPA can suppress immune/inflammatory responses in vivo via a suppression of upstream cytokine production resulting in a decreased fever response and indirectly reducing circulating levels of PGE2. EPA also enhances the production of the cytoprotective prostanoid 15d-PGJ2 indicating the therapeutic benefit of EPA. PMID:23586396

  18. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism.

    PubMed

    Loboda, Agnieszka; Damulewicz, Milena; Pyza, Elzbieta; Jozkowicz, Alicja; Dulak, Jozef

    2016-09-01

    The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap 'n' Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors. PMID:27100828

  19. Endothelial HO-1 induction by model TG-rich lipoproteins is regulated through a NOX4-Nrf2 pathway.

    PubMed

    Latham Birt, Sally H; Purcell, Robert; Botham, Kathleen M; Wheeler-Jones, Caroline P D

    2016-07-01

    Circulating levels of chylomicron remnants (CMRs) increase postprandially and their composition directly reflects dietary lipid intake. These TG-rich lipoproteins likely contribute to the development of endothelial dysfunction, albeit via unknown mechanisms. Here, we investigated how the FA composition of CMRs influences their actions on human aortic endothelial cells (HAECs) by comparing the effects of model CMRs-artificial TG-rich CMR-like particles (A-CRLPs)-containing TGs extracted from fish, DHA-rich algal, corn, or palm oils. HAECs responded with distinct transcriptional programs according to A-CRLP TG content and oxidation status, with genes involved in antioxidant defense and cytoprotection most prominently affected by n-3 PUFA-containing A-CRLPs. These particles were significantly more efficacious inducers of heme oxygenase-1 (HO-1) than n-6 PUFA corn or saturated FA-rich palm CRLPs. Mechanistically, HO-1 induction by all CRLPs requires NADPH oxidase 4, with PUFA-containing particles additionally dependent upon mitochondrial reactive oxygen species. Activation of both p38 MAPK and PPARβ/δ culminates in increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression/nuclear translocation and HO-1 induction. These studies define new molecular pathways coupling endothelial cell activation by model CMRs with adaptive regulation of Nrf2-dependent HO-1 expression and may represent key mechanisms through which dietary FAs differentially impact progression of endothelial dysfunction. PMID:27185859

  20. Overexpression of HO-1 Protects against TNF-α-Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress

    PubMed Central

    Lee, I-Ta; Luo, Shue-Fen; Lee, Chiang-Wen; Wang, Shyi-Wu; Lin, Chih-Chung; Chang, Chia-Chi; Chen, Yuh-Lien; Chau, Lee-Young; Yang, Chuen-Mao

    2009-01-01

    Oxidative stresses are believed to play an important role in the induction of both cell adhesion molecules and pro-inflammatory cytokines, a key event in a variety of inflammatory processes. The enzyme heme oxygenase-1 (HO-1) functions as an antioxidant and serves to protect against tissue injury. In this study, we report that HO-1 was induced in cultured human tracheal smooth muscle cells after either treatment with a potent inducer of HO-1 activity, cobalt protoporphyrin IX, or infection with a recombinant adenovirus that carries the human HO-1 gene. Overexpression of HO-1 protected against tumor necrosis factor (TNF)-α-mediated airway inflammation via the down-regulation of oxidative stress, adhesion molecules, and interleukin-6 in both cultured human tracheal smooth muscle cells and the airways of mice. In addition, HO-1 overexpression inhibited TNF-α-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47phox translocation, and nuclear factor-κB activation. HO-1 overexpression also attenuated TNF-α-induced oxidative stress, which was abrogated in the presence of both the HO-1 inhibitor, zinc protoporphyrin IX, as well as a carbon monoxide scavenger. In addition, HO-1 overexpression reduced the formation of a TNFR1/c-Src/p47phox complex. These results suggest that HO-1 functions as a suppressor of TNF-α signaling, not only by inhibiting the expression of adhesion molecules and generation of interleukin-6, but also by diminishing intracellular reactive oxygen species production and nuclear factor-κB activation in both cultured human tracheal smooth muscle cells and the airways of mice. PMID:19608869

  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. PMID:24361900

  2. Targeting HO-1 by Epigallocatechin-3-Gallate Reduces Contrast-Induced Renal Injury via Anti-Oxidative Stress and Anti-Inflammation Pathways

    PubMed Central

    Hu, Yunhui; Wu, Xiaoyan; Wang, Yongbin; Zhang, Xiaoqun; Fu, Jinjuan; Zou, Xue; Zhang, Jun; Chen, Xiongwen; Jose, Pedro A.; Lu, Xi; Zeng, Chunyu

    2016-01-01

    Both oxidative stress and inflammation are involved in the pathogenesis of contrast-induced nephropathy (CIN). Epigallocatechin-3-gallate (EGCG), a purified catechin from green tea, has antioxidant and anti-inflammatory effects. However, it is unknown whether or not EGCG is effective in treating CIN. Our present study found that intravenous administration of EGCG, either before or just after the establishment of CIN, had a protective effect, determined by normalization of serum creatinine and blood urea nitrogen levels, improvement in renal histopathological scoring and alleviation of apoptosis, accompanied by decreased oxidative stress and inflammation. Because EGCG is a potent inducer of the antioxidant heme oxygenase-1 (HO-1), we studied HO-1 signaling in CIN. HO-1 levels were increased in CIN; treatment with EGCG further increased HO-1 levels, accompanied by an increase in Nrf2, a regulator of antioxidant proteins. Interestingly, blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) prevented the protective effect of EGCG on CIN. ZnPP also blocked the ability of EGCG to increase the activity of an antioxidant (superoxide dismutase), and decrease markers of oxidative stress (myeloperoxidase and malondialdehyde) and inflammation (myeloperoxidase and IL-1β), indicating that HO-1 is the upstream molecule that regulates the EGCG-mediated protection. To determine further the role of HO-1 on the EGCG-mediated inhibition of inflammation, we studied the effect of EGCG on the NLRP3 inflammasome, an upstream signaling of IL-1β. EGCG down-regulated NLRP3 expression, which was blocked by ZnPP, indicating that HO-1 links EGCG with NLRP3. Therefore, EGCG, via up-regulation of HO-1, protects against CIN by amelioration of oxidative stress and inflammation. PMID:26866373

  3. HO-1 gene overexpression enhances the beneficial effects of superparamagnetic iron oxide labeled bone marrow stromal cells transplantation in swine hearts underwent ischemia/reperfusion: an MRI study.

    PubMed

    Jiang, Yibo; Chen, Lijuan; Tang, Yaoliang; Ma, Genshan; Shen, Chengxing; Qi, Chunmei; Zhu, Qi; Yao, Yuyu; Liu, Naifeng

    2010-05-01

    To determine the effect of intracoronary transfer of superparamagnetic iron oxide (SPIO) labeled heme oxygenase-1 (HO-1) overexpressed bone marrow stromal cells (BMSCs) in a porcine myocardial ischemia/reperfusion model. Cell apoptosis was assayed and supernatant cytokine concentrations were measured in BMSCs that underwent hypoxia/reoxygen in vitro. Female mini-swines that underwent 1 h LAD occlusion followed by 1 h reperfusion were randomly allocated to receive intracoronary saline (control), 1 x 10(7) SPIO-labeled BMSCs transfected with pcDNA3.1-Lacz plasmid (Lacz-BMSCs), pcDNA3.1-human HO-1 (HO-1-BMSCs), pcDNA3.1-hHO-1 pretreated with a HO inhibitor, tin protoporphyrin (SnPP, n = 10 each). MRI and postmortem histological analysis were made at 1 week or 3 months thereafter. Post hypoxia/reoxygen in vitro, apoptosis was significantly reduced, supernatant VEGF significantly increased while TNF-alpha and IL-6 significantly reduced in HO-1-BMSCs group compared with Lacz-BMSCs group (all p < 0.05). Myocardial expression of VEGF was significantly higher in HO-1-BMSCs than in Lacz-BMSCs group at 1 week post transplantation (all p < 0.05). Signal voids induced by the SPIO were detected in the peri-infarction region in all BMSC groups at 1 week but not at 3 months post transplantation and the extent of the hypointense signal was the highest in HO-1-BMSCs group, and histological analysis showed that signal voids represented cardiac macrophages that engulfed the SPIO-labeled BMSCs. Pretreatment with SnPP significantly attenuated the beneficial effects of HO-1-BMSCs. Transplantation of HO-1-overexpressed BMSCs significantly enhanced the beneficial effects of BMSCs on improving cardiac function in this model. PMID:20033189

  4. Alcohol dehydrogenases in Acinetobacter sp. strain HO1-N: role in hexadecanse and hexadecanol metabolism

    SciTech Connect

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

    1985-12-01

    Multiple alcohol dehydrogenases (ADH) were demonstrated in Acinetobacter sp. strain HO1-N. ADH-A and ADH-B were distinguished on the basis of electrophoretic mobility, pyridine nucleotide cofactor requirement, and substrate specificity. ADH-A is a soluble, NAD-linked, inducible ethanol dehydrogenase (EDH). An ethanol-negative mutant (Eth1) was isolated which contained 6.5% of wild-type EDH activity and was deficient in ADH-A. Eth1 exhibited normal growth on hexadecane and hexadecanol. A second ethanol-negative mutant (Eth3) was acetaldehyde dehydrogenase (ALDH) deficient, having 12.5% of wild-type ALDH activity. Eth3 had threefold-higher EDH activity than the wild-type strain. ALDH is a soluble, NAD-linked, ethanol-inducible enzyme. Eth3 exhibited normal growth on hexadecane, hexadecanol, and fatty aldehyde. ADH-B is soluble, constitutive, NADP-linked ADH which was active with medium-chain-length alcohols. Hexadecanol dehydrogenase (HDH), a soluble and membrane-bound, NAD-linked ADH, was induced 5- to 11-fold by growth on hexadecane or hexadecanol. HDH was distinct from ADH-A and ADH-B. NAD-linked HDH appears to possess a functional role in hexadecane and hexadecanol dissimilation.

  5. 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

  6. β-Caryophyllene Attenuates Focal Cerebral Ischemia-Reperfusion Injury by Nrf2/HO-1 Pathway in Rats.

    PubMed

    Lou, Jie; Cao, Guangxiu; Li, Ranran; Liu, Jie; Dong, Zhi; Xu, Lu

    2016-06-01

    This study aimed to identify the effect of β-caryophyllene (BCP) pretreatment and elucidate the Nrf2/HO-1 signaling mechanism after focal cerebral ischemia-reperfusion (I-R) injury in rats. Adult male Sprague-Dawley rats were randomly assigned to the sham-operated group, I-R group and BCP pretreated I-R group. At 24 h after reperfusion, neurological deficits and infarct volume were evaluated. Pathological changes of neuron in hippocampuses were observed by Nissil staining and transmission electron microscopy (TEM). Oxidative stress was assessed by malondialdehyde (MDA) level, lipid peroxidation (LPO), nitric oxide (NO), superoxide dismutase (SOD) and Catalase (CAT) activity. The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were analysed by Western blotting and real-time quantitative polymerase chain reaction (Q-PCR). The protein expression of Bcl-2 and Bax was determined by immunohistochemistry. Apoptotic cells were detected using TUNEL staining. In I-R group, neurological deficit scores, cerebral infarct volume, MDA levels, LPO content, NO level, expression of Bax and TUNEL-positive cells were found to be increased at 24 h after I-R injury, while SOD activity, CAT activity and expression of Bcl-2 were decreased. However, results in the BCP pretreatment groups were reversed. And the protein and mRNA expressions of Nrf2 and HO-1 were significantly up-regulated in the BCP pretreated I-R group. Results of Nissil staining and TEM scan manifested that BCP remarkablely improved neuronal injury after I-R in rats. All the above suggested that BCP pretreatment played a neuroprotective role in cerebral I-R injury, which might be exerted by upregulating the expression of Nrf2 and HO-1 to ameliorate oxidative damage and neuronal apoptosis. PMID:26801169

  7. Heat Shock Proteins in Brain: Role of Hsp70, Hsp 27 and HO-1 (Hsp32) and Their Therapeutic Potential

    PubMed Central

    Sharp, Frank R; Zhan, Xinhua; Liu, DaZhi

    2013-01-01

    Heat shock proteins are induced by heat shock via HSF proteins binding to heat shock elements in their promoters. Hsp70 is massively induced in response to misfolded proteins following cerebral ischemia in all cell types, but is induced mainly in neurons in the ischemic penumbra. Over expression of Hsp70 via transgenes and viruses or systemic administration of Hsp70 fusion proteins that allow it to cross the blood brain barrier protect brain against ischemia in most reported studies. Hsp27 can exist as unphosphorylated large oligomers that prevent misfolded protein aggregates and improve cell survival. P-Hsp27 small oligomers bind specific protein targets to improve survival. In brain Protein Kinase D phosphorylates Hsp27 following ischemia which then binds ASK1 to prevent MKK4/7, JNK, Jun induced apoptosis and decrease infarct volumes following focal cerebral ischemia. Heme oxygenase-1 (HO-1) metabolizes heme to carbon monoxide, ferrous ion and biliverdin. CO activates cGMP to promote vasodilation, and biliverdin is converted to bilirubin which can serve as an anti-oxidant both of which may contribute to the reported protective role of HO-1 in cerebral ischemia and subarachnoid hemorrhage. However, ferrous ion can react with hydrogen peroxide to produce pro-oxidant hydroxyl radicals which may explain the harmful role of HO-1 in intracerebral hemorrhage. Heat shock proteins as a class have great potential as treatments for cerebrovascular disease and have yet to be tested in the clinic. PMID:24323422

  8. Quercetin protects primary human osteoblasts exposed to cigarette smoke through activation of the antioxidative enzymes HO-1 and SOD-1.

    PubMed

    Braun, Karl F; Ehnert, Sabrina; Freude, Thomas; Egaña, José T; Schenck, Thilo L; Buchholz, Arne; Schmitt, Andreas; Siebenlist, Sebastian; Schyschka, Lilianna; Neumaier, Markus; Stöckle, Ulrich; Nussler, Andreas K

    2011-01-01

    Smokers frequently suffer from impaired fracture healing often due to poor bone quality and stability. Cigarette smoking harms bone cells and their homeostasis by increased formation of reactive oxygen species (ROS). The aim of this study was to investigate whether Quercetin, a naturally occurring antioxidant, can protect osteoblasts from the toxic effects of smoking. Human osteoblasts exposed to cigarette smoke medium (CSM) rapidly produced ROS and their viability decreased concentration- and time-dependently. Co-, pre- and postincubation with Quercetin dose-dependently improved their viability. Quercetin increased the expression of the anti-oxidative enzymes heme-oxygenase- (HO-) 1 and superoxide-dismutase- (SOD-) 1. Inhibiting HO-1 activity abolished the protective effect of Quercetin. Our results demonstrate that CSM damages human osteoblasts by accumulation of ROS. Quercetin can diminish this damage by scavenging the radicals and by upregulating the expression of HO-1 and SOD-1. Thus, a dietary supplementation with Quercetin could improve bone matter, stability and even fracture healing in smokers. PMID:22203790

  9. 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. PMID:18376820

  10. 15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Homing of Bone Marrow-Derived Mesenchymal Stem Cells Triggered by Chronic Liver Injury via Redox Pathway

    PubMed Central

    Liu, Xin; Jia, Shuangshuang; Li, Weiyang; Yang, Le; Yang, Lin; Wang, Lin; Li, Liying

    2015-01-01

    It has been reported that bone marrow-derived mesenchymal stem cells (BMSCs) have capacity to migrate to the damaged liver and contribute to fibrogenesis in chronic liver diseases. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARγ), is considered a new inhibitor of cell migration. However, the actions of 15d-PGJ2 on BMSC migration remain unknown. In this study, we investigated the effects of 15d-PGJ2 on the migration of BMSCs using a mouse model of chronic liver fibrosis and primary mouse BMSCs. Our results demonstrated that in vivo, 15d-PGJ2 administration inhibited the homing of BMSCs to injured liver by flow cytometric analysis and, in vitro, 15d-PGJ2 suppressed primary BMSC migration in a dose-dependent manner determined by Boyden chamber assay. Furthermore, the repressive effect of 15d-PGJ2 was blocked by reactive oxygen species (ROS) inhibitor, but not PPARγ antagonist, and action of 15d-PGJ2 was not reproduced by PPARγ synthetic ligands. In addition, 15d-PGJ2 triggered a significant ROS production and cytoskeletal remodeling in BMSCs. In conclusion, our results suggest that 15d-PGJ2 plays a crucial role in homing of BMSCs to the injured liver dependent on ROS production, independently of PPARγ, which may represent a new strategy in the treatment of liver fibrosis. PMID:26457076

  11. Anti-angiogenic properties of coenzyme Q0 through downregulation of MMP-9/NF-κB and upregulation of HO-1 signaling in TNF-α-activated human endothelial cells.

    PubMed

    Yang, Hsin-Ling; Korivi, Mallikarjuna; Lin, Ming-Wei; Chen, Ssu-Ching; Chou, Chih-Wei; Hseu, You-Cheng

    2015-11-01

    Various coenzyme Q (CoQ) analogs have been reported as anti-inflammatory and antioxidant substances. However, coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has not been well studied for its pharmacological efficacies, and its response to cytokine stimulation remains unclear. Therefore, we investigated the potential anti-angiogenic properties of CoQ0 in human endothelial (EA.hy 926) cells against tumor necrosis factor-α (TNF-α) stimulation. We found that the non-cytotoxic concentrations of CoQ0 (2.5-10μM) significantly suppressed the TNF-α-induced migration/invasion and tube formation abilities of endothelial cells. CoQ0 suppressed TNF-α-induced activity and protein expressions of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) followed by an abridged adhesion of U937 leukocytes to endothelial cells. CoQ0 treatment remarkably downregulated TNF-α-induced nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) possibly through suppressed I-κBα degradation. Furthermore, CoQ0 triggered the expressions of heme oxygenase-1 (HO-1) and γ-glutamylcysteine synthetase (γ-GCLC), followed by an increased nuclear accumulation of NF-E2 related factor-2 (Nrf2)/antioxidant response element (ARE) activity. In agreement with these, intracellular glutathione levels were significantly increased in CoQ0 treated cells. More interestingly, knockdown of HO-1 gene by specific shRNA showed diminished anti-angiogenic effects of CoQ0 against TNF-α-induced invasion, tube formation and adhesion of leukocyte to endothelial cells. Our findings reveal that CoQ0 protective effects against cytokine-stimulation are mediated through the suppression of MMP-9/NF-κB and/or activation of HO-1 signaling cascades. This novel finding emphasizes the pharmacological efficacies of CoQ0 to treat inflammation and angiogenesis. PMID:26348871

  12. SOURCE APPORTIONMENT OF FINE PARTICULATE MATTER IN THE U.S. AND ASSOCIATIONS WITH LUNG INFLAMMATORY MARKERS IL -8, COX -2 AND HO -1

    EPA Science Inventory

    Associations are well established between particulate matter (PM) and increased human mortality and morbidity. The association between fine PM sources and lung inflammatory markers IL-8, COX-2, and HO-1 was evaluated in this study.

  13. 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

  14. 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

  15. The antioxidative potential of farrerol occurs via the activation of Nrf2 mediated HO-1 signaling in RAW 264.7 cells.

    PubMed

    Ci, Xinxin; Lv, Hongming; Wang, Lidong; Wang, Xiaosong; Peng, Liping; Qin, F Xiao-Feng; Cheng, Genhong

    2015-09-01

    Farrerol, (S)-2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-6,8-dimethyl-4-benzopyrone, isolated from rhododendron, has been shown to have antioxidative potential, but the molecular mechanism underlying this activity remains unclear. The inducible expression of heme oxygenase-1 (HO-1), a potent antioxidative and cytoprotective enzyme, is known to play an important role in cytoprotection in a variety of pathological models. In this study, we evaluated the antioxidative potential of farrerol against oxidative damage and investigated its antioxidative mechanism in RAW 264.7 cells. The molecular mechanism underlying the cytoprotective function of farrerol was determined by analyzing intracellular signaling pathways, transcriptional activation and the inhibitory effect of HO-1 on ROS production. Farrerol induced antioxidant enzymes mRNA expression, HO-1 protein expression and nuclear translocation of NF-E2-related factor 2 in RAW 264.7 macrophage cells. Farrerol down-regulated the expression of the Keap1 protein and the thiol reducing agents attenuated farrerol-induced HO-1 expression. Further investigation utilizing Western blotting and specific inhibitors of Akt, p38, JNK and ERK demonstrated that Akt, p38, and ERK axis of signaling pathway mediates HO-1 expression. Moreover, tert-butyl hydroperoxide (t-BHP)-induced oxidative damage was ameliorated by farrerol treatment in a dose-dependent manner, which was abolished by Akt, p38, ERK and HO-1 inhibitors (Snpp). It is hence likely that farrerol inactivated KEAP-1 or activated the Akt, p38 and ERK to facilitate the release of Nrf2 from Keap1 and subsequent reduced the intracellular production of reactive oxygen species via the induction of HO-1 expression. These results support the central role of HO-1 in the cytoprotective effect of farrerol. PMID:26111761

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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

  2. Penehyclidine Hydrochloride Pretreatment Ameliorates Rhabdomyolysis-Induced AKI by Activating the Nrf2/HO-1 Pathway and Allevi-ating Endoplasmic Reticulum Stress in Rats

    PubMed Central

    Zhao, Wei; Huang, XuDong; Zhang, LiXia; Yang, XinJun; Wang, LiHui; Chen, YunShuang; Wang, JingHua; Wu, GuangLi

    2016-01-01

    Acute kidney injury (AKI) is one of the most severe complications of rhabdomyolysis (RM). The underlying mechanisms and potential preventions need to be investigated. Penehyclidine hydrochloride (PHC) was reported to ameliorate renal ischemia-reperfusion injury, but the effect of PHC on RM-reduced AKI is unknown. In this study, we established a rat model of RM-induced AKI using an intramuscular glycerol injection in the hind limbs. Rats were pretreated with PHC before the glycerol injection, and the heme oxygenase-1 (HO-1) inhibitor ZnPP was introduced to evaluate the effect of HO-1 on RM-induced AKI. PHC pretreatment ameliorated the pathological renal injury and renal dysfunction, and decreased the renal apoptosis rate in RM-induced AKI. PHC significantly up-regulated HO-1 expression, increased HO-1 enzymatic activity and decreased the accumulation of myoglobin in renal tissues. This effect was partly inhibited by ZnPP. PHC pretreatment also effectively up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) and down-regulated glucose regulated protein 78 (GRP78) and caspase-12 at both the gene and protein levels. These results suggest that the protective effects of PHC pretreatment on RM-induced AKI occur at least in part through activating the Nrf2/HO-1 pathway and alleviating endoplasmic reticulum stress (ERS) in rat renal tissues. PMID:26987113

  3. 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

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

    PubMed

    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

  5. 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

  6. 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

  7. 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

  8. 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

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

    PubMed

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

    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

  10. Withaferin A induces heme oxygenase (HO-1) expression in endothelial cells via activation of the Keap1/Nrf2 pathway.

    PubMed

    Heyninck, Karen; Sabbe, Linde; Chirumamilla, Chandra Sekhar; Szarc Vel Szic, Katarzyna; Vander Veken, Pieter; Lemmens, Kristien J A; Lahtela-Kakkonen, Maija; Naulaerts, Stefan; Op de Beeck, Ken; Laukens, Kris; Van Camp, Guy; Weseler, Antje R; Bast, Aalt; Haenen, Guido R M M; Haegeman, Guy; Vanden Berghe, Wim

    2016-06-01

    Withaferin A (WA), a natural phytochemical derived from the plant Withania somnifera, is a well-studied bioactive compound exerting a broad spectrum of health promoting effects. To gain better insight in the potential therapeutic capacity of WA, we evaluated the transcriptional effects of WA on primary human umbilical vein endothelial cells (HUVECs) and an endothelial cell line (EA.hy926). RNA microarray analysis of WA treated HUVEC cells demonstrated increased expression of the antioxidant gene heme oxygenase (HO-1). Transcriptional regulation of this gene is strongly dependent on the transcription factor NF-E2-related factor 2 (Nrf2), which senses chemical changes in the cell and coordinates transcriptional responses to maintain chemical homeostasis via expression of antioxidant genes and cytoprotective Phase II detoxifying enzymes. Under normal conditions, Nrf2 is kept in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), an adaptor protein controlling the half-life of Nrf2 via constant proteasomal degradation. In this study we demonstrate that WA time- and concentration-dependently induces HO-1 expression in endothelial cells via upregulation and increased nuclear translocation of Nrf2. According to the crucial negative regulatory role of Keap1 in Nrf2 expression levels, a direct interaction of WA with Keap1 could be demonstrated. In vitro and in silico evaluations suggest that specific cysteine residues in Keap1 might be involved in the interaction with WA. PMID:27045103

  11. 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

  12. 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.

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

    PubMed Central

    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. MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice.

    PubMed

    Belcher, John D; Young, Mark; Chen, Chunsheng; Nguyen, Julia; Burhop, Kenneth; Tran, Phuc; Vercellotti, Gregory M

    2013-10-10

    Transgenic sickle mice expressing β(S) hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-ĸB and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of heme oxygenase-1 (HO-1) or administration of its products, carbon monoxide (CO) or biliverdin, inhibits microvascular stasis in sickle mice. Infusion of human hemoglobin conjugated with polyethylene glycol and saturated with CO (MP4CO) markedly induced hepatic HO-1 activity and inhibited NF-ĸB activation and H/R-induced microvascular stasis in sickle mice. These effects were mediated by CO; saline or MP4 saturated with O2 (MP4OX) had little to no effect on H/R-induced stasis, though unmodified oxyhemoglobin exacerbated stasis. The HO-1 inhibitor, tin protoporphyrin, blocked MP4CO protection, consistent with HO-1 involvement in the protection afforded by MP4CO. MP4CO also induced nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), an important transcriptional regulator of HO-1 and other antioxidant genes. In a heterozygous (hemoglobin-AS) sickle mouse model, intravenous hemin induced cardiovascular collapse and mortality within 120 minutes, which was significantly reduced by MP4CO, but not MP4OX. These data demonstrate that MP4CO induces cytoprotective Nrf2 and HO-1 and decreases NF-ĸB activation, microvascular stasis, and mortality in transgenic sickle mouse models. PMID:23908468

  15. 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.

  16. Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet

    PubMed Central

    Sodhi, Komal; Puri, Nitin; Favero, Gaia; Stevens, Sarah; Meadows, Charles; Abraham, Nader G.; Rezzani, Rita; Ansinelli, Hayden; Lebovics, Edward; Shapiro, Joseph I.

    2015-01-01

    Background Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox. Hypothesis We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction. Methods and Results We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP. Conclusion Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the

  17. 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

  18. High-fat diet exacerbates renal dysfunction in SHR: reversal by induction of HO-1-adiponectin axis.

    PubMed

    Cao, Jian; Inoue, Kazuyoshi; Sodhi, Komal; Puri, Nitin; Peterson, Stephen J; Rezzani, Rita; Abraham, Nader G

    2012-05-01

    High-dietary fat intake is a major risk factor for development of metabolic and cardiovascular-renal dysfunction including obesity, coronary artery disease, hypertension, and chronic renal failure. We examined the effect of a high-fat diet on renal function and morphology in spontaneously hypertensive rats (SHR), a phenotype designed to mimic metabolic syndrome. High-fat diet induced increase (P < 0.05) in blood pressure, body weight, and renal lipid deposition in these rats. This increase in body weight was accompanied by elevations (P < 0.05) of blood glucose and low-density lipoprotein (LDL) levels, a decrease (P < 0.05) in adiponectin and increases (P < 0.05) in plasma monocyte chemotactic protein-1 (MCP-1) along with renal macrophage infiltration. These pathophysiological perturbations were attenuated (P < 0.05) by heme oxygenase-1 (HO-1) induction by treatment with cobalt protoporphyrin (CoPP). Further effects of CoPP included increased (P < 0.05) renal expression of adiponectin along with enhancement (P < 0.05) of pAKT, pAMPK, and p-eNOS in SHRs fed a high-fat diet. Prevention of such beneficial effects of CoPP by the concurrent administration of the heme-HO inhibitor stannous mesoporphyrin (SnMP) corroborates the role of HO system in mediating such effects. Taken together, our results demonstrate that high-fat diet induces a metabolic syndrome-like phenotype in hypertensive rats, which is amenable to rescue by increases in HO-1- and adiponectin-dependent pathways. PMID:22193921

  19. 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

  20. 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

  1. 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

  2. Nrf2-Mediated HO-1 Induction Contributes to Antioxidant Capacity of a Schisandrae Fructus Ethanol Extract in C2C12 Myoblasts

    PubMed Central

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

    2014-01-01

    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

  3. 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.

  4. The anti-inflammatory effects of E-α-(p-methoxyphenyl)-2',3,4,4'-tetramethoxychalcone are mediated via HO-1 induction.

    PubMed

    Kaufmann, Kai B; Gothwal, Monika; Schallner, Nils; Ulbrich, Felix; Rücker, Hannelore; Amslinger, Sabine; Goebel, Ulrich

    2016-06-01

    Inflammation plays a central role in the pathophysiology of many diseases. The inducible enzyme heme oxygenase-1 (HO-1) protects cells against inflammation and can be induced by electrophilic compounds like the chalcones (1,3-diphenylprop-2-enones) from the class of α,β-unsaturated carbonyl compounds. We hypothesized that the synthetic chalcone E-α-(p-methoxyphenyl)-2',3,4,4'-tetramethoxychalcone (E-α-p-OMe-C6H4-TMC) exerts anti-inflammatory effects in RAW264.7, Jurkat lymphocytes and HK-2 cells via HO-1 induction. RAW264.7 cells were treated with lipopolysaccharide prior to E-α-p-OMe-C6H4-TMC treatment. Subsequently, HO-1 protein induction and activity were analyzed, as well as expression of pro- and anti-inflammatory mediators, transcription factors and mitogen-activated protein kinases to evaluate the possible molecular mechanism. These results were confirmed in human cell lines (Jurkat T-lymphocytes and HK-2 epithelial cells). We found that the E-α-p-OMe-C6H4-TMC exerts significant anti-inflammatory effects in a dose dependent manner, showing no toxic effects in LPS-treated RAW264.7 macrophages. E-α-p-OMe-C6H4-TMC induced HO-1 and SOD-1 protein expression and HO-1 enzyme activity, reduced the upregulation of COX-2 and iNOS, while inducing the translocation of Nrf2. NF-κB activity was attenuated following E-α-p-OMe-C6H4-TMC treatment accompanied by the downregulation of proinflammatory cytokines IL-1β, IL-6 and MCP-1. Pretreatment with E-α-p-OMe-C6H4-TMC revealed significant changes in phosphorylation of ERK and p38, but not JNK. These anti-inflammatory effects of E-α-p-OMe-C6H4-TMC were approved in Jurkat and HK-2 cells, furthermore revealing a downregulation of IL-8 and IL-10. In conclusion, it is tempting to speculate about E-α-p-OMe-C6H4-TMC as a new and non-toxic agent, inducing HO-1 in cells. This opens up new opportunities regarding the development of therapeutic agents using beneficial effects of HO-1 and its products. PMID:27044026

  5. Tenuigenin exhibits anti-inflammatory activity via inhibiting MAPK and NF-κB and inducing Nrf2/HO-1 signaling in macrophages.

    PubMed

    Lv, Hongming; Ren, Wenzhi; Zheng, Yuwei; Wang, Lidong; Lu, Gejin; Yi, Pengfei; Ci, Xinxin

    2016-01-01

    Tenuigenin (TNG), isolated from the root of the Chinese herb Polygala tenuifolia, possesses various biological and pharmacological activities, including anti-oxidation and anti-inflammation activities. In this study, we aimed to further investigate whether its anti-inflammatory activity is associated with the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Our results showed that TNG treatment dramatically reduced prostaglandin E2 (PGE2) and NO production, decreased iNOS and COX-2 gene expression, inhibited JNK1/2, ERK1/2, p38 and NF-κB (p65) phosphorylation, and blocked IκBα phosphorylation and degradation. Further studies revealed that TNG dramatically up-regulated heme oxygenase (HO)-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, which was related to the induction of Nrf2 nuclear translocation and decreased Keap1 protein expression. Additionally, treatment with JNK1/2, ERK1/2 or p38 inhibitors had no effect on the TNG-induced HO-1 protein expression. Furthermore, the LPS-induced iNOS and COX-2 expression levels were inhibited by TNG, which was partially reversed by the HO-1-siRNA and HO-1 inhibitors. Together, these results showed that TNG's anti-inflammatory activity is related to the inhibition of iNOS and COX-2 expression via down-regulation of the MAPK and NF-κB, and up-regulation of the Nrf2/HO-1 signaling pathways. PMID:26499342

  6. Multiple factors from bradykinin-challenged astrocytes contribute to the neuronal apoptosis: involvement of astroglial ROS, MMP-9, and HO-1/CO system.

    PubMed

    Yang, Chuen-Mao; Hsieh, Hsi-Lung; Lin, Chih-Chung; Shih, Ruey-Horng; Chi, Pei-Ling; Cheng, Shin-Ei; Hsiao, Li-Der

    2013-06-01

    Bradykinin (BK) has been shown to induce the expression of several inflammatory mediators, including reactive oxygen species (ROS) and matrix metalloproteinases (MMPs), in brain astrocytes. These mediators may contribute to neuronal dysfunction and death in various neurological disorders. However, the effects of multiple inflammatory mediators released from BK-challenged astrocytes on neuronal cells remain unclear. Here, we found that multiple factors were released from brain astrocytes (RBA-1) exposed to BK in the conditioned culture media (BK-CM), including ROS, MMP-9, and heme oxygenase-1 (HO-1)/carbon monoxide (CO), leading to neuronal cell (SK-N-SH) death. Exposure of SK-N-SH cells to BK-CM or H2O2 reduced cell viability and induced cell apoptosis which were attenuated by N-acetyl cysteine, indicating a role of ROS in these responses. The effect of BK-CM on cell viability and cell apoptosis was also reversed by immunoprecipitation of BK-CM with anti-MMP-9 antibody (MMP-9-IP-CM) or MMP2/9 inhibitor, suggesting the involvement of MMP-9 in BK-CM-mediated responses. Astroglial HO-1/CO in BK-CM induced cell apoptosis and reduced cell viability which was reversed by hemoglobin. Consistently, the involvement of CO in these cellular responses was revealed by incubation with a CO donor CO-RM2 which was reversed by hemoglobin. The role of HO-1 in BK-CM-induced responses was confirmed by overexpression of HO-1 in SK-N-SH infected with Adv-HO-1. BK-CM-induced cell apoptosis was due to the activation of caspase-3 and cleavage of PARP. Together, we demonstrate that BK-induced several neurotoxic factors, including ROS, MMP-9, and CO released from astrocytes, may induce neuronal death through a caspase-3-dependent apoptotic pathway. PMID:23307413

  7. 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

  8. 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

  9. Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO-1 signaling

    PubMed Central

    2014-01-01

    Background Nuclear factor erythroid-2-related factor-2 (Nrf2) is known to protect against tissue injury by orchestrating antioxidant and detoxification responses to oxidative stress. This study investigated whether upregulation of Nrf2-dependent signaling by oleanolic acid (OA), which is known to activate Nrf2, could attenuate renal inflammation and fibrosis in cyclosporine (CsA)-induced kidney injury. Methods Male ICR mice were divided into four treatment groups: Vehicle (VH, n = 6), VH + OA (n = 6), CsA (n = 8), and CsA + OA (n = 8). For the OA-treated groups, OA (25 mg/kg/day) was administered by intraperitoneal injection for the final week of the 4-week experimental period. Renal function, morphologies and signaling were evaluated at the end of the study. Results Treatment with CsA resulted in decreased kidney function and urine osmolality and increased urine volume and urinary albumin levels. The CsA-induced changes were improved by OA treatment. Specifically, administration of OA decreased tubulointerstitial fibrosis and inflammation scores that were increased in CsA-treated mice. Furthermore, OA treatment decreased urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-epi-prostaglandin F2α (8-iso-PGF2α) levels. The beneficial effects of OA were attributed to an increased ratio of nuclear/total Nrf2 and subsequently enhanced expression of heme oxygenase (HO)-1, as well as a stable level of Kelch-like ECH-associated protein 1 (Keap1) expression, indicating that OA enhanced nuclear translocation of Nrf2. Increased apoptotic cell death and a high ratio of B cell leukaemia/lymphoma 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 in CsA-treated mice were also significantly ameliorated by OA treatment. Conclusion Our results suggest that OA activates Nrf2/HO-1 signaling in chronic CsA nephropathy, which may have beneficial effects on inflammation and oxidative stress. PMID:24559268

  10. Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway.

    PubMed

    Cao, Jian; Tsenovoy, Peter L; Thompson, Ellen A; Falck, John R; Touchon, Robert; Sodhi, Komal; Rezzani, Rita; Shapiro, Joseph I; Abraham, Nader G

    2015-01-01

    Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of β-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased β-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, β-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling

  11. The Successive Component-separated Magnetic-Transitions on Pseudoternary Compounds Ho1-xGdxRh2Si2

    NASA Astrophysics Data System (ADS)

    Shigeoka, Toru; Morita, Tetsuhiro; Fujiwara, Tetsuya; Matsubayashi, Kazuyuki; Uwatoko, Yoshiya

    Magnetic measurements on pseudoternary compounds Ho1-xGdxRh2Si2, which substitute Gd having no quadrupole for Ho, were performed. They exhibit a successive component-separated magnetic transition; the c- and ab-components of magnetic moments independently order at different temperatures TN1 and TN2, respectively. The partial ordered state, a frustration appears for TN1 >T >TN2: for the phase II in the magnetic phase diagrams. In the ordered phase, step-like metamagnetic processes appear for TN2 >T; two-step ones appear along the [001] and [100] directions, and a one-step one appears along the [110] direction. The B-T magnetic phase diagrams were constructed. There are six, four and three ordered phases in the B001-T, B100-T and B110-T phase diagram, respectively. Two diagrams of the basal plane directions, B100-T and B110-T, resemble each other. Some interesting or peculiar phase boundaries appear. The Gd composition x dependence of transition temperatures is determined. The transition temperatures TN1 and TN2 increase with increasing x. The x-dependency of TN1 is well scaled by the de Gennes factor: (g-1)2J(J+1) whereas the transition of TN2 is not scaled. Some magnetic features declare that quadrupole interactions play an important role in this compound system.

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

    DOE PAGESBeta

    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

  13. 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

  14. Gartanin Protects Neurons against Glutamate-Induced Cell Death in HT22 Cells: Independence of Nrf-2 but Involvement of HO-1 and AMPK.

    PubMed

    Gao, Xiao-Yun; Wang, Sheng-Nan; Yang, Xiao-Hong; Lan, Wen-Jian; Chen, Zi-Wei; Chen, Jing-Kao; Xie, Jian-Hui; Han, Yi-Fan; Pi, Rong-Biao; Yang, Xiao-Bo

    2016-09-01

    Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities. Herein, the neuroprotection capacity of gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1-10 µM gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after gartanin treatment. Taken together, these findings suggest gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways. PMID:27161377

  15. Curcumin attenuates quinocetone induced apoptosis and inflammation via the opposite modulation of Nrf2/HO-1 and NF-kB pathway in human hepatocyte L02 cells.

    PubMed

    Dai, Chongshan; Li, Bin; Zhou, Yan; Li, Daowen; Zhang, Shen; Li, Hui; Xiao, Xilong; Tang, Shusheng

    2016-09-01

    The potential toxicity of quinocetone (QCT) has raised widely concern, but its mechanism is still unclear. This study aimed to investigate the protective effect of curcumin on QCT induced apoptosis and the underlying mechanism in human hepatocyte L02 cells. The results showed that QCT treatment significantly decreased the cell viability of L02 cell and increased the release of lactate dehydrogenase (LDH), which was attenuated by curcumin pre-treatment at 1.25, 2.5 and 5 μM. Compared to the QCT alone group, curcumin pre-treatment significantly attenuated QCT induced oxidative stress, mitochondrial dysfunction and apoptosis. In addition, curcumin pretreatment markedly attenuated QCT-induced increase of iNOS activity and NO production in a dose-dependent manner. Meanwhile, curcumin pretreatment markedly down-regulated the expression of nuclear factor -kB (NF-kB) and iNOS mRNAs, but up-regulated the expressions of Nrf2 and HO-1 mRNAs, compared to the QCT alone group. Zinc protoporphyrin IX, a HO-1 inhibitor, markedly partly abolished the cytoprotective effect of curcumin against QCT-induced caspase activation, NF-kB mRNA expression. These results indicate that curcumin could effectively inhibit QCT induced apoptosis and inflammatory response in L02 cells, which may involve the activation of Nrf2/HO-1 and inhibition of NF-kB pathway. PMID:27375190

  16. Differential expression patterns of Nqo1, AKR1B8 and Ho-1 in the liver and small intestine of C57BL/6 mice treated with sulforaphane.

    PubMed

    Luo, Lin; Chen, Yeru; Wu, Deqi; Shou, Jiafeng; Wang, Shengcun; Ye, Jie; Tang, Xiuwen; Jun Wang, Xiu

    2015-12-01

    This data article contains complementary figures and results related to the research article entitled "butylated hydroxyanisole induces distinct expression patterns of Nrf2 and detoxification enzymes in the liver and small intestine of C57BL/6 mice" (Luo et al., 2015 [1]), which defined the basal and butylated hydroxyanisole (BHA)-induced expression patterns of Phase II enzymes Nqo1, AKR1B8, and Ho-1 in the liver and small intestine of C57BL/6 mice. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane] (SFN), a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase II cytoprotective enzymes. This dataset reports the histological changes of Nqo1, AKR1B8, and Ho-1 in wild-type (WT) and Nrf2 (-/-) mice induced by SFN. The mice were given a 25 mg/kg single oral dose of SFN for 24 h and 48 h. Immunohistochemistry revealed that, in the liver from WT mice, SFN increased Nqo1 staining in hepatocytes with slight higher staining in the pericentral region. The induction of AKR1B8 appeared mostly in hepatocytes in the periportal region. The basal and inducible Ho-1 was located predominately in Kupffer cells. In the small intestine from WT mice, the inducible expression of Nqo1 and AKR1B8 appeared more obvious in the villus than that in the crypt. PMID:26958603

  17. Differential expression patterns of Nqo1, AKR1B8 and Ho-1 in the liver and small intestine of C57BL/6 mice treated with sulforaphane

    PubMed Central

    Luo, Lin; Chen, Yeru; Wu, Deqi; Shou, Jiafeng; Wang, Shengcun; Ye, Jie; Tang, Xiuwen; Jun Wang, Xiu

    2015-01-01

    This data article contains complementary figures and results related to the research article entitled “butylated hydroxyanisole induces distinct expression patterns of Nrf2 and detoxification enzymes in the liver and small intestine of C57BL/6 mice” (Luo et al., 2015 [1]), which defined the basal and butylated hydroxyanisole (BHA)-induced expression patterns of Phase II enzymes Nqo1, AKR1B8, and Ho-1 in the liver and small intestine of C57BL/6 mice. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane] (SFN), a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase II cytoprotective enzymes. This dataset reports the histological changes of Nqo1, AKR1B8, and Ho-1 in wild-type (WT) and Nrf2-/- mice induced by SFN. The mice were given a 25 mg/kg single oral dose of SFN for 24 h and 48 h. Immunohistochemistry revealed that, in the liver from WT mice, SFN increased Nqo1 staining in hepatocytes with slight higher staining in the pericentral region. The induction of AKR1B8 appeared mostly in hepatocytes in the periportal region. The basal and inducible Ho-1 was located predominately in Kupffer cells. In the small intestine from WT mice, the inducible expression of Nqo1 and AKR1B8 appeared more obvious in the villus than that in the crypt. PMID:26958603

  18. Biosynthesis of 15-deoxy-delta12,14-PGJ2 and the ligation of PPARgamma.

    PubMed

    Bell-Parikh, L Chastine; Ide, Tomomi; Lawson, John A; McNamara, Peter; Reilly, Muredach; FitzGerald, Garret A

    2003-09-01

    15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) has been identified as an endogenous ligand for PPARgamma, inducing adipogenesis in vitro. Additional roles for this molecule in the propagation and resolution of inflammation, ligation of NF-kappaB, and mediation of apoptosis have been proposed. However, quantitative, physiochemical evidence for the formation of 15d-PGJ2 in vivo is lacking. We report that 15d-PGJ2 is detectable using liquid chromatography-mass spectrometry-mass spectrometry at low picomolar concentrations in the medium of 3T3-L1 preadipocytes. However, despite induction of COX-2, production of PGs, including 15d-PGJ2, does not increase during adipocyte differentiation, a process unaltered by COX inhibition. 15d-PGJ2 is detectable as a minor product of COX-2 in human urine. However, its biosynthesis is unaltered during or after COX activation in vivo by LPS. Furthermore, the biosynthesis of 15d-PGJ2 is not augmented in the joint fluid of patients with arthritis, nor is its urinary excretion increased in patients with diabetes or obesity. 15d-PGJ2 is not the endogenous mediator of PPARgamma-dependent adipocyte activation and is unaltered in clinical settings in which PPARgamma activation has been implicated. PMID:12975479

  19. 15-Deoxy-Δ12,14-prostaglandin J2 Induces Apoptosis and Upregulates SOCS3 in Human Thyroid Cancer Cells

    PubMed Central

    Trindade-da-Silva, Carlos Antônio; Reis, Carolina Fernandes; Vecchi, Lara; Napimoga, Marcelo Henrique; Sperandio, Marcelo; Matias Colombo, Bruna França; Alves, Patrícia Terra; Ward, Laura Sterian; Ueira-Vieira, Carlos; Goulart, Luiz Ricardo

    2016-01-01

    The cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural ligand of peroxisome proliferator-activated receptor gamma (PPAR-γ) and a potential mediator of apoptosis in cancer cells. In the present study, we evaluated the effect of 15d-PGJ2 in human thyroid papillary carcinoma cells (TPC-1) using different doses of 15d-PGJ2 (0.6 to 20 μM) to determine IC50 (9.3 μM) via the MTT assay. The supernatant culture medium of the TPC-1 cells that was treated either with 15d-PGJ2 or with vehicle (control) for 24 hours was assessed for IL-6 secretion via CBA assay. RT-qPCR was used to evaluate mRNA expression of IL-6, SOCS1, SOCS3, and STAT3. TPC-1 cells treated with 15d-PGJ2 decreased the secretion and expression of IL-6 and STAT3, while it increased SOCS1 and SOCS3. Overall, we demonstrated that 15d-PGJ2 downregulated IL-6 signaling pathway and led TPC-1 cells into apoptosis. In conclusion, 15d-PGJ2 shows the potential to become a new therapeutic approach for thyroid tumors. PMID:27190500

  20. 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

  1. 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

  2. Epoxyeicosatrienoic acid agonist regulates human mesenchymal stem cell-derived adipocytes through activation of HO-1-pAKT signaling and a decrease in PPARγ.

    PubMed

    Kim, Dong Hyun; Vanella, Luca; Inoue, Kazuyoshi; Burgess, Angela; Gotlinger, Katherine; Manthati, Vijaya Lingam; Koduru, Sreenivasulu Reddy; Zeldin, Darryl C; Falck, John R; Schwartzman, Michal L; Abraham, Nader G

    2010-12-01

    Human mesenchymal stem cells (MSCs) expressed substantial levels of CYP2J2, a major CYP450 involved in epoxyeicosatrienoic acid (EET) formation. MSCs synthesized significant levels of EETs (65.8 ± 5.8 pg/mg protein) and dihydroxyeicosatrienoic acids (DHETs) (15.83 ± 1.62 pg/mg protein), suggesting the presence of soluble epoxide hydrolase (sEH). The addition of an sEH inhibitor to MSC culture decreased adipogenesis. EETs decreased MSC-derived adipocytes in a concentration-dependent manner, 8,9- and 14,15-EET having the maximum reductive effect on adipogenesis. We examined the effect of 12-(3-hexylureido)dodec-8(Z)-enoic acid, an EET agonist, on MSC-derived adipocytes and demonstrated an increased number of healthy small adipocytes, attenuated fatty acid synthase (FAS) levels (P < 0.01), and reduced PPARγ, C/EBPα, FAS, and lipid accumulation (P < 0.05). These effects were accompanied by increased levels of heme oxygenase (HO)-1 and adiponectin (P < 0.05), and increased glucose uptake (P < 0.05). Inhibition of HO activity or AKT by tin mesoporphyrin (SnMP) and LY2940002, respectively, reversed EET-induced inhibition of adipogenesis, suggesting that activation of the HO-1-adiponectin axis underlies EET effect in MSCs. These findings indicate that EETs decrease MSC-derived adipocyte stem cell differentiation by upregulation of HO-1-adiponectin-AKT signaling and play essential roles in the regulation of adipocyte differentiation by inhibiting PPARγ, C/EBPα, and FAS and in stem cell development. These novel observations highlight the seminal role of arachidonic acid metabolism in MSCs and suggest that an EET agonist may have potential therapeutic use in the treatment of dyslipidemia, diabetes, and the metabolic syndrome. PMID:20412023

  3. Epoxyeicosatrienoic Acid Agonist Regulates Human Mesenchymal Stem Cell–Derived Adipocytes Through Activation of HO-1-pAKT Signaling and a Decrease in PPARγ

    PubMed Central

    Kim, Dong Hyun; Vanella, Luca; Inoue, Kazuyoshi; Burgess, Angela; Gotlinger, Katherine; Manthati, Vijaya Lingam; Koduru, Sreenivasulu Reddy; Zeldin, Darryl C.; Falck, John R.; Schwartzman, Michal L.

    2010-01-01

    Human mesenchymal stem cells (MSCs) expressed substantial levels of CYP2J2, a major CYP450 involved in epoxyeicosatrienoic acid (EET) formation. MSCs synthesized significant levels of EETs (65.8 ± 5.8 pg/mg protein) and dihydroxyeicosatrienoic acids (DHETs) (15.83 ± 1.62 pg/mg protein), suggesting the presence of soluble epoxide hydrolase (sEH). The addition of an sEH inhibitor to MSC culture decreased adipogenesis. EETs decreased MSC-derived adipocytes in a concentration-dependent manner, 8,9- and 14,15-EET having the maximum reductive effect on adipogenesis. We examined the effect of 12-(3-hexylureido)dodec-8(Z)-enoic acid, an EET agonist, on MSC-derived adipocytes and demonstrated an increased number of healthy small adipocytes, attenuated fatty acid synthase (FAS) levels (P < 0.01), and reduced PPARγ, C/EBPα, FAS, and lipid accumulation (P < 0.05). These effects were accompanied by increased levels of heme oxygenase (HO)-1 and adiponectin (P < 0.05), and increased glucose uptake (P < 0.05). Inhibition of HO activity or AKT by tin mesoporphyrin (SnMP) and LY2940002, respectively, reversed EET-induced inhibition of adipogenesis, suggesting that activation of the HO-1-adiponectin axis underlies EET effect in MSCs. These findings indicate that EETs decrease MSC-derived adipocyte stem cell differentiation by upregulation of HO-1-adiponectin-AKT signaling and play essential roles in the regulation of adipocyte differentiation by inhibiting PPARγ, C/EBPα, and FAS and in stem cell development. These novel observations highlight the seminal role of arachidonic acid metabolism in MSCs and suggest that an EET agonist may have potential therapeutic use in the treatment of dyslipidemia, diabetes, and the metabolic syndrome. PMID:20412023

  4. 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

  5. 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

  6. 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

  7. Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation of Mouse 3T3 Cells, Via PGC-1α Activation, Which Is Required for HO-1 Expression and Increased Mitochondrial Function.

    PubMed

    Waldman, Maayan; Bellner, Lars; Vanella, Luca; Schragenheim, Joseph; Sodhi, Komal; Singh, Shailendra P; Lin, Daohong; Lakhkar, Anand; Li, Jiangwei; Hochhauser, Edith; Arad, Michael; Darzynkiewicz, Zbigniew; Kappas, Atallah; Abraham, Nader G

    2016-07-15

    Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P < 0.05, in PGC-1α and a decrease in mitochondria-derived ROS (MitoSox), P < 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, P < 0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial superoxide dismutase (SOD) in a PGC-1α-dependent manner, P < 0.05. The increase in PGC-1α was associated with an increase in β-catenin, P < 0.05, adiponectin expression, P < 0.05, and lipid accumulation, P < 0.02. EET decreased heme levels and mitochondria-derived ROS (MitoSox), P < 0.05, compared to adipocytes that were untreated. EET also decreased mesoderm-specific transcript (MEST) mRNA and protein levels (P < 0.05). Adipocyte secretion of EET act in an autocrine/paracrine manner to increase PGC-1α is required for activation of HO-1 expression. This is the first study to dissect the mechanism by which the antiadipogenic and anti-inflammatory lipid, EET, induces the PGC-1α signaling cascade and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, that is, small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation. This is manifested by an increase in mitochondrial function and an increase in the canonical Wnt signaling cascade during adipocyte proliferation and terminal differentiation. PMID:27224420

  8. A Novel Peroxisome Proliferator-activated Receptor (PPAR)γ Agonist 2-Hydroxyethyl 5-chloro-4,5-didehydrojasmonate Exerts Anti-Inflammatory Effects in Colitis.

    PubMed

    Choo, Jieun; Lee, Yunna; Yan, Xin-Jia; Noh, Tae Hwan; Kim, Seong Jin; Son, Sujin; Pothoulakis, Charalabos; Moon, Hyung Ryong; Jung, Jee H; Im, Eunok

    2015-10-16

    Inflammatory bowel disease (IBD) is a chronic inflammatory disease with increasing incidence and prevalence worldwide. Here we investigated the newly synthesized jasmonate analogue 2-hydroxyethyl 5-chloro-4,5-didehydrojasmonate (J11-Cl) for its anti-inflammatory effects on intestinal inflammation. First, to test whether J11-Cl can activate peroxisome proliferator-activated receptors (PPARs), we performed docking simulations because J11-Cl has a structural similarity with anti-inflammatory 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2), one of the endogenous ligands of PPARγ. J11-Cl bound to the ligand binding domain of PPARγ in the same manner as 15d-PGJ2 and rosiglitazone, and significantly increased transcriptional activity of PPARγ. In animal experiments, colitis was significantly reduced in mice with J11-Cl treatment, determined by analyses of survival rate, body weight changes, clinical symptoms, and histological evaluation. Moreover, J11-Cl decreased production of pro-inflammatory cytokines including IL-6, IL-8, and G-CSF as well as chemokines including chemokine (C-C motif) ligand (CCL)20, chemokine (C-X-C motif) ligand (CXCL)2, CXCL3, and chemokine (C-X3-C motif) ligand 1 (CX3CL1) in colon tissues, and LPS or TNF-α-stimulated macrophages and epithelial cells. In contrast, production of anti-inflammatory cytokines including IL-2 and IL-4 as well as the proliferative factor, GM-CSF, was increased by J11-Cl. Furthermore, inhibition of MAPKs and NF-κB activation by J11-Cl was also observed. J11-Cl reduced intestinal inflammation by increasing the transcriptional activity of PPARγ and modulating inflammatory signaling pathways. Therefore, our study suggests that J11-Cl may serve as a novel therapeutic agent against IBD. PMID:26342083

  9. Mechanistic study on the biological effects of silver and gold nanoparticles in Caco-2 cells--induction of the Nrf2/HO-1 pathway by high concentrations of silver nanoparticles.

    PubMed

    Aueviriyavit, Sasitorn; Phummiratch, Duangkamol; Maniratanachote, Rawiwan

    2014-01-01

    The most commonly used metal nanoparticles (NPs) across diverse applications, including in agro-food applications, include silver (AgNPs) and gold (AuNPs). In the present study, we aimed to investigate the biological responses and possible toxicological effects of AgNPs and AuNPs in the Caco-2 cells as an in vitro human GI tract model. Both AgNPs and AuNPs were internalized into the cytoplasm of Caco-2 cells, but not within the nucleus and only exposure to high concentrations of AgNPs, but not AuNPs, caused acute cytotoxicity and depolarization of the mitochondrial membrane potential. In addition, only AgNPs significantly depleted the total intracellular glutathione level, induced the activation of the stress-responsive gene, Nrf2, and dramatically increased the expression of heme oxygenase-1 (HO-1). Furthermore, siRNA silencing of Nrf2 transcripts significantly reduced the AgNP-induced HO-1 mRNA induction, suggesting a key role for Nrf2 in the control of HO-1 expression. Taken together, AgNPs but not AuNPs induced acute cytotoxicity and cellular responses via the oxidative stress-related activation of Nrf2/HO-1 signaling pathway in Caco-2 cells. The expression of HO-1 transcripts may be useful as a sensitive marker for safety evaluation of AgNPs in the GI tract of humans. PMID:24126012

  10. The cytoprotective effects of ethanol extract of Ecklonia cava against oxidative stress are associated with upregulation of Nrf2-mediated HO-1 and NQO-1 expression through activation of the MAPK pathway.

    PubMed

    Choi, Yung Hyun

    2016-01-01

    The aim of the present study was to examine the cytoprotective effect of Ecklonia cava against oxidative stress in C2C12 myoblasts. The ethanol extract of E. cava (EEEC) prevented hydrogen peroxide (H₂O₂)-induced inhibition of the growth of C2C12 myoblasts and exhibited scavenging activity against intracellular reactive oxygen species (ROS) induced by H₂O₂. EEEC treatment attenuated H2O2-induced comet tail formation and phospho-histone γH2A.X expression. Furthermore, EEEC treatment enhanced the level of the phosphorylated form of nuclear factor erythroid 2- related factor 2 (Nrf2) and its nuclear translocation, which was associated with the induction of heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase 1 (NQO-1). Zinc protoporphyrin IX, a HO-1 competitive inhibitor, significantly abolished the protective effects of EEEC against H₂O₂-induced ROS generation and growth inhibition in C2C12 myoblasts. Transient transfection with Nrf2-specific small interfering RNA restored the elevated HO-1 and NQO-1 expression and the phosphorylation of Nrf2 to near normal levels. The EEEC treatment also induced the activation of mitogen-activated protein kinases (MAPKs), and specific inhibitors of MAPKs abolished upregulated HO-1 and NQO-1, as well as the phosphorylation of Nrf2. Taken together, these data suggest that EEEC attenuates oxidative stress by activating Nrf2-mediated HO-1 and inducing NQO-1 via the activation of MAPK signaling pathways. PMID:26492067

  11. Terrein reduces age-related inflammation induced by oxidative stress through Nrf2/ERK1/2/HO-1 signalling in aged HDF cells.

    PubMed

    Lee, Young-Hee; Lee, Sook-Jeong; Jung, Ji-Eun; Kim, Jeong-Seok; Lee, Nan-Hee; Yi, Ho-Keun

    2015-10-01

    This study investigated whether multiple bioactivity of terrein such as anti-inflammatory and anti-oxidant inhibits age-related inflammation by promoting an antioxidant response in aged human diploid fibroblast (HDF) cells. HDF cells were cultured serially for in vitro replicative senescence. To create the ageing cell phenotype, intermediate stage (PD31) HDF cells were brought to stress-induced premature senescence (SIPS) using hydrogen peroxide (H2 O2). Terrein increased cell viability even with H2O2 stress and reduced inflammatory molecules such as intracellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1β) and tumour necrosis factor-alpha (TNF-α). Terrein reduced also phospho-extracellular kinase receptor1/2 (p-EKR1/2) signalling in aged HDF cells. SIPS cells were attenuated for age-related biological markers including reactive oxygen species (ROS), senescence associated beta-galactosidase (SA β-gal.) and the aforementioned inflammatory molecules. Terrein induced the induction of anti-oxidant molecules, copper/zinc-superoxide defence (Cu/ZnSOD), manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1) in SIPS cells. Terrein also alleviated reactive oxygen species formation through the Nrf2/HO-1/p-ERK1/2 pathway in aged cells. The results indicate that terrein has an alleviative function of age-related inflammation characterized as an anti-oxidant. Terrein might be a useful nutraceutical compound for anti-ageing. PMID:26416516

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Targeting 15d-Prostaglandin J2 to Hepatic Stellate Cells: Two Options Evaluated

    PubMed Central

    Hagens, Werner I.; Mattos, Adriana; Greupink, Rick; de Jager-Krikken, Alie; Reker-Smit, Catharina; van Loenen-Weemaes, AnneMiek; Gouw, Annette S. H.; Poelstra, Klaas

    2007-01-01

    Purpose Delivery of apoptosis-inducing compounds to hepatic stellate cells (HSC) may be an effective strategy to reverse liver fibrosis. The aim of this study was therefore to examine the selective targeting of the apoptosis-inducing drug 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) with two different HSC-carriers: human serum albumin modified with the sugar mannose-6-phosphate (M6PHSA) or albumin modified with PDGF-receptor recognizing peptides (pPBHSA). Methods and Results After chemical conjugation of 15dPGJ2 to the carriers, the constructs displayed pharmacological activity and specific receptor-mediated binding to HSC in vitro. Unlike 15dPGJ2-pPBHSA, the cellular binding of 15dPGJ2-M6PHSA was reduced by a scavenger receptor antagonist. In vivo, both conjugates rapidly accumulated in fibrotic livers. Intrahepatic analysis revealed that 15dPGJ2-M6PHSA mainly accumulated in HSC, and to a lesser extent in Kupffer cells. 15dPGJ2-pPBHSA also predominantly accumulated in HSC with additional uptake in hepatocytes. Assessment of target receptors in human cirrhotic livers revealed that M6P/IGFII-receptor expression was present in fibrotic areas. PDGF-β receptor expression was abundantly expressed on human fibroblasts. Conclusions These studies show that 15dPGJ2 coupled to either M6PHSA or pPBHSA is specifically taken up by HSC and is highly effective within these cells. Both carriers differ with respect to receptor specificity, leading to differences in intrahepatic distribution. Nevertheless, both carriers can be used to deliver the apoptosis-inducing drug 15dPGJ2 to HSC in vivo. PMID:17245650

  18. Hemeoxygenase 1 partly mediates the anti-inflammatory effect of dieckol in lipopolysaccharide stimulated murine macrophages.

    PubMed

    Yayeh, Taddesse; Im, Eun Ju; Kwon, Tae-Hyung; Roh, Seong-Soo; Kim, Suk; Kim, Ji Hye; Hong, Seung-Bok; Cho, Jae Youl; Park, Nyun-Ho; Rhee, Man Hee

    2014-09-01

    Eisenia bicyclis is edible brown algae recognized as a rich source of bioactive derivatives mainly phlorotannins reported for their anti-oxidant properties. Of all phlorotannins identified so far, dieckol has shown the most potent effect in anti-inflammatory, radical scavenging and neuroprotective functions. However, whether dieckol up-regulates hemeoxygenase 1 (HO-1) and this mediates its anti-inflammatory effect in murine macrophages remains poorly understood. Dieckol (12.5-50 μM) inhibited nitric oxide production and attenuated inducible nitric oxide synthase, phospho (p)-PI-3K, p-Akt, p-IKK-α/β, p-IκB-α and nuclear p-NF-κBp65 protein expressions, and NF-κB transcriptional activity in LPS (0.1 μg/ml) stimulated murine macrophages. On the other hand, dieckol up-regulated HO-1 which partly mediated its anti-inflammatory effect in murine macrophages. Thus, dieckol appeared to be a potential therapeutic agent against inflammation through HO-1 up-regulation. PMID:24953853

  19. Isovitexin Exerts Anti-Inflammatory and Anti-Oxidant Activities on Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting MAPK and NF-κB and Activating HO-1/Nrf2 Pathways

    PubMed Central

    Lv, Hongming; Yu, Zhenxiang; Zheng, Yuwei; Wang, Lidong; Qin, Xiaofeng; Cheng, Genhong; Ci, Xinxin

    2016-01-01

    Oxidative damage and inflammation are closely associated with the pathogenesis of acute lung injury (ALI). Thus, we explored the protective effect of isovitexin (IV), a glycosylflavonoid, in the context of ALI. To accomplish this, we created in vitro and in vivo models by respectively exposing macrophages to lipopolysaccharide (LPS) and using LPS to induce ALI in mice. In vitro, our results showed that IV treatment reduced LPS-induced pro-inflammatory cytokine secretion, iNOS and COX-2 expression and decreased the generation of ROS. Consistent findings were obtained in vivo. Additionally, IV inhibited H2O2-induced cytotoxicity and apoptosis. However, these effects were partially reversed following the use of an HO-1 inhibitor in vitro. Further studies revealed that IV significantly inhibited MAPK phosphorylation, reduced NF-κB nuclear translocation, and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expression in RAW 264.7 cells. In vivo, pretreatment with IV attenuated histopathological changes, infiltration of polymorphonuclear granulocytes and endothelial activation, decreased the expression of ICAM-1 and VCAM-1, reduced the levels of MPO and MDA, and increased the content of GSH and SOD in ALI. Furthermore, IV treatment effectively increased Nrf2 and HO-1 expression in lung tissues. Therefore, IV may offer a protective role against LPS-induced ALI by inhibiting MAPK and NF-κB and activating HO-1/Nrf2 pathways. PMID:26722219

  20. Luteolin inhibits viral-induced inflammatory response in RAW264.7 cells via suppression of STAT1/3 dependent NF-κB and activation of HO-1.

    PubMed

    Liu, Cheng-Wei; Lin, Hui-Wen; Yang, Deng-Jye; Chen, Shih-Yin; Tseng, Jung-Kai; Chang, Tien-Jye; Chang, Yuan-Yen

    2016-06-01

    Luteolin is a common dietary flavonoid present in Chinese herbal medicines that has been reported to have important anti-inflammatory properties. Previous studies have shown that luteolin is an anti-inflammatory and anti-oxidative agent. In this study, the anti-virus inflammatory capacity of luteolin and its molecular mechanisms of action were analyzed. The cytotoxic effects of luteolin were assessed in the presence or absence of pseudorabies virus (PRV) via LDH and MTT assays. The results showed that luteolin (<10μM) had no toxic effects and there were tendencies toward higher cell survival. In PRV-infected RAW264.7 cells, luteolin potently inhibited the production of NO, iNOS, COX-2 and inflammatory cytokine production. Luteolin did not inhibit the phosphorylation of ERK 1/2, p38, and JNK 1/2 either. We found that PRV-induced NF-κB activation is regulated through inhibition of STAT1and STAT3 phosphorylation in response to luteolin. Additionally, luteolin caused the induction of HO-1 via upregulation of Nrf2, both of which are involved in the secretion of proinflammatory mediators. The blockade of HO-1 expression with SnPP, a HO-1 inhibitor, attenuated HO-1 induction by luteolin and thus mitigated its anti-inflammatory effects during PRV-infected RAW264.7 cells. Taken together, our data indicate that luteolin diminishes the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2, in PRV-infected RAW264.7 cells by inhibiting STAT1/3 dependent NF-κB activation and inducing Nrf2mediated HO-1 expression. PMID:27016074

  1. Baicalein Protects Against Retinal Ischemia by Antioxidation, Antiapoptosis, Downregulation of HIF-1α, VEGF, and MMP-9 and Upregulation of HO-1

    PubMed Central

    Chuang, Min-Jay; Liu, Xiao-Qian; Ho, Li-Kang; Pan, Wynn H.T.; Zhang, Xiu-Mei; Liu, Chi-Ming; Tsai, Shen-Kou; Kong, Chi-Woon; Lee, Shou-Dong; Chen, Mi-Mi; Chao, Fang-Ping

    2013-01-01

    Abstract Purpose Retinal ischemia-associated ocular disorders are vision threatening. This study examined whether the flavonoid baicalein is able to protect against retinal ischemia/reperfusion. Methods Using rats, the intraocular pressure was raised to 120 mmHg for 60 min to induce retinal ischemia. In vitro, an ischemic-like insult, namely oxidative stress, was established by incubating dissociated retinal cells with 100 μM ascorbate and 5 μM FeSO4 (iron) for 1 h. The rats or the dissociated cells had been pretreated with baicalein (in vivo: 0.05 or 0.5 nmol; in vitro: 100 μM), vehicle (1% ethanol), or trolox (in vivo: 5 nmol; in vitro: 100 μM or 1 mM). The effects of these treatments on the retina or the retinal cells were evaluated by electrophysiology, immunohistochemistry, terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL) staining, Western blotting, or in vitro dichlorofluorescein assay. In addition, real-time-polymerase chain reaction was used to assess the retinal expression of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), vascular endothelium growth factor (VEGF), and heme oxygenase-1 (HO-1). Results The retinal changes after ischemia included a decrease in the electroretinogram b-wave amplitude, a loss of choline acetyltransferase immunolabeling amacrine cell bodies/neuronal processes, an increase in vimentin immunoreactivity, which is a marker for Müller cells, an increase in apoptotic cells in the retinal ganglion cell layer linked to a decrease in the Bcl-2 protein, and changes in the mRNA levels of HIF-1α, VEGF, MMP-9, and HO-1. Of clinical importance, the ischemic detrimental effects were concentration dependently and/or significantly (0.05 nmol and/or 0.5 nmol) altered when baicalein was applied 15 min before retinal ischemia. Most of all, 0.5 nmol baicalein significantly reduced the upregulation of MMP-9; in contrast, 5 nmol trolox only had a weak

  2. 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

  3. 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

  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. 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. 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

  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. 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. PMID:26646685

  9. 2,3-Dimethoxy-2′-hydroxychalcone ameliorates TNF-α-induced ICAM-1 expression and subsequent monocyte adhesiveness via NF-kappaB inhibition and HO-1 induction in HaCaT cells

    PubMed Central

    Kim, Hyejin; Youn, Gi Soo; An, Soo Yeon; Kwon, Hyeok Yil; Choi, Soo Young; Park, Jinseu

    2016-01-01

    Up-regulation of adhesion molecules plays an important role in the infiltration of leukocytes into the skin during the development of various inflammatory skin diseases, such as atopic dermatitis. In this study, we investigated the modulatory effects of 2,3-dimethoxy-2′-hydroxychalcone (DMHC) on tumor necrosis factor (TNF)-α-induced intercellular adhesion molecule-1 (ICAM-1) expression and monocyte adhesiveness, as well as the molecular mechanisms underlying its action in the HaCaT human keratinocyte cell line. Pre-treating HaCaT cells with DMHC significantly suppressed TNF-α-induced ICAM-1 expression and subsequent monocyte adhesiveness. DMHC inhibited TNF-α-induced activation of NF-ᴋB. In addition, DMHC induced HO-1 expression as well as NRF2 activation. Furthermore, HO-1 knockdown using siRNA reversed the inhibitory effect of DMHC on TNF-α-induced ICAM-1 expression and adhesion of monocytes to keratinocytes. These results suggest that DMHC may inhibit TNF-α-induced ICAM-1 expression and adhesion of monocytes to keratinocytes by suppressing the signaling cascades leading to NF-ᴋB activation and inducing HO-1 expression in keratinocytes. [BMB Reports 2016; 49(1): 57-62] PMID:26277982

  10. 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

  11. 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

  12. Epigallocatechin-3-Gallate Attenuates Oxidative Stress and Inflammation in Obstructive Nephropathy via NF-κB and Nrf2/HO-1 Signalling Pathway Regulation.

    PubMed

    Wang, Yanqiu; Wang, Bowen; Du, Feng; Su, Xuesong; Sun, Guangping; Zhou, Guangyu; Bian, Xiaohui; Liu, Na

    2015-09-01

    Oxidative stress and inflammation contribute importantly to the pathogenesis of chronic kidney disease (CKD). Epigallocatechin-3-gallate (EGCG), which is the most abundant and most active catechin polyphenol extracted from green tea, has been proved to have many bioactivities. In this study, the renoprotective effect of EGCG was evaluated in a widely used kidney disease model, the unilateral ureteral obstruction (UUO) mice model. After 14 days of EGCG administration, mean arterial blood pressure, body-weight and obstructed kidney weight were measured. Levels of blood urea nitrogen (BUN) and creatinine (CR) and activities of glutamic-pyruvic transaminase (GPT) and lactate dehydrogenase (LDH) in serum were estimated as indicators of renal function. Periodic acid-Schiff (PAS) staining was performed to observe the pathological changes of the obstructed kidney. Antioxidant enzymes and pro-inflammatory cytokine production were estimated to reflect the oxidative stress and inflammatory state in the obstructed kidney. Finally, the main proteins in the NF-κB and Nrf2 signalling pathway and DNA binding activity of NF-κB and Nrf2 were measured to investigate the effect of EGCG on these two pathways. The results demonstrated that EGCG could restore UUO-induced kidney weight loss and renal dysfunction. In addition, UUO-induced oxidative stress and inflammatory responses in the obstructed kidney were also prevented by EGCG. Furthermore, EGCG could induce both NF-κB and Nrf2 nuclear translocation in the UUO kidney and promote heme oxygenase-1 (HO-1) production. These results indicated that the renoprotective effect of EGCG might be through its NF-κB and Nrf2 signalling pathway regulations. PMID:25625183

  13. Infant Stimulation.

    ERIC Educational Resources Information Center

    International Children's Centre, Paris (France).

    This set of documents consists of English, French, and Spanish translations of four pamphlets on infant stimulation. The pamphlets provide information designed for lay persons, educators and primary care personnel, academics and professionals, and for health administrators and family-planning organizations. The contents cover infant needs; infant…

  14. 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

  15. 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.

  16. 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

  17. HO-1 Induction by CO-RM2 Attenuates TNF-α-Induced Cytosolic Phospholipase A2 Expression via Inhibition of PKCα-Dependent NADPH Oxidase/ROS and NF-κB

    PubMed Central

    Chi, Pei-Ling; Liu, Chun-Ju; Lee, I-Ta; Chen, Yu-Wen; Hsiao, Li-Der; Yang, Chuen-Mao

    2014-01-01

    Rheumatoid arthritis (RA) is characterized by chronic inflammatory infiltration of the synovium and elevation of proinflammatory cytokines. Cytosolic phospholipase A2 (cPLA2) is involved in the development of inflammatory diseases. Heme oxygenase-1 (HO-1) has been shown to possess anti-inflammatory properties. The objective of the study was to investigate the detailed mechanisms of TNF-α-induced cPLA2 expression and to determine whether carbon monoxide releasing molecule-2 (CO-RM2) suppresses TNF-α-induced expression of NF-κB-related proinflammatory genes, including cPLA2, via HO-1 induction in RA synovial fibroblasts (RASFs). Here, we reported that TNF-α-induced cPLA2 expression was mediated through TNFR1/PKCα-dependent signaling pathways, including NADPH oxidase (NOX) activation/ROS production and NF-κB activation. CO-RM2 significantly suppressed TNF-α-induced cPLA2 expression by inhibiting the ROS generation and the phosphorylation of NF-κB p65 and IKKα/β, but not the phosphorylation of p38 MAPK and JNK1/2. These results were further confirmed by a ChIP assay to detect the NF-κB DNA-binding activity. Our results demonstrated that induction of HO-1 by CO-RM2 exerted anti-inflammatory and antioxidant effects which were required in concert to prevent the activation of NF-κB leading to induction of various inflammatory genes implicated in the pathogenesis of RA. PMID:24616552

  18. Hesperetin Suppresses Inflammatory Responses in Lipopolysaccharide-Induced RAW 264.7 Cells via the Inhibition of NF-κB and Activation of Nrf2/HO-1 Pathways.

    PubMed

    Ren, Hua; Hao, Jilong; Liu, Taotao; Zhang, Dongyan; Lv, Hongming; Song, E; Zhu, Chao

    2016-06-01

    Hesperetin (Hesp), a common flavanone glycoside, was extracted from the fruit peel of Citrus aurantium L. (Rutaceae). Hesp has been shown to possess various biological properties, including antioxidant, neuroprotective, and anti-inflammatory properties. In this study, we investigated the protective effect of Hesp on inflammatory responses in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Our results indicated that Hesp treatment dramatically suppressed secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β; reduced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) gene expression; inhibited NF-κB (p65) phosphorylation; and blocked IκBα phosphorylation and degradation. Further studies revealed Hesp markedly enhanced the heme oxygenase (HO)-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, which were involved with inducing Nrf2 nuclear translocation and decreasing Keap1 protein expression. Together, these results indicated that the anti-inflammatory effect of Hesp may be associated with NF-κB inhibition and Nrf2/HO-1 activation. PMID:26994999

  19. Sophoraflavanone G from Sophora alopecuroides inhibits lipopolysaccharide-induced inflammation in RAW264.7 cells by targeting PI3K/Akt, JAK/STAT and Nrf2/HO-1 pathways.

    PubMed

    Guo, Chao; Yang, Lei; Luo, Jun; Zhang, Chao; Xia, Yuanzheng; Ma, Ting; Kong, Lingyi

    2016-09-01

    Sophoraflavanone G (SG), a prenylated flavonoid from Sophora alopecuroides, has been reported to have many pharmacological activities including anti-inflammation. However, the molecular mechanisms of its anti-inflammatory activity remain largely unclear. In this study we investigated the effects and the underlying molecular mechanisms of SG on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. Pretreatment with SG inhibited LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) through reducing the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). SG also decreased the expressions of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), both in the protein and gene levels. Further experiments demonstrated that SG downregulated the LPS-induced upregulation of phosphorylated phosphoinositide-3-kinase and Akt (PI3K/Akt). SG also attenuated the expression of phosphorylated Janus kinase signal transducer and activator of transcription (JAK/STAT). In addition, SG upregulated heme oxygenase-1 (HO-1) expression via nuclear translocation of nuclear factor E2-related factor 2 (Nrf2). Taken together, SG may act as a natural agent to treat some inflammatory diseases by targeting PI3K/Akt, JAK/STAT and Nrf2/HO-1 pathways. PMID:27351825

  20. 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. PMID:27294302

  1. 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

  2. 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

  3. 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. PMID:25977183

  4. Dietary extra virgin olive oil attenuates kidney injury in pristane-induced SLE model via activation of HO-1/Nrf-2 antioxidant pathway and suppression of JAK/STAT, NF-κB and MAPK activation.

    PubMed

    Aparicio-Soto, Marina; Sánchez-Hidalgo, Marina; Cárdeno, Ana; Rosillo, María Ángeles; Sánchez-Fidalgo, Susana; Utrilla, Jose; Martín-Lacave, Inés; Alarcón-de-la-Lastra, Catalina

    2016-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a widespread organ involvement. Recent studies have suggested that extra virgin olive oil (EVOO) might possess preventive effects on this immunoinflammation-related disease. However, its role in SLE remained unknown. In this work, we evaluated the effects of EVOO diet in a pristane-induced SLE model in mice. Three-month-old mice received an injection of pristane or saline solution and were fed with different experimental diets: sunflower oil diet or EVOO diet. After 24weeks, mice were sacrificed, spleens were collected and kidneys were removed for immunoinflammatory detections. The kidney expression of microsomal prostaglandin E synthase 1, heme oxygenase 1 (HO-1), nuclear factor E2-related factor 2 (Nrf-2), mitogen-activated protein kinases (MAPKs), Janus kinase/signal transducer and activator of transcription (JAK/STAT) and nuclear transcription factor-kappa B (NF-κB) pathways were studied by western blotting. In addition to macroscopic and histological analyses, serum matrix metalloproteinase 3 (MMP-3) levels and proinflammatory cytokines production in splenocytes were evaluated by enzyme-linked immunoassay. We have demonstrated that EVOO diet significantly reduced renal damage and decreased MMP-3 serum and PGE2 kidney levels as well as the proinflammatory cytokines production in splenocytes. Our data indicate that Nrf-2 and HO-1 protein expressions were up-regulated in those mice fed with EVOO and the activation of JAK/STAT, MAPK and NF-κB pathways were drastically ameliorated. These results support the interest of EVOO as a beneficial functional food exerting a preventive/palliative role in the management of SLE. PMID:26525667

  5. 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

  6. Early postnatal treatment with soluble epoxide hydrolase inhibitor or 15-deoxy-Δ(12,14)-prostagandin J2 prevents prenatal dexamethasone and postnatal high saturated fat diet induced programmed hypertension in adult rat offspring.

    PubMed

    Lu, Pei-Chen; Sheen, Jiunn-Ming; Yu, Hong-Ren; Lin, Yu-Ju; Chen, Chih-Cheng; Tiao, Mao-Meng; Tsai, Ching-Chou; Huang, Li-Tung; Tain, You-Lin

    2016-07-01

    Prenatal dexamethasone (DEX) exposure, postnatal high-fat (HF) intake, and arachidonic acid pathway are closely related to hypertension. We tested whether a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-deoxy-Δ(12,14)-prostagandin J2 (15dPGJ2) therapy can rescue programmed hypertension in the DEX+HF two-hit model. Four groups of Sprague Dawley rats were studied: control, DEX+HF, AUDA, and 15dPGJ2. Dexamethasone (0.1mg/kg body weight) was intraperitoneally administered to pregnant rats from gestational day 16-22. Male offspring received high-fat diet (D12331, Research Diets) from weaning to 4 months of age. In AUDA group, mother rats received 25mg/L in drinking water during lactation. In the 15dPGJ2 group, male offspring received 15dPGJ2 1.5mg/kg BW by subcutaneous injection once daily for 1 week after birth. We found postnatal HF diet aggravated prenatal DEX-induced programmed hypertension, which was similarly prevented by early treatment with AUDA or 15dPGJ2. The beneficial effects of AUDA and 15d-PGJ2 therapy include inhibition of SEH, increases of renal angiotensin converting enzyme-2 (ACE2) and angiotensin II type 2 receptor (AT2R) protein levels, and restoration of nitric oxide bioavailability. Better understanding of the impact of arachidonic acid pathway in the two-hit model will help prevent programmed hypertension in children exposed to corticosteroids and postnatal HF intake. PMID:27210044

  7. 15-deoxy-Δ12,14-PGJ2 promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis

    PubMed Central

    Koyani, Chintan N.; Windischhofer, Werner; Rossmann, Christine; Jin, Ge; Kickmaier, Sandra; Heinzel, Frank R.; Groschner, Klaus; Alavian-Ghavanini, Ali; Sattler, Wolfgang; Malle, Ernst

    2014-01-01

    Background Prostaglandins (PGs), lipid autacoids derived from arachidonic acid, play a pivotal role during inflammation. PGD2 synthase is abundantly expressed in heart tissue and PGD2 has recently been found to induce cardiomyocyte apoptosis. PGD2 is an unstable prostanoid metabolite; therefore the objective of the present study was to elucidate whether its final dehydration product, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2, present at high levels in ischemic myocardium) might cause cardiomyocyte damage. Methods and results Using specific (ant)agonists we show that 15d-PGJ2 induced formation of intracellular reactive oxygen species (ROS) and phosphorylation of p38 and p42/44 MAPKs via the PGD2 receptor DP2 (but not DP1 or PPARγ) in the murine atrial cardiomyocyte HL-1 cell line. Activation of the DP2-ROS-MAPK axis by 15d-PGJ2 enhanced transcription and translation of TNFα and induced apoptosis in HL-1 cardiomyocytes. Silencing of TNFα significantly attenuated the extrinsic (caspase-8) and intrinsic apoptotic pathways (bax and caspase-9), caspase-3 activation and downstream PARP cleavage and γH2AX activation. The apoptotic machinery was unaffected by intracellular calcium, transcription factor NF-κB and its downstream target p53. Of note, 9,10-dihydro-15d-PGJ2 (lacking the electrophilic carbon atom in the cyclopentenone ring) did not activate cellular responses. Selected experiments performed in primary murine cardiomyocytes confirmed data obtained in HL-1 cells namely that the intrinsic and extrinsic apoptotic cascades are activated via DP2/MAPK/TNFα signaling. Conclusions We conclude that the reactive α,β-unsaturated carbonyl group of 15d-PGJ2 is responsible for the pronounced upregulation of TNFα promoting cardiomyocyte apoptosis. We propose that inhibition of DP2 receptors could provide a possibility to modulate 15d-PGJ2-induced myocardial injury. PMID:24698234

  8. Enteric glia modulate epithelial cell proliferation and differentiation through 15-deoxy-Δ12,14-prostaglandin J2

    PubMed Central

    Bach-Ngohou, Kalyane; Mahé, Maxime M; Aubert, Philippe; Abdo, Hind; Boni, Sébastien; Bourreille, Arnaud; Denis, Marc G; Lardeux, Bernard; Neunlist, Michel; Masson, Damien

    2010-01-01

    The enteric nervous system (ENS) and its major component, enteric glial cells (EGCs), have recently been identified as a major regulator of intestinal epithelial barrier functions. Indeed, EGCs inhibit intestinal epithelial cell (IEC) proliferation and increase barrier resistance and IEC adhesion via the release of EGC-derived soluble factors. Interestingly, EGC regulation of intestinal epithelial barrier functions is reminiscent of previously reported peroxisome proliferator-activated receptor γ (PPARγ)-dependent functional effects. In this context, the present study aimed at identifying whether EGC could synthesize and release the main PPARγ ligand, 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2), and regulate IEC functions such as proliferation and differentiation via a PPARγ dependent pathway. First, we demonstrated that the lipocalin but not the haematopoetic form for prostaglandin D synthase (PGDS), the enzyme responsible of 15dPGJ2 synthesis, was expressed in EGCs of the human submucosal plexus and of the subepithelium, as well as in rat primary culture of ENS and EGC lines. Next, 15dPGJ2 was identified in EGC supernatants of various EGC lines. 15dPGJ2 reproduced EGC inhibitory effects upon IEC proliferation, and inhibition of lipocalin PGDS expression by shRNA abrogated these effects. Furthermore, EGCs induced nuclear translocation of PPARγ in IEC, and both EGC and 15dPGJ2 effects upon IEC proliferation were prevented by the PPARγ antagonist GW9662. Finally, EGC induced differentiation-related gene expression in IEC through a PPARγ-dependent pathway. Our results identified 15dPGJ2 as a novel glial-derived mediator involved in the control of IEC proliferation/differentiation through activation of PPARγ. They also suggest that alterations of glial PGDS expression may modify intestinal epithelial barrier functions and be involved in the development of pathologies such as cancer or inflammatory bowel diseases. PMID:20478974

  9. Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells

    SciTech Connect

    Zhao Guixiang; Etherton, Terry D.; Martin, Keith R.; Vanden Heuvel, John P.; Gillies, Peter J.; West, Sheila G.; Kris-Etherton, Penny M. . E-mail: pmk3@psu.edu

    2005-10-28

    The effects of linoleic acid (LA), {alpha}-linolenic acid (ALA), and docosahexaenoic acid (DHA) were compared to that of palmitic acid (PA), on inflammatory responses in human monocytic THP-1 cells. When cells were pre-incubated with fatty acids for 2-h and then stimulated with lipopolysaccharide for 24-h in the presence of fatty acids, secretion of interleukin (IL)-6, IL-1{beta}, and tumor necrosis factor-{alpha} (TNF{alpha}) was significantly decreased after treatment with LA, ALA, and DHA versus PA (P < 0.01 for all); ALA and DHA elicited more favorable effects. These effects were comparable to those for 15-deoxy-{delta}{sup 12,14}-prostaglandin J2 (15d-PGJ2) and were dose-dependent. In addition, LA, ALA, and DHA decreased IL-6, IL-1{beta}, and TNF{alpha} gene expression (P < 0.05 for all) and nuclear factor (NF)-{kappa}B DNA-binding activity, whereas peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) DNA-binding activity was increased. The results indicate that the anti-inflammatory effects of polyunsaturated fatty acids may be, in part, due to the inhibition of NF-{kappa}B activation via activation of PPAR{gamma}.

  10. 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

  11. ACTH (cosyntropin) stimulation test

    MedlinePlus

    ... The ACTH stimulation test measures how well the adrenal glands respond to adrenocorticotropic hormone ( ACTH ). ACTH is a ... produced in the pituitary gland that stimulates the adrenal glands to release a hormone called cortisol. How the ...

  12. 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.

  13. 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

  14. 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 Central

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

    2014-01-01

    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. PMID:25535073

  15. 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

  16. Cordycepin, 3'-deoxyadenosine, prevents rat hearts from ischemia/reperfusion injury via activation of Akt/GSK-3β/p70S6K signaling pathway and HO-1 expression.

    PubMed

    Park, Eun-Seok; Kang, Do-Hyun; Yang, Min-Kyu; Kang, Jun Chul; Jang, Yong Chang; Park, Jong Seok; Kim, Si-Kwan; Shin, Hwa-Sup

    2014-03-01

    Cordycepin (3'-deoxyadenosine) isolated from Cordyceps militaris, a species of the fungal genus Cordyceps, has been shown to exhibit many pharmacological functions, such as anticancer, anti-inflammatory, and antioxidant activities. In this study, we investigated the preventive role of cordycepin in ischemic/reperfusion (I/R) injury of isolated rat hearts and anesthetized rats. After Sprague-Dawley rats received cordycepin (3, 10, and 30 mg/kg) or control (0.5 % carboxyl methylcellulose) orally once a day for a week, hearts were isolated and mounted on Langendorff heart perfusion system. Isolated hearts were perfused with Krebs-Henseleit buffer for 15-min pre-ischemic stabilization period and subjected to 30-min global ischemia and 30-min reperfusion. Cordycepin administration (10 mg/kg, p.o.) significantly increased left ventricular developed pressure during the reperfusion period compared to that in the control group, but without any effect on coronary flow. Cordycepin (10 mg/kg, p.o.) significantly increased the phosphorylation of Akt/GSK-3β/p70S6K pathways, which are known to modulate multiple survival pathways. In addition, cordycepin decreased Bax and cleaved caspase-3 expression while increasing Bcl-2 expression, Bcl-2/Bax ratio, and heme oxygenase (HO-1) expression in isolated rat hearts. In anesthetized rats subjected to 30 min occlusion of left anterior descending coronary artery/2.5-h reperfusion, cordycepin (1, 3, and 10 mg/kg, i.v.) administered 15 min before the onset of ischemia dose-dependently decreased the infarct size in left ventricle. In conclusion, cordycepin could be an attractive therapeutic candidate with oral activity against I/R-associated heart diseases such as myocardial infarction. PMID:24178833

  17. Hyperbaric Oxygen Preconditioning Attenuates Hemorrhagic Transformation through Increasing PPARγ in Hyperglycemic MCAO Rats

    PubMed Central

    Bian, Hetao; Hu, Qin; Liang, Xiping; Chen, Di; Li, Bo; Tang, Jiping; Zhang, John H.

    2014-01-01

    Hyperbaric oxygen preconditioning (HBO-PC) has been demonstrated to attenuate hemorrhagic transformation (HT) after middle cerebral artery occlusion (MCAO) in hyperglycemic rats. However, the mechanisms remain to be illustrated. Recently, HBO-PC has been shown to activate peroxisome proliferator-activated receptor-gamma (PPARγ) by increasing 15d-PGJ2 in primary cultured neurons. We hypothesize that HBO-PC reduces HT by suppressing inflammation through increasing 15d-PGJ2 and activating PPARγ in hyperglycemic MCAO rats. HBO (2.5 ATA) was administrated for 1 hour daily for 5 consecutive days. The PPARγ inhibitor GW9662 was administrated intraperitoneally to designated animals. Infarction volume, hemorrhage volume, neurological scores and mortality were analyzed. The levels of 15d-PGJ2, PPARγ, TNF-α and IL-1β, tight junction proteins as well as the activity of MMP-2 and MMP-9 were evaluated 24 hours after MCAO. HBO-PC reduced HT, improved neurological function, down-regulated inflammatory molecules and inhibited the activation of MMP-9 by increasing 15d-PGJ2 and PPARγ at 24 hours after MCAO. The results suggested HBO-PC might be an alternative measure to decrease HT in ischemic stroke. PMID:25542160

  18. 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

  19. 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

  20. Music acupuncture stimulation method.

    PubMed

    Brătilă, F; Moldovan, C

    2007-01-01

    Harmonic Medicine is the model using the theory that the body rhythms synchronize to an outer rhythm applied for therapeutic purpose, can restores the energy balance in acupuncture channels and organs and the condition of well-being. The purpose of this scientific work was to demonstrate the role played by harmonic sounds in the stimulation of the Lung (LU) Meridian (Shoutaiyin Feijing) and of the Kidney (KI) Meridian (Zushaoyin Shenjing). It was used an original method that included: measurement and electronic sound stimulation of the Meridian Entry Point, measurement of Meridian Exit Point, computer data processing, bio feed-back adjustment of the music stimulation parameters. After data processing, it was found that the sound stimulation of the Lung Meridian Frequency is optimal between 122 Hz and 128 Hz, with an average of 124 Hz (87% of the subjects) and for Kidney Meridian from 118 Hz to 121 Hz, with an average of 120 Hz (67% of the subjects). The acupuncture stimulation was more intense for female subjects (> 7%) than for the male ones. We preliminarily consider that an informational resonance phenomenon can be developed between the acupuncture music stimulation frequency and the cellular dipole frequency, being a really "resonant frequency signature" of an acupoint. The harmonic generation and the electronic excitation or low-excitation status of an acupuncture point may be considered as a resonance mechanism. By this kind of acupunctural stimulation, a symphony may act and play a healer role. PMID:18767418

  1. Anti-inflammatory effect of ginsenoside Rg5 in lipopolysaccharide-stimulated BV2 microglial cells.

    PubMed

    Lee, Yu Young; Park, Jin-Sun; Jung, Ji-Sun; Kim, Dong-Hyun; Kim, Hee-Sun

    2013-01-01

    Microglia are resident immune cells in the central nervous system. They play a role in normal brain development and neuronal recovery. However, overactivation of microglia causes neuronal death, which is associated with neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Therefore, controlling microglial activation has been suggested as an important target for treatment of neurodegenerative diseases. In the present study, we investigated the anti-inflammatory effect of ginsenoside Rg5 in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and rat primary microglia. The data showed that Rg5 suppressed LPS-induced nitric oxide (NO) production and proinflammatory TNF-α secretion. In addition, Rg5 inhibited the mRNA expressions of iNOS, TNF-α, IL-1b, COX-2 and MMP-9 induced by LPS. Further mechanistic studies revealed that Rg5 inhibited the phophorylations of PI3K/Akt and MAPKs and the DNA binding activities of NF-kB and AP-1, which are upstream molecules controlling inflammatory reactions. Moreover, Rg5 suppressed ROS production with upregulation of hemeoxygenase-1 (HO-1) expression in LPS-stimulated BV2 cells. Overall, microglial inactivation by ginsenoside Rg5 may provide a therapeutic potential for various neuroinflammatory disorders. PMID:23698769

  2. Stimulating Children to Write.

    ERIC Educational Resources Information Center

    Edwards, Roy

    1985-01-01

    Special education students can be stimulated to write through a variety of activities, including representation, publicity and display tasks, activities featuring photographs, use of music and poetry, and projects in which students finish stories and describe novel materials. (CL)

  3. 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 ...

  4. Spinal cord stimulation

    MedlinePlus

    Spinal cord stimulation is a treatment for pain that uses a mild electric current to block nerve impulses ... stretched into the space on top of your spinal cord. These wires will be connected to a small ...

  5. Growth hormone stimulation test

    MedlinePlus

    The growth hormone (GH) stimulation test measures the ability of the body to produce GH. ... killing medicine (antiseptic). The first sample is drawn early in the morning. Medicine is given through the ...

  6. The point mutation UCH-L1 C152A protects primary neurons against cyclopentenone prostaglandin-induced cytotoxicity: implications for post-ischemic neuronal injury

    PubMed Central

    Liu, H; Li, W; Rose, M E; Hickey, R W; Chen, J; Uechi, G T; Balasubramani, M; Day, B W; Patel, K V; Graham, S H

    2015-01-01

    Cyclopentenone prostaglandins (CyPGs), such as 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2), are reactive prostaglandin metabolites exerting a variety of biological effects. CyPGs are produced in ischemic brain and disrupt the ubiquitin-proteasome system (UPS). Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a brain-specific deubiquitinating enzyme that has been linked to neurodegenerative diseases. Using tandem mass spectrometry (MS) analyses, we found that the C152 site of UCH-L1 is adducted by CyPGs. Mutation of C152 to alanine (C152A) inhibited CyPG modification and conserved recombinant UCH-L1 protein hydrolase activity after 15dPGJ2 treatment. A knock-in (KI) mouse expressing the UCH-L1 C152A mutation was constructed with the bacterial artificial chromosome (BAC) technique. Brain expression and distribution of UCH-L1 in the KI mouse was similar to that of wild type (WT) as determined by western blotting. Primary cortical neurons derived from KI mice were resistant to 15dPGJ2 cytotoxicity compared with neurons from WT mice as detected by the WST-1 cell viability assay and caspase-3 and poly ADP ribose polymerase (PARP) cleavage. This protective effect was accompanied with significantly less ubiquitinated protein accumulation and aggregation as well as less UCH-L1 aggregation in C152A KI primary neurons after 15dPGJ2 treatment. Additionally, 15dPGJ2-induced axonal injury was also significantly attenuated in KI neurons as compared with WT. Taken together, these studies indicate that UCH-L1 function is important in hypoxic neuronal death, and the C152 site of UCH-L1 has a significant role in neuronal survival after hypoxic/ischemic injury. PMID:26539913

  7. Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines.

    PubMed

    Turpaev, Kyril; Welsh, Nils

    2016-08-01

    We presently report that treatment with tyrphostin AG-126 (2-(3-hydroxy-4-nitrobenzylidene)malononitrile) and ten other aromatic malononitrile compounds (AMN) improves the resistance of insulin-producing βTC6, RIN-5AH, and MIN6 cells to oxidative stress and pro-inflammatory cytokines. On the molecular level AMN compounds promote nuclear accumulation of the Nrf2 transcription factor and expression of the cytoprotective genes heme ogygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1), inhibit cytokine-dependent inducible nitric oxide synthase (iNOS) induction, suppress intracellular production of reactive oxygen species in βTC6 and counteract to impairments of glucose-stimulated insulin secretion induced by pro-inflammatory cytokines in MIN6 cells. Nrf2 up-regulation and HO-1 induction by AG-126 are attenuated at the presence of siRNA against Nrf2 and brusatol, an inhibitor of the Nrf2 signaling pathway. Our present results indicate that in respect of inhibition of IL-1β-dependent iNOS induction, βTC6 cells are more sensitive to EMK 1071 (2-((5-methylthiophen-2-yl)methylene)malononitrile) and EMK 31 (2-(4-hydroxy-3-methoxybenzylidene)malononitrile) as compared to other analyzed AMN compounds. We suggest that the ability of AMN compounds to inhibit iNOS induction and other cytokine-induced transcriptional events might be a tool to achieve improved β-cell survival and functionality. PMID:27178899

  8. Deep Brain Stimulation

    PubMed Central

    Perlmutter, Joel S.; Mink, Jonathan W.

    2015-01-01

    Deep brain stimulation (DBS) has provided remarkable benefits for people with a variety of neurologic conditions. Stimulation of the ventral intermediate nucleus of the thalamus can dramatically relieve tremor associated with essential tremor or Parkinson disease (PD). Similarly, stimulation of the subthalamic nucleus or the internal segment of the globus pallidus can substantially reduce bradykinesia, rigidity, tremor, and gait difficulties in people with PD. Multiple groups are attempting to extend this mode of treatment to other conditions. Yet, the precise mechanism of action of DBS remains uncertain. Such studies have importance that extends beyond clinical therapeutics. Investigations of the mechanisms of action of DBS have the potential to clarify fundamental issues such as the functional anatomy of selected brain circuits and the relationship between activity in those circuits and behavior. Although we review relevant clinical issues, we emphasize the importance of current and future investigations on these topics. PMID:16776585

  9. 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.

  10. 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.

  11. Neural stimulation with optical radiation

    PubMed Central

    Richter, Claus-Peter; Matic, Agnella Izzo; Wells, Jonathon D.; Jansen, E. Duco; Walsh, Joseph T.

    2012-01-01

    This paper reviews the existing research on infrared neural stimulation, a means of artificially stimulating neurons that has been proposed as an alternative to electrical stimulation. Infrared neural stimulation (INS) is defined as the direct induction of an evoked potential in response to a transient targeted deposition of optical energy. The foremost advantage of using optical radiation for neural stimulation is its spatial resolution. Exogenously applied or trans-genetically synthesized fluorophores are not used to achieve stimulation. Here, current work on INS is presented for motor nerves, sensory nerves, central nervous system, and in vitro preparations. A discussion follows addressing the mechanism of INS and its potential use in neuroprostheses. A brief review of neural depolarization involving other optical methods is also presented. Topics covered include optical stimulation concurrent with electrical stimulation, optical stimulation using exogenous fluorophores, and optical stimulation by transgenic induction of light-gated ion channels. PMID:23082105

  12. Neural stimulation with optical radiation.

    PubMed

    Richter, Claus-Peter; Matic, Agnella Izzo; Wells, Jonathon D; Jansen, E Duco; Walsh, Joseph T

    2011-01-01

    This paper reviews the existing research on infrared neural stimulation, a means of artificially stimulating neurons that has been proposed as an alternative to electrical stimulation. Infrared neural stimulation (INS) is defined as the direct induction of an evoked potential in response to a transient targeted deposition of optical energy. The foremost advantage of using optical radiation for neural stimulation is its spatial resolution. Exogenously applied or trans-genetically synthesized fluorophores are not used to achieve stimulation. Here, current work on INS is presented for motor nerves, sensory nerves, central nervous system, and in vitro preparations. A discussion follows addressing the mechanism of INS and its potential use in neuroprostheses. A brief review of neural depolarization involving other optical methods is also presented. Topics covered include optical stimulation concurrent with electrical stimulation, optical stimulation using exogenous fluorophores, and optical stimulation by transgenic induction of light-gated ion channels. PMID:23082105

  13. 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

  14. Copeptin under glucagon stimulation.

    PubMed

    Lewandowski, Krzysztof C; Lewiński, Andrzej; Skowrońska-Jóźwiak, Elżbieta; Stasiak, Magdalena; Horzelski, Wojciech; Brabant, Georg

    2016-05-01

    Stimulation of growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion by glucagon is a standard procedure to assess pituitary dysfunction but the pathomechanism of glucagon action remains unclear. As arginine vasopressin (AVP) may act on the release of both, GH and ACTH, we tested here the role of AVP in GST by measuring a stable precursor fragment, copeptin, which is stoichiometrically secreted with AVP in a 1:1 ratio. ACTH, cortisol, GH, and copeptin were measured at 0, 60, 90, 120, 150, and 180 min during GST in 79 subjects: healthy controls (Group 1, n = 32), subjects with pituitary disease, but with adequate cortisol and GH responses during GST (Group 2, n = 29), and those with overt hypopituitarism (Group 3, n = 18). Copeptin concentrations significantly increased over baseline 150 and 180 min following glucagon stimulation in controls and patients with intact pituitary function but not in hypopituitarism. Copeptin concentrations were stimulated over time and the maximal increment correlated with ACTH, while correlations between copeptin and GH were weaker. Interestingly, copeptin as well as GH secretion was significantly attenuated when comparing subjects within the highest to those in the lowest BMI quartile (p < 0.05). Copeptin is significantly released following glucagon stimulation. As this release is BMI-dependent, the time-dependent relation between copeptin and GH may be obscured, whereas the close relation to ACTH suggests that AVP/copeptin release might be linked to the activation of the adrenal axis. PMID:26578365

  15. Brain stimulation in migraine.

    PubMed

    Brighina, Filippo; Cosentino, Giuseppe; Fierro, Brigida

    2013-01-01

    Migraine is a very prevalent disease with great individual disability and socioeconomic burden. Despite intensive research effort in recent years, the etiopathogenesis of the disease remains to be elucidated. Recently, much importance has been given to mechanisms underlying the cortical excitability that has been suggested to be dysfunctional in migraine. In recent years, noninvasive brain stimulation techniques based on magnetic fields (transcranial magnetic stimulation, TMS) and on direct electrical currents (transcranial direct current stimulation, tDCS) have been shown to be safe and effective tools to explore the issue of cortical excitability, activation, and plasticity in migraine. Moreover, TMS, repetitive TMS (rTMS), and tDCS, thanks to their ability to interfere with and/or modulate cortical activity inducing plastic, persistent effects, have been also explored as potential therapeutic approaches, opening an interesting perspective for noninvasive neurostimulation for both symptomatic and preventive treatment of migraine and other types of headache. In this chapter we critically review evidence regarding the role of noninvasive brain stimulation in the pathophysiology and treatment of migraine, delineating the advantages and limits of these techniques together with potential development and future application. PMID:24112926

  16. Heliostat Stimulator operator's manual

    SciTech Connect

    Not Available

    1980-11-01

    The Heliostat Stimulator is a portable test tool, housed in a suitcase, which can be used to perform the following functions: (1) acceptance testing of newly manufactured Heliostat Controllers (HC) and Heliostat Field Controllers (HFC); (2) aid in the installation and alignment of Heliostats; and (3) provide diagnostic troubleshooting capability in the event of Heliostat failure in the field.

  17. 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

  18. 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.

  19. Occipital nerve stimulation.

    PubMed

    Mammis, Antonios; Agarwal, Nitin; Mogilner, Alon Y

    2015-01-01

    Occipital nerve stimulation (ONS) is a form of neuromodulation therapy aimed at treating intractable headache and craniofacial pain. The therapy utilizes neurostimulating electrodes placed subcutaneously in the occipital region and connected to a permanently implanted programmable pulse generator identical to those used for dorsal column/spinal cord stimulation. The presumed mechanisms of action involve modulation of the trigeminocervical complex, as well as closure of the physiologic pain gate. ONS is a reversible, nondestructive therapy, which can be tailored to a patient's individual needs. Typically, candidates for successful ONS include those patients with migraines, Chiari malformation, or occipital neuralgia. However, recent MRSA infections, unrealistic expectations, and psychiatric comorbidities are generally contraindications. As with any invasive procedure, complications may occur including lead migration, infection, wound erosion, device failure, muscle spasms, and pain. The success of this therapy is dependent on careful patient selection, a preimplantation trial, meticulous implantation technique, programming strategies, and complication avoidance. PMID:25411143

  20. 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

  1. 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.

  2. 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.

  3. Rosiglitzone Suppresses Angiotensin II-Induced Production of KLF5 and Cell Proliferation in Rat Vascular Smooth Muscle Cells

    PubMed Central

    Gao, Dengfeng; Hao, Guanghua; Meng, Zhe; Ning, Ning; Yang, Guang; Liu, Zhongwei; Dong, Xin; Niu, Xiaolin

    2015-01-01

    Krüppel-like factor (KLF) 5, which initiates vascular smooth muscle cell (VSMC) proliferation, also participates in Angiotensin (Ang) II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, in aortas of Ang II-infused rats, vascular remodeling and KLF5 expression were markedly increased, and its target gene cyclin D1 was overexpressed. Co-treatment with rosiglitazone diminished these changes. In growth-arrested VSMCs, PPAR-γ agonists (rosiglitazone and 15d-PGJ2) dose-dependently inhibited Ang II-induced cell proliferation and expression of KLF5 and cyclin D1. Moreover, these effects were attenuated by the PPAR-γ antagonists GW9662, bisphenol A diglycidyl ether and PPAR-γ specific siRNA. Furthermore, rosiglitazone inhibited Ang II-induced phosphorylation of protein kinase C (PKC) ζ and extracellular signal-regulated kinase (ERK) 1/2 and activation of early growth response protein (Egr). In conclusion, in Ang II-stimulated VSMCs, rosiglitazone might have an antiproliferative effect through mechanisms that include reducing KLF5 expression, and a crosstalk between PPAR-γ and PKCζ/ERK1/2/Egr may be involved in. These findings not only provide a previously unrecognized mechanism by which PPAR-γ agonists inhibit VSMC proliferation, but also document a novel evidence for the beneficial vascular effect of PPAR-γ activation. PMID:25874449

  4. Broadband stimulated Raman backscattering

    NASA Astrophysics Data System (ADS)

    Landgraf, B.; Aurand, B.; Lehmann, G.; Gangolf, T.; Schnell, M.; Kühl, T.; Spielmann, C.

    2016-07-01

    Broadband amplification employing stimulated Raman backscattering is demonstrated. Using seed pulses with a bandwidth of about 200 nm, we study the amplification in a wide spectral range in a single laser shot. With chirped pump pulses and a Ne gas jet, we observed under optimized conditions, amplification in a range of about 80 nm, which is sufficient to support the amplification of sub-20 fs pulses. This broad amplification range is also in excellent agreement with PIC simulations. The conversion efficiency is at certain wavelengths as high as 1.2% and was measured to be better than 6 × 10‑3 on average.

  5. Geothermal well stimulation

    SciTech Connect

    Sinclair, A.R.; Pittard, F.J.; Hanold, R.J.

    1980-01-01

    All available data on proppants and fluids were examined to determine areas in technology that need development for 300 to 500/sup 0/F (150/sup 0/ to 265/sup 0/C) hydrothermal wells. While fluid properties have been examined well into the 450/sup 0/F range, proppants have not been previously tested at elevated temperatures except in a few instances. The latest test data at geothermal temperatures is presented and some possible proppants and fluid systems that can be used are shown. Also discussed are alternative stimulation techniques for geothermal wells.

  6. 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

  7. Therapeutic stimulation versus ablation.

    PubMed

    Hariz, Marwan I; Hariz, Gun-Marie

    2013-01-01

    The renaissance of functional stereotactic neurosurgery was pioneered in the mid 1980s by Laitinen's introduction of Leksell's posteroventral pallidotomy for Parkinson´s disease (PD). This ablative procedure experienced a worldwide spread in the 1990s, owing to its excellent effect on dyskinesias and other symptoms of post-l-dopa PD. Modern deep brain stimulation (DBS), pioneered by Benabid and Pollak in 1987 for the treatment of tremor, first became popular when it was applied to the subthalamic nucleus (STN) in the mid 1990s, where it demonstrated a striking effect on all cardinal symptoms of advanced PD, and permitted reduced dosages of medication. DBS, as a nondestructive, adaptable, and reversible procedure that is proving safe in bilateral surgery on basal ganglia, has great appeal to clinicians and patients alike, despite the fact that it is expensive, laborious, and relies on very strict patient selection criteria, especially for STN DBS. Psychiatric surgery has experienced the same phenomenon, with DBS supplanting completely stereotactic ablative procedures. This chapter discusses the pros and cons of ablation versus stimulation and investigates the reasons why DBS has overshadowed proven efficient ablative procedures such as pallidotomy for PD, and capsulotomy and cingulotomy for obsessive-compulsive disorder and depression. PMID:24112885

  8. BIOPHYSICAL STIMULATION FOR NONUNIONS.

    PubMed

    Della Bella, E; Tschon, M; Stagni, C; Dallari, D; Fini, M

    2015-01-01

    Nonunions account for 5-10% on the total number of fractures. Biophysical stimulation is a non-surgical, conservative, frequently used therapy in nonunions and a greater efficacy has been demonstrated for pulsed electromagnetic fields (PEMF). The mechanisms of action of PEMF at cellular and molecular levels are still under debate and no dose-response study is available. Moreover, the vast majority of in vitro studies were conducted on healthy cells. The primary aim of the research was to investigate the capacity of PEMF with different exposure times to stimulate the osteogenic process in cells from the callus of a nonunion patient. Another important objective was the characterization of nonunion cells in terms of clonogenicity, cluster of differentiation expression and the tri-lineage differentiation capacity. Overall, the results indicated the presence of osteochondroprogenitor cells in the callus of a nonunion, with an impairment in the osteogenic differentiation process. PEMF may enhance cell viability, the formation of osteoid matrix and accelerate the process of osteogenic differentiation. BMP-4 production, TIMP1 and TIMP2 expression were influenced, as well as VEGFA, whose early upregulation may account for a possible improvement in both the osteogenic and vasculogenic processes. In conclusion, even with some discussed limitations, these preliminary data showed the presence of a multipotent progenitor population and suggested some hints of the effect of PEMF on nonunion cells. PMID:26652488

  9. New compound, 5-O-isoferuloyl-2-deoxy-D-ribono-γ-lacton from Clematis mandshurica: Anti-inflammatory effects in lipopolysaccharide-stimulated BV2 microglial cells.

    PubMed

    Dilshara, Matharage Gayani; Lee, Kyoung-Tae; Lee, Chang-Min; Choi, Yung Hyun; Lee, Hak-Ju; Choi, Il-Whan; Kim, Gi-Young

    2015-01-01

    Microglia are main immune cells to exacerbate neural disorders in persistent overactivating. Therefore, it is a good strategy to regulate microglia for the treatment of neural disorders. In the present study, we isolated and characterized a novel compound, 5-O-isoferuloyl-2-deoxy-D-ribono-γ-lacton (5-DRL) from Clematis mandshurica, and evaluated its anti-inflammatory effect in lipopolysaccharide (LPS)-treated BV2 microglial cells. 5-DRL inhibited the expression of LPS-stimulated proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2), as well as their regulatory genes inducible NO syntheses (iNOS) and cyclooxygenase-2 (COX-2). 5-DRL also downregulated the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) through suppression of the nuclear translocation of the NF-κB subunits, p65 and p50. Consistent with the inhibition of iNOS and COX-2 via NF-κB activity with 5-DRL, an inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC), also led to the suppression of LPS-induced iNOS and COX-2 expression. Additionally, 5-DRL corresponding with antioxidants, N-acetylcysteine (NAC) and glutathione (GSH), remarkably inhibited reactive oxygen species (ROS) generation. Both NAC and GSH, thus attenuated the expression of iNOS and COX-2 by suppressing NF-κB activation, indicating that 5-DRL suppresses LPS-induced iNOS and COX-2 expression through downregulation of the ROS-dependent NF-κB signaling pathway. The present study also indicated that 5-DRL suppresses NO and PGE2 production by inducing heme oxygenase-1 (HO-1) via nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, the present data indicate that 5-DRL attenuates the production of proinflammatory mediators such as NO and PGE2 as well as their regulatory genes in LPS-stimulated BV2 microglial cells by inhibiting ROS-dependent NF-κB activation and stimulating the Nrf2/HO-1 signal pathway. These data may be implicated in the application of 5-DRL in LPS-stimulated

  10. Cytoprotective Role of Nrf2 in Electrical Pulse Stimulated C2C12 Myotube

    PubMed Central

    Horie, Masaki; Warabi, Eiji; Komine, Shoichi; Oh, Sechang; Shoda, Junichi

    2015-01-01

    Regular physical exercise is central to a healthy lifestyle. However, exercise-related muscle contraction can induce reactive oxygen species and reactive nitrogen species (ROS/RNS) production in skeletal muscle. The nuclear factor-E2-related factor-2 (Nrf2) transcription factor is a cellular sensor for oxidative stress. Regulation of nuclear Nrf2 signaling regulates antioxidant responses and protects organ structure and function. However, the role of Nrf2 in exercise- or contraction-induced ROS/RNS production in skeletal muscle is not clear. In this study, using differentiated C2C12 cells and electrical pulse stimulation (EPS) of muscle contraction, we explored whether Nrf2 plays a role in the skeletal muscle response to muscle contraction-induced ROS/RNS. We found that EPS (40 V, 1 Hz, 2 ms) stimulated ROS/RNS accumulation and Nrf2 activation. We also showed that expression of NQO1, HO-1 and GCLM increased after EPS-induced muscle contraction and was remarkably suppressed in cells with Nrf2 knockdown. We also found that the antioxidant N-acetylcysteine (NAC) significantly attenuated Nrf2 activation after EPS, whereas the nitric oxide synthetase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) did not. Furthermore, Nrf2 knockdown after EPS markedly decreased ROS/RNS redox potential and cell viability and increased expression of the apoptosis marker Annexin V in C2C12 myotubes. These results indicate that Nrf2 activation and expression of Nrf2 regulated-genes protected muscle against the increased ROS caused by EPS-induced muscle contraction. Thus, our findings suggest that Nrf2 may be a key factor for preservation of muscle function during muscle contraction. PMID:26658309

  11. 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

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. Femtosecond Stimulated Raman Spectroscopy.

    PubMed

    Dietze, Daniel R; Mathies, Richard A

    2016-05-01

    Femtosecond stimulated Raman spectroscopy (FSRS) is an ultrafast nonlinear optical technique that provides vibrational structural information with high temporal (sub-50 fs) precision and high spectral (10 cm(-1) ) resolution. Since the first full demonstration of its capabilities ≈15 years ago, FSRS has evolved into a mature technique, giving deep insights into chemical and biochemical reaction dynamics that would be inaccessible with any other technique. It is now being routinely applied to virtually all possible photochemical reactions and systems spanning from single molecules in solution to thin films, bulk crystals and macromolecular proteins. This review starts with an historic overview and discusses the theoretical and experimental concepts behind this technology. Emphasis is put on the current state-of-the-art experimental realization and several variations of FSRS that have been developed. The unique capabilities of FSRS are illustrated through a comprehensive presentation of experiments to date followed by prospects. PMID:26919612

  17. 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

  18. Stimulated coherent transition radiation

    SciTech Connect

    Hung-chi Lihn

    1996-03-01

    Coherent radiation emitted from a relativistic electron bunch consists of wavelengths longer than or comparable to the bunch length. The intensity of this radiation out-numbers that of its incoherent counterpart, which extends to wavelengths shorter than the bunch length, by a factor equal to the number of electrons in the bunch. In typical accelerators, this factor is about 8 to 11 orders of magnitude. The spectrum of the coherent radiation is determined by the Fourier transform of the electron bunch distribution and, therefore, contains information of the bunch distribution. Coherent transition radiation emitted from subpicosecond electron bunches at the Stanford SUNSHINE facility is observed in the far-infrared regime through a room-temperature pyroelectric bolometer and characterized through the electron bunch-length study. To measure the bunch length, a new frequency-resolved subpicosecond bunch-length measuring system is developed. This system uses a far-infrared Michelson interferometer to measure the spectrum of coherent transition radiation through optical autocorrelation with resolution far better than existing time-resolved methods. Hence, the radiation spectrum and the bunch length are deduced from the autocorrelation measurement. To study the stimulation of coherent transition radiation, a special cavity named BRAICER is invented. Far-infrared light pulses of coherent transition radiation emitted from electron bunches are delayed and circulated in the cavity to coincide with subsequent incoming electron bunches. This coincidence of light pulses with electron bunches enables the light to do work on electrons, and thus stimulates more radiated energy. The possibilities of extending the bunch-length measuring system to measure the three-dimensional bunch distribution and making the BRAICER cavity a broadband, high-intensity, coherent, far-infrared light source are also discussed.

  19. Usage possibilities of laser stimulation in ophthalmology

    NASA Astrophysics Data System (ADS)

    Switka-Wieclawska, Iwona; Kecik, Tadeusz

    1996-03-01

    The laser stimulation is used in ophthalmology as a supplement toother way of therapy. Nowadays, the following types of procedures are being performed: eyeball anterior segment stimulation, lacrimal gland stimulation, eyeball posterior pole stimulation, trigeminal nerve opening stimulation. Laser stimulation can be used as an independent procedure or together with pharmacological treatment.

  20. 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.

  1. 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.

  2. 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. PMID:11067581

  3. Anti-inflammatory potential of peat moss extracts in lipopolysaccharide-stimulated RAW 264.7 macrophages.

    PubMed

    Choi, Woo-Suk; Jeong, Jin-Woo; Kim, Sung Ok; Kim, Gi-Young; Kim, Byung-Woo; Kim, Cheol Min; Seo, Yong-Bae; Kim, Woe-Yeon; Lee, Sang-Yeol; Jo, Kwon-Ho; Choi, Young Ju; Choi, Yung Hyun; Kim, Gun-Do

    2014-10-01

    The aim of the present study was to identify the anti-inflammatory and anti-oxidative effects of peat moss aqueous extract (PME) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. To demonstrate the anti-inflammatory and antioxidant effects of PME, the levels of nitric oxide (NO) and cytokines were measured using Griess reagent and cytokine ELISA kits, respectively. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analysis were conducted to evaluate the expression of genes and proteins. Immunofluorescence was used to measure the expression and translocation of transcription factors. Pre-treatment with PME inhibited the production of prostaglandin E(2) and NO by suppressing the gene expression of cyclooxygenase-2 and inducible NO synthase, respectively. The LPS-stimulated gene expression and the production of tumor necrosis factor-α and interleukin-1β were significantly reduced by PME. In the LPS-stimulated RAW 264.7 cells, nuclear factor‑κB (NF-κB) translocated from the cytosol to the nucleus, while pre-treatment with PME induced the sequestration of NF-κB in the cytosol through the inhibition of IκBα degradation. In the same manner, PME contributed to the inhibition of the activation of mitogen-activated protein kinases. In addition, the PME-treated RAW 264.7 cells facilitated the activation of nuclear factor-like 2 (Nrf2) , and in turn, enhanced heme oxygenase-1 (HO-1) expression. These results indicate that PME exerts anti-inflammatory and antioxidant effects, and suggest that PME may neutralize inflammation and prevent cellular damage by oxidative stress. PMID:25109657

  4. 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%.

  5. 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…

  6. 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…

  7. Early Identification and Infant Stimulation

    ERIC Educational Resources Information Center

    Lintz, Brenda

    1976-01-01

    This article describes the Zucker Center's program in Toledo, Ohio which identifies children with developmental delays and enrolls them in a demonstration infant stimulation program. The center provides educational programs in neonatal care, nutrition, general stimulation, and parenting techniques. Available from: PS 504 969. (JMB)

  8. Dichotic Stimulation and Mental Retardation.

    ERIC Educational Resources Information Center

    Mosley, James L.; Virbancic, Mirna I.

    1990-01-01

    This paper reviews literature on the use of dichotic stimulation in individuals with mental retardation, and examines how noninvasive dichotic stimulation relates to hemisphere lateralization. Common findings are discussed concerning direction and magnitude of ear asymmetries, patterns of intrusion errors, and speech lateralization of Down…

  9. 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. PMID:25432887

  10. 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. PMID:27013938

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma.

    PubMed

    Eucker, Jan; Sterz, Jan; Krebbel, Holger; Zavrski, Ivana; Kaiser, Martin; Zang, Chuanbing; Heider, Ulrike; Jakob, Christian; Elstner, Elena; Sezer, Orhan

    2006-08-01

    Peroxisome proliferator-activated receptor-gamma, a nuclear receptor and transcription factor, and its natural and synthetic ligands have become a focus of novel approaches to induction of apoptosis in solid tumors and hematologic malignancies, including malignant B-lineage cells. The effect on mantle cell lymphoma, a subtype with dismal prognosis, has not yet been analyzed. We investigated the effect of 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), pioglitazone (PGZ) or rosiglitazone (RGZ) on human mantle cell lymphoma cell lines (GRANTA-519, Hbl-2 and JeKo-1). Mantle cell lymphoma cell lines exhibited a high expression of Peroxisome proliferator-activated receptor-gamma protein in Western blot analysis. MTT assays revealed anti-proliferative effects induced by both 15d-PGJ2, the natural activator of Peroxisome proliferator-activated receptor-gamma, and PGZ and RGZ, synthetic Peroxisome proliferator-activated receptor-gamma ligands, in a dose-dependent manner. At a dose of 50 micromol/l, 15d-PGJ2 induced growth inhibition in all cell lines. The anti-proliferative effect of PGZ and RGZ was slightly lower. Induction of apoptosis was indicated by annexin V staining. At a dose of 50 micromol/l, 15d-PGJ2 led to apoptosis in all cell lines (87-99%) after 48 h of incubation. Again, the apoptotic effect with thiazolidinediones was slightly lower at the same dose level. This is the first study evaluating Peroxisome proliferator-activated receptor-gamma expression and its therapeutic implications in human mantle cell lymphoma cells. Thiazolidinediones comprise anti-lymphoma activity in vitro and should be further explored for the treatment of mantle cell lymphoma. PMID:16926626

  16. A precision mechanical nerve stimulator

    NASA Technical Reports Server (NTRS)

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

    1988-01-01

    An electromechanical device, used to apply and monitor stimulating pulses to a mammalian motor nerve, has been successfully developed at NASA Langley Research Center. Two existing force transducers, a flight skin friction balance and a miniature skin friction balance which were designed for making aerodynamic drag measurements, were modified and incorporated to form this precision instrument. The nerve stimulator is a type one servomechanism capable of applying and monitoring stimulating pulses of 0 to 10 grams with a precision of better than +/- 0.05 grams. Additionally, the device can be independently used to apply stimulating pulses by displacing the nerve from 0 to 0.25 mm with a precision of better than +/- 0.001 mm while measuring the level of the load applied.

  17. 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.

  18. Neural stimulation and recording electrodes.

    PubMed

    Cogan, Stuart F

    2008-01-01

    Electrical stimulation of nerve tissue and recording of neural electrical activity are the basis of emerging prostheses and treatments for spinal cord injury, stroke, sensory deficits, and neurological disorders. An understanding of the electrochemical mechanisms underlying the behavior of neural stimulation and recording electrodes is important for the development of chronically implanted devices, particularly those employing large numbers of microelectrodes. For stimulation, materials that support charge injection by capacitive and faradaic mechanisms are available. These include titanium nitride, platinum, and iridium oxide, each with certain advantages and limitations. The use of charge-balanced waveforms and maximum electrochemical potential excursions as criteria for reversible charge injection with these electrode materials are described and critiqued. Techniques for characterizing electrochemical properties relevant to stimulation and recording are described with examples of differences in the in vitro and in vivo response of electrodes. PMID:18429704

  19. Magnetically stimulated fluid flow patterns

    ScienceCinema

    Martin, Jim; Solis, Kyle

    2014-08-06

    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.

  20. 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.

  1. 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)

  2. 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

  3. Emerging Neural Stimulation Technologies for Bladder Dysfunctions

    PubMed Central

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

    2015-01-01

    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. PMID:25833475

  4. 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.

  5. The protective effects of 15-deoxy-delta-(12,14)-prostaglandin J2 in spinal cord injury.

    PubMed

    Kerr, Bradley J; Girolami, Elizabeth I; Ghasemlou, Nader; Jeong, Suh Young; David, Samuel

    2008-03-01

    Secondary tissue damage that occurs within days after spinal cord injury contributes significantly to permanent paralysis, sensory loss, and other functional disabilities. The acute inflammatory response is thought to contribute largely to this secondary damage. We show here that 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), a metabolite of prostaglandin D2 (PGD2) that has anti-inflammatory actions, given daily for the first 2 weeks after spinal cord contusion injury in mice, results in significant improvement of sensory and locomotor function. 15d-PGJ2-treated mice also show diminished signs of microglia/macrophage activation, increased neuronal survival, greater serotonergic innervation, and reduced demyelination in the injured spinal cord. These changes are accompanied by a reduction in chemokine and pro-inflammatory cytokine expression. Our results also indicate that 15d-PGJ2 is likely to reduce inflammation in the injured spinal cord by attenuating multiple signaling pathways: reducing activation of NF-kappa B; enhancing expression of suppressor of cytokine signaling1 and reducing the activation of Janus activated Kinase 2. PMID:18205174

  6. Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2-related factor 2 resulting in activation of phase-2 antioxidant enzymes (γ-GCS, HO-1, NQO1) in ultraviolet radiation-treated normal human epidermal keratinocytes (NHEK).

    PubMed

    Kleszczyński, Konrad; Zillikens, Detlef; Fischer, Tobias W

    2016-09-01

    Melatonin is an ubiquitous molecule with a variety of functions including potent antioxidative properties. Due to its lipophilic character, it easily crosses cellular and intracellular membranes and reaches all subcellular organelles. Because of its ability to scavenge free radicals, melatonin protects against oxidative stress, for example, induced by ultraviolet radiation (UVR). Here, we investigated, in a dose-dependent (0, 10, 25, and 50 mJ/cm(2) ) and time-dependent (0, 4, 24, 48 hr post-UVR) manner, whether melatonin prevents the UVR-mediated alterations in ATP synthesis and the generation of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEK). Additionally, we evaluated the molecular mechanism of action of melatonin with regard to activation of phase-2 antioxidative enzymes via nuclear erythroid 2-related factor (Nrf2). We found that (i) melatonin counteracted UVR-induced alterations in the ATP synthesis and reduced free radical formation; (ii) melatonin induced the translocation of Nrf2 transcription factor from the cytosol into the nucleus resulting in, (iii) melatonin enhanced gene expression of phase-2 antioxidative enzymes including γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), and NADPH: quinone dehydrogenase-1 (NQO1) representing an elevated antioxidative response of keratinocytes. These results suggest that melatonin not only directly scavenges ROS, but also significantly induces the activation of phase-2 antioxidative enzymes via the Nrf2 pathway uncovering a new action mechanism that supports the ability of keratinocytes to protect themselves from UVR-mediated oxidative stress. PMID:27117941

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. Action research through stimulated recall

    NASA Astrophysics Data System (ADS)

    O'Brien, John

    1993-12-01

    The emphasis in classroom learning research has moved from process-product models to the mediating process paradigm. The stimulated-recall interview and thik aloud techniques are the two main processes that have been used in attempts to find out what goes on inside students' heads while they are learning. For example, this researcher has used the stimulated-recall interview technique to identify the workplace thinking of a marine science researcher, and the in-class thinking of a year eleven biology student. Such studies as these have produced findings with important implications for the classroom teacher in the role of action researcher. This paper describes how to conduct stimulated-recall interviews and discusses some classroom implications from the two studies.

  13. Ovarian stimulation in cancer patients.

    PubMed

    Cakmak, Hakan; Rosen, Mitchell P

    2013-05-01

    The patients referred for fertility preservation owing to a malignant disease do not represent the typical population of subfertile patients treated in IVF units. Cancer may affect multiple tissues throughout the body and can result in a variety of complications during controlled ovarian stimulation. Determination of the controlled ovarian stimulation protocol and gonadotropin dose for oocyte/embryo cryopreservation requires an individualized assessment. This review highlights the new protocols that are emerging to reduce time constraints and emphasizes management considerations to decrease complications. PMID:23635348

  14. 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

  15. ELECTROSTATIC STIMULATION OF FABRIC FILTRATION

    EPA Science Inventory

    The paper gives results of an investigation of the concept of electrostatic stimulation of fabric filtration (ESFF) at pilot scale. The pilot unit consisted of a conventional baghouse in parallel with an ESFF baghouse, allowing direct comparison. Reported results are for pulse-cl...

  16. 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…

  17. [Energy resonance through cutaneous stimulation].

    PubMed

    Fouchier, Patrick

    2014-12-01

    Energy resonance through cutaneous stimulation is a method basedon "listening" through the fingers to the body's vibrations at various points on the skin corresponding to the meridians used in Chinese medicine. It helps to relieve the patient by balancing the body's energies. It can be carried out by any caregiver after specific training. PMID:25630081

  18. 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.

  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. Magnetic-motor-root stimulation: review.

    PubMed

    Matsumoto, Hideyuki; Hanajima, Ritsuko; Terao, Yasuo; Ugawa, Yoshikazu

    2013-06-01

    Magnetic stimulation can activate the human central and peripheral nervous systems non-invasively and virtually painlessly. Magnetic stimulation over the spinal enlargements can activate spinal nerves at the neuroforamina (magnetic-neuroforamina stimulation). This stimulation method provides us with information related to the latency of compound-muscle action potential (CMAP), which is usually interpreted as peripheral motor-conduction time (PMCT). However, this stimulation method has faced several problems in clinical applications. One is that supramaximal CMAPs were unobtainable. Another is that magnetic stimulation did not usually activate the spinal nerves in the spinal canal, i.e., the cauda equina, which prevented an evaluation of its conduction. For these reasons, magnetic-neuroforamina stimulation was rarely used to evaluate the conduction of peripheral nerves. It was mainly used to evaluate the conduction of the corticospinal tract using the parameter of central motor-conduction time (CMCT), which was calculated by subtracting PMCT from the latency of motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) over the primary motor cortex. Recently, supramaximal stimulation has been achieved in magnetic-neuroforamina stimulation, and this has contributed to the measurement of both CMAP size and latency. The achievement of supramaximal stimulation is ascribed to the increase in magnetic-stimulator output and a novel coil, the magnetic augmented translumbosacral stimulation (MATS) coil. The most proximal part of the cauda equina can be reliably activated using the MATS coil (magnetic-conus stimulation), thus contributing to the measurement of cauda equina conduction time (CECT) and cortico-conus motor-conduction time (CCCT). These recent developments in magnetic-motor-root stimulation enable us to more precisely evaluate the conduction of the proximal part of peripheral nerves and that of the corticospinal tract for lower-limb muscles

  1. 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

  2. Deep brain stimulation: new directions.

    PubMed

    Ostergard, T; Miller, J P

    2014-12-01

    The role of deep brain stimulation (DBS) in the treatment of movement disorders is well established, but there has recently been a proliferation of additional indications that have been shown to be amenable to this technology. The combination of innovative approaches to neural interface technology with novel target identification based on previously discovered clinical effects of lesioning procedures has led to a fundamental paradigm for new directions in the application of DBS. The historical use of neurosurgical lesioning procedures in the treatment of psychiatric diseases such as obsessive compulsive disorder provided an initial opportunity to expand the use of DBS. The list is rapidly expanding and now includes major depressive disorder, Tourette's syndrome, addiction disorders, and eating disorders. Keen observations by neurosurgeons using these devices have lead to the incidental discovery of treatments for diseases without previous neurosurgical treatments. These discoveries are breaking new ground in the treatment of disorders of cognition, headache syndromes, disorders of consciousness, and epilepsy. Two features of DBS make it well-suited for treatment of disorders of nervous system function. First, the reversible, non-lesional nature of DBS allows for investigation of new targets without the morbidity of permanent side effects. Second, the programmable nature of DBS allows practitioners to alter stimulation patterns to minimize side effects and potentially improve efficacy through reprogramming. More importantly, proper scientific evaluation of new targets is aided by the ability to turn stimulation on and off with evaluators blinded to the stimulation status. Knowledge of these emerging therapies is important for practitioners, as there are many situations where a single target can effectively treat the symptoms of more than one disease. The intersection of advances in neuromodulation, neurophysiology, neuroimaging, and functional neuroanatomy has

  3. 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.

  4. Multimedia stimulation for psychophysiological investigation.

    PubMed

    McCullagh, P J; Gent, G P; McAllister, H G

    1999-01-01

    This paper describes a multimedia approach to sensory stimulation in psychophysiological studies. High resolution colour images are presented to a subject by a Delphi stimulus program, controlled by a data acquisition system which concurrently records cognitive Event Related Potentials from the subject. The acquisition PC is linked to the stimulus PC using serial communications and requests slide material using a character based protocol. The sound card in the data acquisition system can present concurrent complex auditory stimuli for multimedia experiments. PMID:10724966

  5. Interleukin-6 Stimulates Defective Angiogenesis.

    PubMed

    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

    2015-08-01

    The cytokine IL6 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 IL6 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, IL6-stimulated aortic ring vessel sprouts had defective pericyte coverage compared with VEGF-stimulated vessels. The mechanism of IL6 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-IL6 antibody, pericyte coverage of vessels was restored. In addition, in human ovarian cancer biopsies, there was an association between levels of IL6 mRNA, Jagged1, and Ang2. Our findings have implications for the use of cancer therapies that target VEGF or IL6 and for understanding abnormal angiogenesis in cancers, chronic inflammatory disease, and stroke. PMID:26081809

  6. Phosphate stimulates CFTR Cl- channels.

    PubMed Central

    Carson, M R; Travis, S M; Winter, M C; Sheppard, D N; Welsh, M J

    1994-01-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels appear to be regulated by hydrolysis of ATP and are inhibited by a product of hydrolysis, ADP. We assessed the effect of the other product of hydrolysis, inorganic phosphate (P(i)), on CFTR Cl- channel activity using the excised inside-out configuration of the patch-clamp technique. Millimolar concentrations of P(i) caused a dose-dependent stimulation of CFTR Cl- channel activity. Single-channel analysis demonstrated that the increase in macroscopic current was due to an increase in single-channel open-state probability (po) and not single-channel conductance. Kinetic modeling of the effect of P(i) using a linear three-state model indicated that the effect on po was predominantly the result of an increase in the rate at which the channel passed from the long closed state to the bursting state. P(i) also potentiated activity of channels studied in the presence of 10 mM ATP and stimulated Cl- currents in CFTR mutants lacking much of the R domain. Binding studies with a photoactivatable ATP analog indicated that Pi decreased the amount of bound nucleotide. These results suggest that P(i) increased CFTR Cl- channel activity by stimulating a rate-limiting step in channel opening that may occur by an interaction of P(i) at one or both nucleotide-binding domains. Images FIGURE 8 PMID:7532021

  7. 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 ...

  8. 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

  9. 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.

  10. 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.

  11. 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)

  12. 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...

  13. Heme and HO-1 Inhibition of HCV, HBV, and HIV

    PubMed Central

    Schmidt, Warren N.; Mathahs, M. Meleah; Zhu, Zhaowen

    2012-01-01

    Hepatitis C virus, human immunodeficiency virus, and hepatitis B virus are chronic viral infections that cause considerable morbidity and mortality throughout the world. In the decades following the identification and sequencing of these viruses, in vitro experiments demonstrated that heme oxygenase-1, its oxidative products, and related compounds of the heme oxygenase system inhibit replication of all 3 viruses. The purpose of this review is to critically evaluate and summarize the seminal studies that described and characterized this remarkable behavior. It will also discuss more recent work that discovered the antiviral mechanisms and target sites of these unique antiviral agents. In spite of the fact that these viruses are diverse pathogens with quite profound differences in structure and life cycle, it is significant that heme and related compounds show striking similarity for viral target sites across all three species. Collectively, these findings strongly indicate that we should move forward and develop heme and related tetrapyrroles into versatile antiviral agents that could be used therapeutically in patients with single or multiple viral infections. PMID:23060790

  14. Transcutaneous functional electrical stimulator "Compex Motion".

    PubMed

    Keller, Thierry; Popovic, Milos R; Pappas, Ion P I; Müller, Pierre-Yves

    2002-03-01

    Research groups in the field of functional electrical stimulation (FES) are often confronted with the fact that existing and commercially available FES stimulators do not provide sufficient flexibility and cannot be used to perform different FES tasks. The lack of flexibility of the commercial systems until now forced various FES research teams to develop their own stimulators. This paper presents a newly developed firmware and graphical programming software for the commercial Compex 2 stimulator which enhances the versatility and capabilities of the stimulator from a medical and therapeutic device to a neuroprosthesis and research tool. The new stimulator, called Compex Motion, can now be used to develop various custom-made neuroprostheses, neurological assessment devices, muscle exercise systems, and experimental setups for physiological studies. It can be programmed to generate any arbitrary stimulation sequence that can be controlled or regulated by various external sensors, sensory systems, or laboratory equipment. By interconnecting two or more Compex Motion stimulators, the number of stimulation channels can be increased to multiples of four channels, 8, 12, 16, 20, and so forth. The stimulation sequences and the control strategies are programmed and stored on exchangeable credit card-sized memory chip cards. The stimulator has four biphasic current-regulated stimulation channels and two general purpose analog input channels that can be configured to measure the output voltage of a variety of sensors such as goniometers, inclinometers, gyroscopes, or electromyographic (EMG) sensors. For real-time EMG control of the stimulation patterns, an EMG processing algorithm with software stimulation artifact blanking was implemented. The Compex Motion stimulator is manufactured by the Swiss company Compex SA and is currently undergoing clinical trials. PMID:11940017

  15. Hypothalamic thermal stimulation modulates vasopressin release in hyperosmotically stimulated rabbits.

    PubMed

    Keil, R; Gerstberger, R; Simon, E

    1994-10-01

    Under thermoneutral conditions conscious rabbits received systemic infusions of NaCl as hypertonic solution (90 mueq.min-1.kg body wt-1), which raised their plasma osmolality from 283 to 312 mosmol/kgH2O. Rabbits receiving isotonic saline served as controls. Hypertonic stimulation induced a 60% reduction of both respiratory frequency and evaporative water loss. Rectal temperature rose by 0.4 degrees C despite enhanced peripheral vasodilation as indicated by increased ear skin temperature. Plasma vasopressin (AVP), aldosterone (ALDO), and corticosterone (COR) were significantly elevated from 6 to 16 pg/ml, 90 to 180 pg/ml, and 17 to 40 ng/ml, respectively. To elucidate the importance of central temperature for AVP and adrenal corticosteroid release, hypothalamic thermal stimulations (20 min) were superimposed during established iso- and hyperosmotic steady-state conditions. Different from isosmotic controls, hyperosmotic animals responded to hypothalamic cooling (37 degrees C) with a significant decrease in plasma AVP from 16 to 13 pg/ml and to hypothalamic warming (41 degrees C) with a significant rise from 16 to 19 pg/ml. A weak temperature effect on COR release was also disclosed, especially of hypothalamic cooling, which significantly lowered plasma COR from 42 to 34 ng/ml. These results provide evidence for positive local temperature coefficients of hypothalamic control of AVP release and suggest a similar property also for the control of COR release by the hypothalamo-adenohypophysial axis. PMID:7943420

  16. 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

  17. Vagal nerve stimulator: Evolving trends

    PubMed Central

    Ogbonnaya, Sunny; Kaliaperumal, Chandrasekaran

    2013-01-01

    Over three decades ago, it was found that intermittent electrical stimulation from the vagus nerve produces inhibition of neural processes, which can alter brain activity and terminate seizures. This paved way for the concept of vagal nerve stimulator (VNS). We describe the evolution of the VNS and its use in different fields of medicine. We also review the literature focusing on the mechanism of action of VNS producing desired effects in different conditions. PUBMED and EMBASE search was performed for ‘VNS’ and its use in refractory seizure management, depression, obesity, memory, and neurogenesis. VNS has been in vogue over for the past three decades and has proven to reduce the intensity and frequency of seizure by 50% in the management of refractory seizures. Apart from this, VNS has been shown to promote neurogenesis in the dentate gyrus of rat hippocampus after 48 hours of stimulation of the vagus nerve. Improvement has also been observed in non-psychotic major depression from a randomized trial conducted 7 years ago. The same concept has been utilized to alter behavior and cognition in rodents, and good improvement has been observed. Recent studies have proven that VNS is effective in obesity management in patients with depression. Several hypotheses have been postulated for the mechanism of action of VNS contributing to its success. VNS has gained significant popularity with promising results in epilepsy surgery and treatment-resistant depression. The spectrum of its use has also extended to other fields of medicine including obesity, memory, and neurogenesis, and there is still a viable scope for its utility in the future. PMID:23633829

  18. Multichannel magnetic stimulation system design considering mutual couplings among the stimulation coils.

    PubMed

    Han, Byung H; Chun, In K; Lee, Sang C; Lee, Soo Y

    2004-05-01

    We introduce some simulation and experiment results of the multichannel magnetic stimulator development that has been carried out as an initial attempt to realize a multichannel functional magnetic stimulator. For efficient functional magnetic stimulations, precise spatial localization of stimulation sites without any movements of the stimulation coils is very important. We have found that the mutual coupling effect among the adjacent stimulation coils in the coil array has to be considered in the determination of the charge voltages in some coil array configurations. Experimental results obtained with a 4-channel magnetic stimulator are presented. PMID:15132507

  19. 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.

  20. 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. PMID:26691398

  1. 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

  2. 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.

  3. 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. PMID:26061152

  4. 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

  5. Opiate withdrawal behavior after focal brain stimulation.

    PubMed

    Williams, D A; Thorn, B E

    1984-11-01

    Electrical stimulation of the brainstem abolishes pain, while continued stimulation induces tolerance to the analgesic effect. Analgesic drugs producing tolerance also induce physical dependence, suggesting that the phenomenon of tolerance is associated with addiction. There is evidence that the neural mechanism for stimulation-produced analgesia is related to the release of opiate substances within the brain. We therefore propose that repeated or protracted brain stimulation elicits dependence upon the endorphins released by electrical stimulation of the neurons themselves. To investigate this possibility, rats were given repetitive bursts of analgesic electrical brain stimulation for two hours. Immediately thereafter, they were injected with the opiate antagonist, naloxone. Behaviors associated with low grade opiate withdrawal were observed. These data suggest that prolonged analgesic stimulation can result in naloxone-precipitated behaviors similar to the behaviors exhibited during opiate withdrawal. PMID:6542676

  6. Intraphagosomal oxygen in stimulated macrophages.

    PubMed

    James, P E; Grinberg, O Y; Michaels, G; Swartz, H M

    1995-05-01

    A new electron paramagnetic resonance (EPR)-based method was developed to obtain selective information on pO2 in a specific intracellular compartment (phagosomes). This method did not require the use of a broadening agent thereby eliminating one of the potential sources of experimental error with EPR oximetry. An oxygen-sensitive probe (4-(Trimethylammonium) 2,2,6,6-tetramethylpiperidine-d17-1-oxyl iodide (d-Cat1)) which has a net positive charge, was incorporated selectively into the phagosomes of macrophages stimulated with zymosan. Extracellular oxygen was measured by addition of a neutral nitroxide (4-oxo-2,2,6,6-tetramethylpiperidine-d16-1-oxyl (15N PDT)) to this same sample. Measurements based on EPR linewidths showed the average intraphagosomal oxygen concentration to be 11.2 +/- 3.4 microM lower than that measured from the extracellular compartment when the sample was perfused with air, and this was increased on stimulation of mitochondrial consumption or by increasing the oxygen concentration in the extracellular compartment. These experiments provide what we believe to be the first reported measurements of the oxygen concentration in a specific intracellular location (intraphagosomal) and its comparison with the oxygen concentration in the extracellular space. The observed gradient cannot be explained in terms of known coefficients of diffusion, and these results are consistent with previous reports that a gradient in oxygen concentration can occur between the average intracellular and extracellular concentration of oxygen. PMID:7706368

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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

  14. Axonal model for temperature stimulation.

    PubMed

    Fribance, Sarah; Wang, Jicheng; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2016-10-01

    Recent studies indicate that a rapid increase in local temperature plays an important role in nerve stimulation by laser. To analyze the temperature effect, our study modified the classical HH axonal model by incorporating a membrane capacitance-temperature relationship. The modified model successfully simulated the generation and propagation of action potentials induced by a rapid increase in local temperature when the Curie temperature of membrane capacitance is below 40 °C, while the classical model failed to simulate the axonal excitation by temperature stimulation. The new model predicts that a rapid increase in local temperature produces a rapid increase in membrane capacitance, which causes an inward membrane current across the membrane capacitor strong enough to depolarize the membrane and generate an action potential. If the Curie temperature of membrane capacitance is 31 °C, a temperature increase of 6.6-11.2 °C within 0.1-2.6 ms is required for axonal excitation and the required increase is smaller for a faster increase. The model also predicts that: (1) the temperature increase could be smaller if the global axon temperature is higher; (2) axons of small diameter require a smaller temperature increase than axons of large diameter. Our study indicates that the axonal membrane capacitance-temperature relationship plays a critical role in inducing the transient membrane depolarization by a rapidly increasing temperature, while the effects of temperature on ion channel kinetics cannot induce depolarization. The axonal model developed in this study will be very useful for analyzing the axonal response to local heating induced by pulsed infrared laser. PMID:27342462

  15. Noninvasive transcranial brain stimulation and pain.

    PubMed

    Rosen, Allyson C; Ramkumar, Mukund; Nguyen, Tam; Hoeft, Fumiko

    2009-02-01

    Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are two noninvasive brain stimulation techniques that can modulate activity in specific regions of the cortex. At this point, their use in brain stimulation is primarily investigational; however, there is clear evidence that these tools can reduce pain and modify neurophysiologic correlates of the pain experience. TMS has also been used to predict response to surgically implanted stimulation for the treatment of chronic pain. Furthermore, TMS and tDCS can be applied with other techniques, such as event-related potentials and pharmacologic manipulation, to illuminate the underlying physiologic mechanisms of normal and pathological pain. This review presents a description and overview of the uses of two major brain stimulation techniques and a listing of useful references for further study. PMID:19126365

  16. NONINVASIVE BRAIN STIMULATION IN TRAUMATIC BRAIN INJURY

    PubMed Central

    Demirtas-Tatlidede, Asli; Vahabzadeh-Hagh, Andrew M.; Bernabeu, Montserrat; Tormos, Jose M.; Pascual-Leone, Alvaro

    2012-01-01

    Brain stimulation techniques have evolved in the last few decades with more novel methods capable of painless, noninvasive brain stimulation. While the number of clinical trials employing noninvasive brain stimulation continues to increase in a variety of medication-resistant neurological and psychiatric diseases, studies evaluating their diagnostic and therapeutic potential in traumatic brain injury (TBI) are largely lacking. This review introduces different techniques of noninvasive brain stimulation, which may find potential use in TBI. We cover transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), low-level laser therapy (LLLT) and transcranial doppler sonography (TCD) techniques. We provide a brief overview of studies to date, discuss possible mechanisms of action, and raise a number of considerations when thinking about translating these methods to clinical use. PMID:21691215

  17. 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.

  18. 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.

  19. ``Bloch wave'' modification of stimulated Raman by stimulated Brillouin scattering

    NASA Astrophysics Data System (ADS)

    Dodd, E. S.; Vu, H. X.; DuBois, D. F.; Bezzerides, B.

    2013-03-01

    Using the reduced-description particle-in-cell (RPIC) method, we study the coupling of backward stimulated Raman scattering (BSRS) and backward stimulated Brillouin scattering (BSBS) in regimes where the reflectivity involves the nonlinear behavior of particles trapped in the daughter plasma waves. The temporal envelope of a Langmuir wave (LW) obeys a Schrödinger equation where the potential is the periodic electron density fluctuation resulting from an ion-acoustic wave (IAW). The BSRS-driven LWs in this case have a Bloch wave structure and a modified dispersion due to the BSBS-driven spatially periodic IAW, which includes frequency band gaps at kLW˜kIAW/2˜k0 (kLW, kIAW, and k0 are the wave number of the LW, IAW, and incident pump electromagnetic wave, respectively). This band structure and the associated Bloch wave harmonic components are distinctly observed in RPIC calculations of the electron density fluctuation spectra and this structure may be observable in Thomson scatter. Bloch wave components grow up in the LW spectrum, and are not the result of isolated BSRS. Self-Thomson scattered light from these Bloch wave components can have forward scattering components. The distortion of the LW dispersion curve implies that the usual relationship connecting the frequency shift of the BSRS-scattered light and the density of origin of this light may become inaccurate. The modified LW frequency results in a time-dependent frequency shift that increases as the IAW grows, detunes the BSRS frequency matching condition, and reduces BSRS growth. A dependence of the BSRS reflectivity on the IAW Landau damping results because this damping determines the levels of IAWs. The time-dependent reflectivity in our simulations is characterized by bursts of sub-picosecond pulses of BSRS alternating with multi-ps pulses of BSBS, and BSRS is observed to decline precipitously as soon as SBS begins to grow from low levels. In strong BSBS regimes, the Bloch wave effects in BSRS are

  20. 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

  1. 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)

  2. Optical stimulation of peripheral nerves in vivo

    NASA Astrophysics Data System (ADS)

    Wells, Jonathon D.

    This dissertation documents the emergence and validation of a new clinical tool that bridges the fields of biomedical optics and neuroscience. The research herein describes an innovative method for direct neurostimulation with pulsed infrared laser light. Safety and effectiveness of this technique are first demonstrated through functional stimulation of the rat sciatic nerve in vivo. The Holmium:YAG laser (lambda = 2.12 mum) is shown to operate at an optimal wavelength for peripheral nerve stimulation with advantages over standard electrical neural stimulation; including contact-free stimulation, high spatial selectivity, and lack of a stimulation artifact. The underlying biophysical mechanism responsible for transient optical nerve stimulation appears to be a small, absorption driven thermal gradient sustained at the axonal layer of nerve. Results explicitly prove that low frequency optical stimulation can reliably stimulate without resulting in tissue thermal damage. Based on the positive results from animal studies, these optimal laser parameters were utilized to move this research into the clinic with a combined safety and efficacy study in human subjects undergoing selective dorsal rhizotomy. The clinical Holmium:YAG laser was used to effectively stimulate human dorsal spinal roots and elicit functional muscle responses recorded during surgery without evidence of nerve damage. Overall these results predict that this technology can be a valuable clinical tool in various neurosurgical applications.

  3. Vestibular Stimulation for Stress Management in Students

    PubMed Central

    Kumar, Sai Sailesh; Rajagopalan, Archana

    2016-01-01

    Introduction Although several methods are developed to alleviate stress among college students, logistic limitations in adopting them have limited their utility. Aim Hence, we aimed to test a very practical approach to alleviate stress among college students by achieving vestibular stimulation using swings. Materials and Methods In this study 60 male and female participants were randomly assigned into vestibular stimulation or control groups. Depression, anxiety, stress scores, sleep quality, heart rate, blood pressure, Autonomic functions, respiratory, haematological, cognitive function, Quality of life were recorded before and after 1st, 7th, 14th, 21st, 28th days of vestibular stimulation. Results STAI S and STAI T scores were significantly improved on day 28th following vestibular stimulation. Diastolic and mean arterial blood pressure were significantly decreased and remained within normal limits in vestibular group on day 28th following vestibular stimulation. Postural fall in blood pressure was significantly improved on day 14 onwards, following vestibular stimulation. Respiratory rate was significantly improved on day 7 onwards, following vestibular stimulation. PSQI sleep disturbance, PSQI sleep latency, PSQI total score and bleeding time was significantly improved following vestibular stimulation. Conclusion Our study supports the adoption of vestibular stimulation for stress management. Hence, placement of swings in college campuses must be considered, which may be a simple approach to alleviate stress among college students. PMID:27042457

  4. Unilateral magnetic stimulation of the phrenic nerve.

    PubMed Central

    Mills, G. H.; Kyroussis, D.; Hamnegard, C. H.; Wragg, S.; Moxham, J.; Green, M.

    1995-01-01

    BACKGROUND--Electrical stimulation of the phrenic nerve is a useful non-volitional method of assessing diaphragm contractility. During the assessment of hemidiaphragm contractility with electrical stimulation, low twitch transdiaphragmatic pressures may result from difficulty in locating and stimulating the phrenic nerve. Cervical magnetic stimulation overcomes some of these problems, but this technique may not be absolutely specific and does not allow the contractility of one hemidiaphragm to be assessed. This study assesses both the best means of producing supramaximal unilateral magnetic phrenic stimulation and its reproducibility. This technique is then applied to patients. METHODS--The ability of four different magnetic coils to produce unilateral phrenic stimulation in five normal subjects was assessed from twitch transdiaphragmatic pressure (TwPDI) measurements and diaphragmatic electromyogram (EMG) recordings. The results from magnetic stimulation were compared with those from electrical stimulation. To determine whether the magnetic field affects the contralateral phrenic nerve as well as the intended phrenic nerve, EMG recordings from each hemidiaphragm were compared during stimulation on the same side and the opposite side relative to the recording electrodes. The EMG recordings were made from skin surface electrodes in five normal subjects and from needle electrodes placed in the diaphragm during cardiac surgery in six patients. Similarly, the direction of hemidiaphragm movement was evaluated by ultrasonography. To determine the usefulness of the technique in patients the 43 mm mean diameter double coil was used in 54 patients referred for assessment of possible respiratory muscle weakness. These results were compared with unilateral electrical phrenic stimulation, maximum sniff PDI, and TwPDI during cervical magnetic stimulation. RESULTS--In the five normal subjects supramaximal stimulation was established for eight out of 10 phrenic nerves with the 43

  5. Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats.

    PubMed

    Yen, Ting-Lin; Chen, Ray-Jade; Jayakumar, Thanasekaran; Lu, Wan-Jung; Hsieh, Cheng-Ying; Hsu, Ming-Jen; Yang, Chih-Hao; Chang, Chao-Chien; Lin, Yen-Kuang; Lin, Kuan-Hung; Sheu, Joen-Rong

    2016-04-01

    Stroke pathogenesis involves complex oxidative stress-related pathways. The nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) pathways have been considered molecular targets in pharmacologic intervention for ischemic diseases. Andrographolide, a labdane diterpene, has received increasing attention in recent years because of its various pharmacologic activities. We determined that andrographolide modulates the mitogen-activated protein kinase (MAPK)-Nrf2-HO-1 signaling cascade in primary cerebral endothelial cells (CECs) to provide positive protection against middle cerebral artery occlusion (MCAO)-induced ischemic stroke in rats. In the present study, andrographolide (10 μM) increased HO-1 protein and messenger RNA expressions, Nrf2 phosphorylation, and nuclear translocation in CECs, and these activities were disrupted by a p38 MAPK inhibitor, SB203580, but not by the extracellular signal-regulated kinase inhibitor PD98059 or c-Jun amino-terminal kinase inhibitor SP600125. Similar results were observed in confocal microscopy analysis. Moreover, andrographolide-induced Nrf2 and HO-1 protein expressions were significantly inhibited by Nrf2 small interfering RNA. Moreover, HO-1 knockdown attenuated the protective effect of andrographolide against oxygen-glucose deprivation-induced CEC death. Andrographolide (0.1 mg/kg) significantly suppressed free radical formation, blood-brain barrier disruption, and brain infarction in MCAO-insulted rats, and these effects were reversed by the HO-1 inhibitor zinc protoporphyrin IX. The mechanism is attributable to HO-1 activation, as directly evidenced by andrographolide-induced pronounced HO-1 expression in brain tissues, which was highly localized in the cerebral capillary. In conclusion, andrographolide increased Nrf2-HO-1 expression through p38 MAPK regulation, confirming that it provides protection against MCAO-induced brain injury. These findings provide strong evidence that andrographolide could

  6. Ovarian stimulation in patients with breast cancer

    PubMed Central

    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

  7. 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

  8. 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.

  9. 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.

  10. Sphenopalatine Ganglion Stimulation in Neurovascular Headaches.

    PubMed

    Schoenen, Jean

    2015-01-01

    The interest for the sphenopalatine ganglion (SPG) in neurovascular headaches dates back to 1908 when Sluder presented his work on the role of the SPG in 'nasal headaches', which are now part of the trigeminal autonomic cephalalgias and cluster headache (ICHD-III-beta). Since then various interventions with blocking or lesional properties have targeted the SPG (transnasal injection of lidocaine and other agents, alcohol or steroid injections, radiofrequency lesions, or even ganglionectomy); success rates vary, but benefit is usually transient. Here we briefly review some anatomophysiological characteristics of the SPG and hypotheses about its pathophysiological role in neurovascular headaches before describing recent therapeutic results obtained with electrical stimulation of the SPG. Based on results of a prospective randomized controlled study, SPG stimulation appears to be an effective treatment option for patients with chronic cluster headaches; efficacy data indicate that acute electrical stimulation of the SPG provides significant attack pain relief and in many cases pain freedom compared to sham stimulation. Moreover, in some patients SPG stimulation has been associated with a significant and clinically meaningful reduction in cluster headache attack frequency; this preventive effect of SPG stimulation warrants further investigation. For migraine attacks, the outcome of a proof-of-concept study using a temporary electrode implanted in the pterygopalatine fossa was less encouraging; however, an ongoing multicenter trial is evaluating the efficacy of long-term SPG stimulation against sham stimulation for acute and preventive treatment in patients with frequent migraine. PMID:26394372

  11. [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. PMID:24195387

  12. 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)[

  13. Brain Stimulation May Help People with Anorexia

    MedlinePlus

    ... html Brain Stimulation May Help People With Anorexia Depression treatment cut urge to restrict food, study says To ... after they underwent repetitive transcranial stimulation (rTMS), a treatment approved for depression. "With rTMS we targeted ... an area of the ...

  14. Are Prescription Stimulants “Smart Pills”?

    PubMed Central

    Smith, M. Elizabeth; Farah, Martha J.

    2013-01-01

    Use of prescription stimulants by normal healthy individuals to enhance cognition is said to be on the rise. Who is using these medications for cognitive enhancement, and how prevalent is this practice? Do prescription stimulants in fact enhance cognition for normal healthy people? We review the epidemiological and cognitive neuroscience literatures in search of answers to these questions. Epidemiological issues addressed include the prevalence of nonmedical stimulant use, user demographics, methods by which users obtain prescription stimulants, and motivations for use. Cognitive neuroscience issues addressed include the effects of prescription stimulants on learning and executive function, as well as the task and individual variables associated with these effects. Little is known about the prevalence of prescription stimulant use for cognitive enhancement outside of student populations. Among college students, estimates of use vary widely but, taken together, suggest that the practice is commonplace. The cognitive effects of stimulants on normal healthy people cannot yet be characterized definitively, despite the volume of research that has been carried out on these issues. Published evidence suggests that declarative memory can be improved by stimulants, with some evidence consistent with enhanced consolidation of memories. Effects on the executive functions of working memory and cognitive control are less reliable but have been found for at least some individuals on some tasks. In closing, we enumerate the many outstanding questions that remain to be addressed by future research and also identify obstacles facing this research. PMID:21859174

  15. 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

  16. Ovarian stimulation and granulosa-cell tumour.

    PubMed

    Willemsen, W; Kruitwagen, R; Bastiaans, B; Hanselaar, T; Rolland, R

    1993-04-17

    Ovarian stimulation in the treatment of infertility is far from physiological because patients and their ovaries are exposed to high concentrations of gonadotropins. Many studies have focused on the two most common side-effects of ovarian stimulation--ie, hyperstimulation and multiple pregnancy. We describe 12 patients in whom granulosa-cell tumour was discovered after ovarian stimulation treatment with clomiphene citrate and/or gonadotropins. Although we cannot prove a causal link between the tumour and the medication, investigations in animals have shown a relation between gonadotropin exposition and the development of granulosa-cell tumours. The possible relation of ovarian stimulation and granulosa-cell tumours in human beings has not been published before. We postulate three explanations for this finding; first, the granulosa-cell tumour is present in the ovary, waiting for a hormonal trigger; second, increased follicle stimulating hormone concentrations are oncogenic to granulosa cell; and third, the onset of the granulosa-cell tumour during ovarian stimulation is coincidental. We recommend that ovarian stimulation is done only if there is a valid indication after proper assessment of the ovaries, and that women who have had ovarian stimulation are followed for longer than at present. PMID:8096944

  17. Wirelessly powering miniature implants for optogenetic stimulation

    NASA Astrophysics Data System (ADS)

    Yeh, Alexander J.; Ho, John S.; Tanabe, Yuji; Neofytou, Evgenios; Beygui, Ramin E.; Poon, Ada S. Y.

    2013-10-01

    Conventional methods for in vivo optogenetic stimulation require optical fibers or mounted prosthesis. We present an approach for wirelessly powering implantable stimulators using electromagnetic midfield. By exploiting the properties of the midfield, we demonstrate the ability to generate high intensity light pulses in a freely moving animal.

  18. 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

  19. 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

  20. 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.

  1. Spatially selective photoconductive stimulation of live neurons

    PubMed Central

    Campbell, Jacob; Singh, Dipika; Hollett, Geoffrey; Dravid, Shashank M.; Sailor, Michael J.; Arikkath, Jyothi

    2014-01-01

    Synaptic activity is intimately linked to neuronal structure and function. Stimulation of live cultured primary neurons, coupled with fluorescent indicator imaging, is a powerful technique to assess the impact of synaptic activity on neuronal protein trafficking and function. Current technology for neuronal stimulation in culture include chemical techniques or microelectrode or optogenetic based techniques. While technically powerful, chemical stimulation has limited spatial resolution and microelectrode and optogenetic techniques require specialized equipment and expertise. We report an optimized and improved technique for laser based photoconductive stimulation of live neurons using an inverted confocal microscope that overcomes these limitations. The advantages of this approach include its non-invasive nature and adaptability to temporal and spatial manipulation. We demonstrate that the technique can be manipulated to achieve spatially selective stimulation of live neurons. Coupled with live imaging of fluorescent indicators, this simple and efficient technique should allow for significant advances in neuronal cell biology. PMID:24904287

  2. Microscopic magnetic stimulation of neural tissue

    PubMed Central

    Bonmassar, Giorgio; Lee, Seung Woo; Freeman, Daniel K.; Polasek, Miloslav; Fried, Shelley I.; Gale, John T.

    2012-01-01

    Electrical stimulation is currently used to treat a wide range of cardiovascular, sensory and neurological diseases. Despite its success, there are significant limitations to its application, including incompatibility with magnetic resonance imaging, limited control of electric fields and decreased performance associated with tissue inflammation. Magnetic stimulation overcomes these limitations but existing devices (that is, transcranial magnetic stimulation) are large, reducing their translation to chronic applications. In addition, existing devices are not effective for deeper, sub-cortical targets. Here we demonstrate that sub-millimeter coils can activate neuronal tissue. Interestingly, the results of both modelling and physiological experiments suggest that different spatial orientations of the coils relative to the neuronal tissue can be used to generate specific neural responses. These results raise the possibility that micro-magnetic stimulation coils, small enough to be implanted within the brain parenchyma, may prove to be an effective alternative to existing stimulation devices. PMID:22735449

  3. Adaptive deep brain stimulation in Parkinson's disease.

    PubMed

    Beudel, M; Brown, P

    2016-01-01

    Although Deep Brain Stimulation (DBS) is an established treatment for Parkinson's disease (PD), there are still limitations in terms of effectivity, side-effects and battery consumption. One of the reasons for this may be that not only pathological but also physiological neural activity can be suppressed whilst stimulating. For this reason, adaptive DBS (aDBS), where stimulation is applied according to the level of pathological activity, might be advantageous. Initial studies of aDBS demonstrate effectiveness in PD, but there are still many questions to be answered before aDBS can be applied clinically. Here we discuss the feedback signals and stimulation algorithms involved in adaptive stimulation in PD and sketch a potential road-map towards clinical application. PMID:26411502

  4. Development of VCSELs for optical nerve stimulation

    NASA Astrophysics Data System (ADS)

    Dummer, Matthew; Johnson, Klein; Hibbs-Brenner, Mary; Keller, Matthew; Gong, Tim; Wells, Jonathon; Bendett, Mark

    2011-03-01

    Neural stimulation using infrared optical pulses has numerous potential advantages over traditional electrical stimulation, including improved spatial precision and no stimulation artifact. However, realization of optical stimulation in neural prostheses will require a compact and efficient optical source. One attractive candidate is the vertical cavity surface emitting laser. This paper presents the first report of VCSELs developed specifically for neurostimulation applications. The target emission wavelength is 1860 nm, a favorable wavelength for stimulating neural tissues. Continuous wave operation is achieved at room temperature, with maximum output power of 2.9 mW. The maximum lasing temperature observed is 60° C. Further development is underway to achieve power levels necessary to trigger activation thresholds.

  5. Callus stimulation in distraction osteogenesis.

    PubMed

    Mofid, Mehrdad M; Inoue, Nozomu; Atabey, Atay; Marti, Guy; Chao, Edmund Y S; Manson, Paul N; Vander Kolk, Craig A

    2002-04-15

    Distraction osteogenesis has been described as in vivo tissue engineering. The ability to stimulate this process for the repair of bony defects or lengthening of congenitally shortened facial structures is likely to significantly impact the field of craniofacial surgery. The purpose of this study was to determine whether mechanical stimulation of the distracted rabbit mandible would accelerate the maturation of the bony callus when applied during the early consolidation period. Twenty adult New Zealand White rabbits underwent unilateral mandibular osteotomy. A uni-directional internal distractor device (Synthes, Paoli, Pa.) was positioned along a plane perpendicular to the line of osteotomy. After a 7-day latency period, distraction was commenced at a rate of 1.0 mm/day for 12 days in all animals. In a control group of 10 rabbits, a consolidation period of 8 weeks was observed before they were killed. In the experimental group of 10 rabbits, daily alternate compression and distraction of 1 mm (sequential compression and distraction) was performed for 3 weeks followed by a 5-week period of rigid fixation. Each animal received a dose of a fluorescent label at three different time points during the study: at the end of the distraction period, 3 weeks after the completion of the distraction phase, and 3 days before it was killed. All animals were killed 8 weeks after the completion of the distraction phase. Undecalcified histologic analysis and 3-point bending tests to failure were performed on the extracted mandibles. The results of the experimental and control groups were compared. Four animals in the control group and three animals in the experimental group were excluded from the study because of screw loosening resulting in distractor dislodgment or because of infection. On histologic analysis, cortical thickness at the center of the callus was found to be significantly greater in the experimental group compared with the control group when normalized to the

  6. Bacterial porins stimulate bone resorption.

    PubMed Central

    Meghji, S; Henderson, B; Nair, S P; Tufano, M A

    1997-01-01

    Porins are abundant outer membrane proteins of gram-negative bacteria involved in transport of low-molecular-mass molecules. During the past decade, porins from a number of bacteria have also been shown to have proinflammatory activities including inducing the synthesis of proinflammatory mediators (cytokines, platelet-activating factor, and nitric oxide) in cultured cells and inducing inflammation in vivo. With this range of actions, it was possible that porins could also interact with bone cells to cause aberrant bone remodeling and that this could contribute to the bone destruction seen in gram-negative bone infections. By using purified preparations of Salmonella typhimurium and Pseudomonas aeruginosa porins, in the presence of polymyxin B, it was possible to induce concentration-dependent loss of calcium from cultured murine calvaria at porin concentrations in the range of 1 to 10 nM. The mechanism of action of the porins was determined by the inclusion of inhibitors of cyclooxygenase or inflammatory cytokines in the culture media. The bone-resorbing activity of both porins was not inhibited by the cyclooxygenase inhibitor indomethacin or by neutralizing the activity of tumor necrosis factor. Indeed, relatively high concentrations of these agents produced an unexpected increase in the bone resorption induced by the porins. In contrast, porin-induced bone resorption could be inhibited by relatively high concentrations of the natural inhibitor of interleukin-1 (IL-1 receptor antagonist). It appears that these porins stimulate bone resorption by a mechanism distinct from that of lipopolysaccharide, and the possibility therefore exists that porins play a role in bone destruction in gram-negative bacterial infections of bone. PMID:9119467

  7. 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

    2015-01-01

    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

  8. Enhancement of Analgesic Effect by Combination of Non-Noxious Stimulation and Noxious Stimulation in Humans.

    PubMed

    Fujii-Abe, Keiko; Umino, Masahiro; Fukayama, Haruhisa; Kawahara, Hiroshi

    2016-02-01

    The aim of the this study was to investigate the combined effects of heterosegmental non-noxious and noxious stimulation on electrically induced tooth pain. The late component of somatosensory-evoked potentials (SEP), induced by electrical tooth stimulation and pain intensity, were examined under electrical stimulation to forearms. Noxious, non-noxious, and combined non-noxious and noxious electrical stimulation were applied to median nerves on the forearms. Four experimental sessions (ie, control session, combined non-noxious and noxious stimulation session, non-noxious stimulation session, and noxious stimulation session were performed for each subject at each 10-minute interval for 30 minutes. The amplitudes of the SEP and VAS scores in the combined stimulation session decreased significantly compared with those in the control session and the reduction rates were 51.1% (13.4 μV) and 41.0% (23.5 mm), respectively. These results show that the combined stimulation has a more potent analgesic effect than that of either the non-noxious or the noxious stimulation. It is suggested that a potent analgesia was produced by an activated central mechanism, including endogenous opioid and descending pain inhibitory systems due to combined non-noxious and noxious stimulation. PMID:25490991

  9. 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

  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. [Model based study of myocardial stimulation mechanisms].

    PubMed

    Weiss, I; Urbaszek, A; Schaldach, M

    1997-01-01

    The present study investigated the mechanisms of electrical stimulation of a myocardial fibre with the aim of developing improved minimally invasive stimulation methods. Using a dynamic myocyte model, the ionic currents crossing the voltage-dependent channels of the membrane are computed. To trigger an action potential, the membrane must first be depolarized to the threshold potential, when further depolarization continues spontaneously through the avalanche-like opening of the sodium channels. For the development of an action potential, not merely the amount of charge injected into the cell during the stimulus is of importance, but an above-threshold magnitude of the stimulation current is also required. The smallest energy required is achieved when the stimulus duration is chosen to be equal to the chronaxie. A second aspect of the study concerned the far-field stimulation of a muscle fibre, achieved by generating a potential gradient along the fibre. First, using a continuous fibre model, the fibre activating function is computed. In a more detailed study, the discrete segmental structure of the fibre determined by the gap junctions is taken into account, and the impact of these junctions on the activating function analysed. By optimizing the electrode configuration, an appropriate activating function results which guarantees successful stimulation when its maximum is above than threshold potential. The most important finding is that the myocardium can be stimulated by floating electrodes, thus opening up new possibilities for a less invasive electro-stimulation of the heart. PMID:9172726

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. Crack detection by stimulated infrared thermography

    NASA Astrophysics Data System (ADS)

    Bodnar, Jean-Luc

    2014-03-01

    In this paper, the potential of stimulated infrared thermography is studied for the detection of cracks located in metallic materials. To start with, the feasibility of the method is shown with the use of numerical simulations. Stimulated infrared thermography allows detecting emerging cracks in samples whether reflective or not as well as non-emerging cracks. In addition, crack detection is due to the radiative effects and/or the thermal effects induced by the defects. Then, the experimental device implemented for the study is detailed. Finally, experiments confirm that stimulated infrared thermography enables to detect microscopic cracks, whether emerging or non-emerging, in metal samples.

  19. Development of a tactile stimulator with simultaneous visual and auditory stimulation using E-Prime software.

    PubMed

    Kim, Hyung-Sik; Yeon, Hong-Won; Choi, Mi-Hyun; Kim, Ji-Hye; Choi, Jin-Seung; Park, Jang-Yeon; Jun, Jae-Hoon; Yi, Jeong-Han; Tack, Gye-Rae; Chung, Soon-Cheol

    2013-01-01

    In this study, a tactile stimulator was developed, which can stimulate visual and auditory senses simultaneously by using the E-Prime software. This study tried to compensate for systematic stimulation control and other problems that occurred with previously developed tactile stimulators. The newly developed system consists of three units: a control unit, a drive unit and a vibrator. Since the developed system is a small, lightweight, simple structure with low electrical consumption, a maximum of 35 stimulation channels and various visual and auditory stimulation combinations without delay time, the previous systematic problem is corrected in this study. The system was designed to stimulate any part of the body including the fingers. Since the developed tactile stimulator used E-Prime software, which is widely used in the study of visual and auditory senses, the stimulator is expected to be highly practical due to a diverse combination of stimuli, such as tactile-visual, tactile-auditory, visual-auditory and tactile-visual-auditory stimulation. PMID:22149159

  20. 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

  1. 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 ...

  2. Treatment Pulse Application for Magnetic Stimulation

    PubMed Central

    Choi, Sun-Seob; Kim, Whi-Young

    2011-01-01

    Treatment and diagnosis can be made in difficult areas simply by changing the output pulse form of the magnetic stimulation device. However, there is a limitation in the range of treatments and diagnoses of a conventional sinusoidal stimulation treatment pulse because the intensity, width, and form of the pulse must be changed according to the lesion type. This paper reports a multidischarge method, where the stimulation coils were driven in sequence via multiple switching control. The limitation of the existing simple sinusoidal pulse form could be overcome by changing the intensity, width, and form of the pulse. In this study, a new sequential discharge method was proposed to freely alter the pulse width. The output characteristics of the stimulation treatment pulse were examined according to the trigger signal delay applied to the switch at each stage by applying a range of superposition pulses to the magnetic simulation device, which is widely used in industry and medicine. PMID:21738404

  3. Deep brain stimulation, ethics, and society.

    PubMed

    Bell, Emily; Racine, Eric

    2010-01-01

    Discussion surrounding ethical and social issues in deep brain stimulation (DBS) has increased. This article introduces a special section on the ethics of DBS in The Journal of Clinical Ethics. PMID:20866015

  4. Rewiring Neural Interactions by Micro-Stimulation

    PubMed Central

    Rebesco, James M.; Stevenson, Ian H.; Körding, Konrad P.; Solla, Sara A.; Miller, Lee E.

    2010-01-01

    Plasticity is a crucial component of normal brain function and a critical mechanism for recovery from injury. In vitro, associative pairing of presynaptic spiking and stimulus-induced postsynaptic depolarization causes changes in the synaptic efficacy of the presynaptic neuron, when activated by extrinsic stimulation. In vivo, such paradigms can alter the responses of whole groups of neurons to stimulation. Here, we used in vivo spike-triggered stimulation to drive plastic changes in rat forelimb sensorimotor cortex, which we monitored using a statistical measure of functional connectivity inferred from the spiking statistics of the neurons during normal, spontaneous behavior. These induced plastic changes in inferred functional connectivity depended on the latency between trigger spike and stimulation, and appear to reflect a robust reorganization of the network. Such targeted connectivity changes might provide a tool for rerouting the flow of information through a network, with implications for both rehabilitation and brain–machine interface applications. PMID:20838477

  5. Perceived intensity of somatosensory cortical electrical stimulation

    PubMed Central

    Blair, Hugh T.; Blaisdell, Aaron P.; Judy, Jack W.

    2010-01-01

    Artificial sensations can be produced by direct brain stimulation of sensory areas through implanted microelectrodes, but the perceptual psychophysics of such artificial sensations are not well understood. Based on prior work in cortical stimulation, we hypothesized that perceived intensity of electrical stimulation may be explained by the population response of the neurons affected by the stimulus train. To explore this hypothesis, we modeled perceived intensity of a stimulation pulse train with a leaky neural integrator. We then conducted a series of two-alternative forced choice behavioral experiments in which we systematically tested the ability of rats to discriminate frequency, amplitude, and duration of electrical pulse trains delivered to the whisker barrel somatosensory cortex. We found that the model was able to predict the performance of the animals, supporting the notion that perceived intensity can be largely accounted for by spatiotemporal integration of the action potentials evoked by the stimulus train. PMID:20440610

  6. 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.

  7. Glass Probe Stimulation of Hair Cell Stereocilia.

    PubMed

    Peng, Anthony W; Ricci, Anthony J

    2016-01-01

    Hair cells are designed to sense mechanical stimuli of sound using their apical stereocilia hair bundles. Mechanical deflection of this hair bundle is converted into an electrical signal through gating of mechano-electric transduction channels. Stiff probe stimulation of hair bundles is an invaluable tool for studying the transduction channel and its associated processes because of the speed and ability to precisely control hair bundle position. Proper construction of these devices is critical to their ultimate performance as is appropriate placement of the probe onto the hair bundle. Here we describe the construction and use of a glass probe coupled to a piezo-electric actuator for stimulating hair bundles, including the basic technique for positioning of the stimulating probe onto the hair bundle. These piezo-electric stimulators can be adapted to other mechanically sensitive systems. PMID:27259944

  8. 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.

  9. [Immune stimulative potency of milk proteins].

    PubMed

    Ambroziak, Adam; Cichosz, Grazyna

    2014-02-01

    Milk proteins are characterized by the highest immune stimulative potency from among all the proteins present in human diet. Whey proteins and numerous growth factors that regulate insulin secretion, differentiation of intestine epithelium cells, and also tissue restoration, are priceless in stimulation the immune system. Lactoferrin shows the most comprehensive pro-health properties: antioxidative, anticancer, immune stimulative and even chemopreventive. Also peptides and amino acids formed from casein and whey proteins possess immune stimulative activity. The most valuable proteins, i.e. lactoferrin, immune globulins, lactoperoxidase and lisozyme, together with bioactive peptides, are resistant to pepsin and trypsin activity. This is why they maintain their exceptional biological activity within human organism. Properly high consumption of milk proteins conditions correct function of immune system, especially at children and elderly persons. PMID:24720113

  10. Epidural cortical stimulation and aphasia therapy

    PubMed Central

    Cherney, Leora R.; Harvey, Richard L.; Babbitt, Edna M.; Hurwitz, Rosalind; Kaye, Rosalind C.; Lee, Jaime B.; Small, Steven. L.

    2013-01-01

    Background There are several methods of delivering cortical brain stimulation to modulate cortical excitability and interest in their application as an adjuvant strategy in aphasia rehabilitation after stroke is growing. Epidural cortical stimulation, although more invasive than other methods, permits high frequency stimulation of high spatial specificity to targeted neuronal populations. Aims First, we review evidence supporting the use of epidural cortical stimulation for upper limb recovery after focal cortical injury in both animal models and human stroke survivors. These data provide the empirical and theoretical platform underlying the use of epidural cortical stimulation in aphasia. Second, we summarize evidence for the application of epidural cortical stimulation in aphasia. We describe the procedures and primary outcomes of a safety and feasibility study (Cherney, Erickson & Small, 2010), and provide previously unpublished data regarding secondary behavioral outcomes from that study. Main Contribution In a controlled study comparing epidural cortical stimulation plus language treatment (CS/LT) to language treatment alone (LT), eight stroke survivors with nonfluent aphasia received intensive language therapy for 6 weeks. Four of these participants also underwent surgical implantation of an epidural stimulation device which was activated only during therapy sessions. Behavioral data were collected before treatment, immediately after treatment, and at 6 and 12 weeks following the end of treatment. The effect size for the primary outcome measure, the Western Aphasia Battery Aphasia Quotient, was benchmarked as moderate from baseline to immediately post-treatment, and large from baseline to the 12-week follow-up. Similarly, effect sizes obtained at the 12-week follow-up for the Boston Naming Test, the Communicative Effectiveness Index, and for correct information units on a picture description task were greater than those obtained immediately post treatment

  11. Neural stimulation: clinical and laboratory experiences.

    PubMed

    Pudenz, R H

    1993-03-01

    This is a report of some of the experiences of the author and his associates with electrical stimulation of the animal and human nervous systems. It was presented as a personal history rather than a review of recent investigations and publications concerned with safe and effective stimulation of neural tissue with the ultimate goals of developing neural prostheses. Much of the information presented herein has been published. PMID:8456389

  12. 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.

  13. 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

  14. Transcranial magnetic stimulation in disorders of consciousness.

    PubMed

    Lapitska, Natallia; Gosseries, Olivia; Delvaux, Valérie; Overgaard, Morten; Nielsen, Feldbaek; Maertens de Noordhout, Alain; Moonen, Gustave; Laureys, Steven

    2009-01-01

    We have reviewed the literature on transcranial magnetic stimulation studies in patients with brain death, coma, vegetative, minimally conscious, and locked-in states. Transcranial magnetic stimulation permits non-invasive study of brain excitability and may extend our understanding of the underlying mechanisms of these disorders. However, use of this technique in severe brain damage remains methodologically ill-defined and must be further validated prior to clinical application in these challenging patients. PMID:20157993

  15. 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

  16. 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.

  17. Spinal evoked potentials following transcranial magnetic stimulation.

    PubMed

    Nemoto, J; Sasaki, T; Kikuchi, Y; Konno, Y; Sakuma, J; Kodama, N

    2001-06-01

    Motor evoked potentials by magnetic stimulation is less invasive and causes no pain as opposed to high current electric stimulation. However, the distribution of the magnetic field generated by the round coil has not been fully studied. In this report, we mapped the extent of the magnetic induction flux density, and then the evoked potentials from the spinal cord were investigated by transcranial magnetic stimulation. We also examined the origin of the evoked potentials obtained by the magnetic stimulation. The following results were obtained. The magnetic induction flux density was at its maximum at the edge of the coil. The potentials consisted of a first negative wave and subsequent multiphasic waves. The first negative wave was similar to a response of the subcorticospinal tract in the lower brain stem, while the subsequent multiphasic waves were similar to those of the pyramidal tract. Although magnetic stimulation has certain advantages over electric stimulation, several problems remain to be solved for the monitoring of motor functions in the clinical settings. PMID:11764415

  18. [Transcranial and invasive brain stimulation for depression].

    PubMed

    Plewnia, C; Padberg, F

    2012-08-01

    Considering the substantial proportion of depressed patients which does not sufficiently benefit from antidepressant pharmacotherapy or psychotherapy, there is increasing interest in non-pharmacological antidepressant strategies. Thus, a whole array of stimulation approaches has been developed as potential new antidepressant interventions. These methods include transcranial convulsive and non-convulsive approaches, e.g. electroconvulsive therapy (ECT), magnetic seizure therapy (MST), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) as well as invasive techniques, e.g. deep brain stimulation (DBS), vagus nerve stimulation (VNS) and epidural cortical stimulation (ECS). Each method represents a specific therapeutic approach with distinct targets within neural networks involved in the pathophysiology of depression. The ECT procedure is an established treatment with the highest efficacy of all antidepressant interventions and TMS reaches the highest level of evidence among the novel neurostimulation approaches and may be clinically used. However, the field yields a promising rapid development which may substantially enrich the armamentarium of antidepressant interventions in the near future. PMID:22843027

  19. 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

  20. The Codacs™ Direct Acoustic Cochlear Implant Actuator: Exploring Alternative Stimulation Sites and Their Stimulation Efficiency

    PubMed Central

    Grossöhmichen, Martin; Salcher, Rolf; Kreipe, Hans-Heinrich; Lenarz, Thomas; Maier, Hannes

    2015-01-01

    This work assesses the efficiency of the Codacs system actuator (Cochlear Ltd., Sydney Australia) in different inner ear stimulation modalities. Originally the actuator was intended for direct perilymph stimulation after stapedotomy using a piston prosthesis. A possible alternative application is the stimulation of middle ear structures or the round window (RW). Here the perilymph stimulation with a K-piston through a stapes footplate (SFP) fenestration (N = 10) as well as stimulation of the stapes head (SH) with a Bell prosthesis (N = 9), SFP stimulation with an Omega/Aerial prosthesis (N = 8) and reverse RW stimulation (N = 10) were performed in cadaveric human temporal bones (TBs). Codacs actuator output is expressed as equivalent sound pressure level (eq. SPL) using RW and SFP displacement responses, measured by Laser Doppler velocimetry as reference. The axial actuator coupling force in stimulation of stapes and RW was adjusted to ~ 5 mN. The Bell prosthesis and Omega/Aerial prosthesis stimulation generated similar mean eq. SPLs (Bell: 127.5–141.8 eq. dB SPL; Omega/Aerial: 123.6–143.9 eq. dB SPL), being significantly more efficient than K-piston perilymph stimulation (108.6–131.6 eq. dB SPL) and RW stimulation (108.3–128.2 eq. dB SPL). Our results demonstrate that SH, SFP and RW are adequate alternative stimulation sites for the Codacs actuator using coupling prostheses and an axial coupling force of ~ 5 mN. Based on the eq. SPLs, all investigated methods were adequate for in vivo hearing aid applications, provided that experimental conditions including constant coupling force will be implemented. PMID:25785860

  1. Brain stimulation in posttraumatic stress disorder

    PubMed Central

    Novakovic, Vladan; Sher, Leo; Lapidus, Kyle A.B.; Mindes, Janet; A.Golier, Julia; Yehuda, Rachel

    2011-01-01

    Posttraumatic stress disorder (PTSD) is a complex, heterogeneous disorder that develops following trauma and often includes perceptual, cognitive, affective, physiological, and psychological features. PTSD is characterized by hyperarousal, intrusive thoughts, exaggerated startle response, flashbacks, nightmares, sleep disturbances, emotional numbness, and persistent avoidance of trauma-associated stimuli. The efficacy of available treatments for PTSD may result in part from relief of associated depressive and anxiety-related symptoms in addition to treatment of core symptoms that derive from reexperiencing, numbing, and hyperarousal. Diverse, heterogeneous mechanisms of action and the ability to act broadly or very locally may enable brain stimulation devices to address PTSD core symptoms in more targeted ways. To achieve this goal, specific theoretical bases derived from novel, well-designed research protocols will be necessary. Brain stimulation devices include both long-used and new electrical and magnetic devices. Electroconvulsive therapy (ECT) and Cranial electrotherapy stimulation (CES) have both been in use for decades; transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), deep brain stimulation (DBS), transcranial Direct Current Stimulation (tDCS), and vagus nerve stimulation (VNS) have been developed recently, over approximately the past twenty years. The efficacy of brain stimulation has been demonstrated as a treatment for psychiatric and neurological disorders such as anxiety (CES), depression (ECT, CES, rTMS, VNS, DBS), obsessive-compulsive disorder (OCD) (DBS), essential tremor, dystonia (DBS), epilepsy (DBS, VNS), Parkinson Disease (DBS), pain (CES), and insomnia (CES). To date, limited data on brain stimulation for PTSD offer only modest guidance. ECT has shown some efficacy in reducing comorbid depression in PTSD patients but has not been demonstrated to improve most core PTSD symptoms. CES and VNS have shown some efficacy in

  2. 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. PMID:26191712

  3. 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

  4. Transcription of Liver X Receptor Is Down-Regulated by 15-Deoxy-Δ12,14-Prostaglandin J2 through Oxidative Stress in Human Neutrophils

    PubMed Central

    Alba, Gonzalo; Reyes, María Edith; Santa-María, Consuelo; Ramírez, Remedios; Geniz, Isabel; Jiménez, Juan; Martín-Nieto, José; Pintado, Elízabeth; Sobrino, Francisco

    2012-01-01

    Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. They play important roles in controlling cholesterol homeostasis and as regulators of inflammatory gene expression and innate immunity, by blunting the induction of classical pro-inflammatory genes. However, opposite data have also been reported on the consequences of LXR activation by oxysterols, resulting in the specific production of potent pro-inflammatory cytokines and reactive oxygen species (ROS). The effect of the inflammatory state on the expression of LXRs has not been studied in human cells, and constitutes the main aim of the present work. Our data show that when human neutrophils are triggered with synthetic ligands, the synthesis of LXRα mRNA became activated together with transcription of the LXR target genes ABCA1, ABCG1 and SREBP1c. An inflammatory mediator, 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2), hindered T0901317-promoted induction of LXRα mRNA expression together with transcription of its target genes in both neutrophils and human macrophages. This down-regulatory effect was dependent on the release of reactive oxygen species elicited by 15dPGJ2, since it was enhanced by pro-oxidant treatment and reversed by antioxidants, and was also mediated by ERK1/2 activation. Present data also support that the 15dPGJ2-induced serine phosphorylation of the LXRα molecule is mediated by ERK1/2. These results allow to postulate that down-regulation of LXR cellular levels by pro-inflammatory stimuli might be involved in the development of different vascular diseases, such as atherosclerosis. PMID:23115616

  5. Aldo-keto Reductase 1C3 (AKR1C3) is overexpressed in skin squamous cell carcinoma (SCC) and affects SCC growth via prostaglandin metabolism

    PubMed Central

    Mantel, Alon; Carpenter-Mendini, Amanda; VanBuskirk, JoAnne; Pentland, Alice P.

    2014-01-01

    Aldo-keto reductase 1C3 (AKR1C3) is an enzyme involved in metabolizing prostaglandins (PGs) and sex hormones. It metabolizes PGD2 to 9α11β-PGF2, diverting the spontaneous conversion of PGD2 to the PPARγ agonist, 15-Deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2). AKR1C3 is overexpressed in various malignancies, suggesting a tumor promoting function. This work investigates AKR1C3 expression in human non-melanoma skin cancers, revealing overexpression in squamous cell carcinoma (SCC). Effects of AKR1C3 overexpression were then evaluated using 3 SCC cell lines. AKR1C3 was detected in all SCC cell lines and its expression was upregulated in response to its substrate, PGD2. Although attenuating AKR1C3 expression in SCC cells by siRNA did not affect growth, treatment with PGD2 and its dehydration metabolite, 15d-PGJ2, decreased SCC proliferation in a PPARγ-dependent manner. In addition, treatment with the PPARγ agonist pioglitazone profoundly inhibited SCC proliferation. Finally, we generated an SCC cell line that stably overexpressed AKR1C3 (SCC-AKR1C3). SCC-AKR1C3 metabolized PGD2 to 9α11β-PGF2 12 fold faster than the parent cell line and was protected from the anti-proliferative effect mediated by PGD2. This work suggests that PGD2 and its metabolite 15d-PGJ2 attenuate SCC proliferation in a PPARγ-dependent manner, therefore activation of PPARγ by agonists such as Pioglitazone may benefit those at high risk of SCC. PMID:24917395

  6. 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

  7. 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.

  8. 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

  9. Effects of PPARgamma agonists on cell survival and focal adhesions in a Chinese thyroid carcinoma cell line.

    PubMed

    Chen, Ying; Wang, Seu-Mei; Wu, Jiahn-Chun; Huang, Shih-Horng

    2006-07-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists cause cell death in several types of cancer cells. The aim of this study was to examine the effects of two PPARgamma agonists, ciglitazone and 15-deoxy-delta(12,14)-prostaglandin J2 (15dPGJ2), on the survival of thyroid carcinoma CGTH W-2 cells. Both ciglitazone and 15dPGJ2 decreased cell viability in a time- and dose-dependent manner. Cell death was mainly due to apoptosis, with a minor contribution from necrosis. Increased levels of active caspase 3, cleaved poly (ADP-ribose) polymerase (PARP), and cytosolic cytochrome-c were noted. In addition, ciglitazone and 15dPGJ2 induced detachment of CGTH W-2 cells from the culture substratum. Both the protein levels and immunostaining signals of focal adhesion (FA) proteins, including vinculin, integrin beta1, focal adhesion kinase (FAK), and paxillin were decreased after PPARgamma agonist treatment. Meanwhile, reduced phosphorylation of FAK and paxillin was noted. Furthermore, PPARgamma agonists induced expression of protein tyrosine phosphatase-PEST (PTP-PEST), and of phosphatase and tensin homologue deleted on chromosome ten (PTEN). The upregulation of these phosphatases might contribute to the dephosphorylation of FAK and paxillin, since pre-treatment with orthovanadate prevented PPARgamma agonist-induced dephosphorylation of FAK and paxillin. Perturbation of CGTH W-2 cells with anti-integrin beta1 antibodies induced FA disruption and apoptosis in the same cells, thus the downregulation of integrin beta1 by PPARgamma agonists resulted in FA disassembly and might induce apoptosis via anoikis. Our results suggested the presence of crosstalk between apoptosis and integrin-FA signaling. Moreover, upregulation and activation of PTEN was correlated with reduced phosphorylation of Akt, and this consequence disfavored cell survival. In conclusion, PPARgamma agonists induced apoptosis of thyroid carcinoma cells via the cytochrome-c caspase 3 and PTEN

  10. 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

  11. 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

  12. 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

  13. Radiant energy required for infrared neural stimulation

    DOE PAGESBeta

    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

  14. GABAAergic stimulation modulates intracellular protein arginine methylation.

    PubMed

    Denman, Robert B; Xie, Wen; Merz, George; Sung, Ying-Ju

    2014-06-20

    Changes in cytoplasmic pH are known to regulate diverse cellular processes and influence neuronal activities. In neurons, the intracellular alkalization is shown to occur after stimulating several channels and receptors. For example, it has previously demonstrated in P19 neurons that a sustained intracellular alkalinization can be mediated by the Na(+)/H(+) antiporter. In addition, the benzodiazepine binding subtypes of the γ-amino butyric acid type A (GABAA) receptor mediate a transient intracellular alkalinization when they are stimulated. Because the activities of many enzymes are sensitive to pH shift, here we investigate the effects of intracellular pH modulation resulted from stimulating GABAA receptor on the protein arginine methyltransferases (PRMT) activities. We show that the major benzodiazepine subtype (2α1, 2β2, 1γ2) is constitutively expressed in both undifferentiated P19 cells and retinoic acid (RA) differentiated P19 neurons. Furthermore stimulation with diazepam and, diazepam plus muscimol produce an intracellular alkalinization that can be detected ex vivo with the fluorescence dye. The alkalinization results in significant perturbation in protein arginine methylation activity as measured in methylation assays with specific protein substrates. Altered protein arginine methylation is also observed when cells are treated with the GABAA agonist muscimol but not an antagonist, bicuculline. These data suggest that pH-dependent and pH-independent methylation pathways can be activated by GABAAergic stimulation, which we verified using hippocampal slice preparations from a mouse model of fragile X syndrome. PMID:24793772

  15. Effectiveness of sensory stimulation on tactile extinction.

    PubMed

    Nico, D

    1999-07-01

    Eleven brain-damaged patients with extinction were asked to report double tactile stimuli before, during, and after optokinetic stimulation and transcutaneous electrical stimulation of the posterior neck region. The goal of the study was to test whether tactile extinction is sensitive to these experimental manipulations in order to better understand the nature of the disorder. Both of these sensory stimulations are known to be effective in modulating only higher-order (cognitive) disorders of spatial coding, such as visual hemineglect, deficit of position sense, hemianesthesia, etc. When applied to the side contralateral to the cerebral lesion, both optokinetic and transcutaneous electrical stimulation significantly affected patients' performances, increasing the amount of detections of contralesional double stimuli. A tendency towards worse performance was observed when sensory stimulation was applied to the ipsilesional side. The reported effectiveness in reducing tactile extinction suggests that the deficit can not be fully ascribed to a peripheral sensory disorder and that it reflects damage to a higher-order cognitive function involved in contralesional space representation or in the deployment of attention to that side of space. The nature of the close relationship between extinction and hemineglect is also discussed from the point of view of extinction as a deficit of space coding. PMID:10424416

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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

  1. Supraspinal stimulation for treatment of refractory pain.

    PubMed

    Parmar, V K; Gee, L; Smith, H; Pilitsis, J G

    2014-08-01

    Refractory pain syndromes often have far reaching effects and are quite a challenge for primary care providers and specialists alike to treat. With the help of site-specific neuromodulation and appropriate patient selection these difficult to treat pain syndromes may be managed. In this article, we focus on supraspinal stimulation (SSS) for treatment of intractable pain and discuss off-label uses of deep brain stimulation (DBS) and motor cortex stimulation (MCS) in context to emerging indications in neuromodulation. Consideration for neuromodulatory treatment begins with rigorous patient selection based on exhaustive conservative management, elimination of secondary gains, and a proper psychology evaluation. Trial stimulation prior to DBS is nearly always performed while trial stimulation prior to MCS surgery is symptom dependent. Overall, a review of the literature demonstrates that DBS should be considered for refractory conditions including nociceptive/neuropathic pain, phantom limb pain, and chronic cluster headache (CCH). MCS should be considered primarily for trigeminal neuropathic pain (TNP) and central pain. DBS outcome studies for post-stroke pain as well as MCS studies for complex regional pain syndrome (CRPS) show more modest results and are also discussed in detail. PMID:24956545

  2. 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

  3. 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…

  4. 21 CFR 870.3850 - Carotid sinus nerve stimulator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Carotid sinus nerve stimulator. 870.3850 Section... nerve stimulator. (a) Identification. A carotid sinus nerve stimulator is an implantable device used to decrease arterial pressure by stimulating Hering's nerve at the carotid sinus. (b) Classification....

  5. 21 CFR 870.3850 - Carotid sinus nerve stimulator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Carotid sinus nerve stimulator. 870.3850 Section... nerve stimulator. (a) Identification. A carotid sinus nerve stimulator is an implantable device used to decrease arterial pressure by stimulating Hering's nerve at the carotid sinus. (b) Classification....

  6. 21 CFR 870.3850 - Carotid sinus nerve stimulator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Carotid sinus nerve stimulator. 870.3850 Section... nerve stimulator. (a) Identification. A carotid sinus nerve stimulator is an implantable device used to decrease arterial pressure by stimulating Hering's nerve at the carotid sinus. (b) Classification....

  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  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. Early experiences with tachycardia-triggered vagus nerve stimulation using the AspireSR stimulator.

    PubMed

    El Tahry, Riëm; Hirsch, Martin; Van Rijckevorsel, Kenou; Santos, Susana Ferrao; de Tourtchaninoff, Marianne; Rooijakkers, Herbert; Coenen, Volker; Schulze-Bonhage, Andreas

    2016-06-01

    Many epilepsy patients treated with vagus nerve stimulation additionally use an "on-demand" function, triggering an extra stimulation to terminate a seizure or diminish its severity. Nevertheless, a substantial number of patients are not able to actively trigger stimulations by use of a magnet, due to the absence of an aura or inability for voluntary actions in the early phase of a seizure. To address this need, a novel implantable pulse generator, the AspireSR VNS system, was developed to provide automated ictal stimulation triggered by a seizure-detecting algorithm. We report our experience with three patients in assessing the functionality of ictal stimulation, illustrating the detection system in practice. Detection of ictal tachycardia and variable additional detections of physiological tachycardia depended on the individual seizure-detecting algorithm settings. PMID:27248796

  18. Piezoelectric Nanoparticle-Assisted Wireless Neuronal Stimulation.

    PubMed

    Marino, Attilio; Arai, Satoshi; Hou, Yanyan; Sinibaldi, Edoardo; Pellegrino, Mario; Chang, Young-Tae; Mazzolai, Barbara; Mattoli, Virgilio; Suzuki, Madoka; Ciofani, Gianni

    2015-07-28

    Tetragonal barium titanate nanoparticles (BTNPs) have been exploited as nanotransducers owing to their piezoelectric properties, in order to provide indirect electrical stimulation to SH-SY5Y neuron-like cells. Following application of ultrasounds to cells treated with BTNPs, fluorescence imaging of ion dynamics revealed that the synergic stimulation is able to elicit a significant cellular response in terms of calcium and sodium fluxes; moreover, tests with appropriate blockers demonstrated that voltage-gated membrane channels are activated. The hypothesis of piezoelectric stimulation of neuron-like cells was supported by lack of cellular response in the presence of cubic nonpiezoelectric BTNPs, and further corroborated by a simple electroelastic model of a BTNP subjected to ultrasounds, according to which the generated voltage is compatible with the values required for the activation of voltage-sensitive channels. PMID:26168074

  19. Adaptive Inverse optimal neuromuscular electrical stimulation.

    PubMed

    Wang, Qiang; Sharma, Nitin; Johnson, Marcus; Gregory, Chris M; Dixon, Warren E

    2013-12-01

    Neuromuscular electrical stimulation (NMES) is a prescribed treatment for various neuromuscular disorders, where an electrical stimulus is provided to elicit a muscle contraction. Barriers to the development of NMES controllers exist because the muscle response to an electrical stimulation is nonlinear and the muscle model is uncertain. Efforts in this paper focus on the development of an adaptive inverse optimal NMES controller. The controller yields desired limb trajectory tracking while simultaneously minimizing a cost functional that is positive in the error states and stimulation input. The development of this framework allows tradeoffs to be made between tracking performance and control effort by putting different penalties on error states and control input, depending on the clinical goal or functional task. The controller is examined through a Lyapunov-based analysis. Experiments on able-bodied individuals are provided to demonstrate the performance of the developed controller. PMID:23757569

  20. 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

  1. Pathways of Translation: Deep Brain Stimulation

    PubMed Central

    Gionfriddo, Michael R.; Greenberg, Alexandra J.; Wahegaonkar, Abhijeet L.; Lee, Kendall H.

    2014-01-01

    Electrical stimulation of the brain has a 2000 year history. Deep brain stimulation (DBS), one form of neurostimulation, is a functional neurosurgical approach in which a high frequency electric current stimulates targeted brain structures for therapeutic benefit. It is an effective treatment for certain neuropathologic movement disorders and an emerging therapy for psychiatric conditions and epilepsy. Its translational journey did not follow the typical bench-to-bedside path, but rather reversed the process. The shift from ancient and medieval folkloric remedy to accepted medical practice began with independent discoveries about electricity during the 17th century and was fostered by technological advances of the 20th. In this article we review that journey and discuss how the quest to expand its applications and continue to improve outcomes is taking DBS from the bedside back to the bench. PMID:24330698

  2. Auditory stimulation and cardiac autonomic regulation

    PubMed Central

    Valenti, Vitor E.; Guida, Heraldo L.; Frizzo, Ana C. F.; Cardoso, Ana C. V.; Vanderlei, Luiz Carlos M.; de Abreu, Luiz Carlos

    2012-01-01

    Previous studies have already demonstrated that auditory stimulation with music influences the cardiovascular system. In this study, we described the relationship between musical auditory stimulation and heart rate variability. Searches were performed with the Medline, SciELO, Lilacs and Cochrane databases using the following keywords: “auditory stimulation”, “autonomic nervous system”, “music” and “heart rate variability”. The selected studies indicated that there is a strong correlation between noise intensity and vagal-sympathetic balance. Additionally, it was reported that music therapy improved heart rate variability in anthracycline-treated breast cancer patients. It was hypothesized that dopamine release in the striatal system induced by pleasurable songs is involved in cardiac autonomic regulation. Musical auditory stimulation influences heart rate variability through a neural mechanism that is not well understood. Further studies are necessary to develop new therapies to treat cardiovascular disorders. PMID:22948465

  3. Stimulated Electronic X-Ray Raman Scattering

    NASA Astrophysics Data System (ADS)

    Weninger, Clemens; Purvis, Michael; Ryan, Duncan; London, Richard A.; Bozek, John D.; Bostedt, Christoph; Graf, Alexander; Brown, Gregory; Rocca, Jorge J.; Rohringer, Nina

    2013-12-01

    We demonstrate strong stimulated inelastic x-ray scattering by resonantly exciting a dense gas target of neon with femtosecond, high-intensity x-ray pulses from an x-ray free-electron laser (XFEL). A small number of lower energy XFEL seed photons drive an avalanche of stimulated resonant inelastic x-ray scattering processes that amplify the Raman scattering signal by several orders of magnitude until it reaches saturation. Despite the large overall spectral width, the internal spiky structure of the XFEL spectrum determines the energy resolution of the scattering process in a statistical sense. This is demonstrated by observing a stochastic line shift of the inelastically scattered x-ray radiation. In conjunction with statistical methods, XFELs can be used for stimulated resonant inelastic x-ray scattering, with spectral resolution smaller than the natural width of the core-excited, intermediate state.

  4. What Galvanic Vestibular Stimulation Actually Activates

    PubMed Central

    Curthoys, Ian S.; MacDougall, Hamish Gavin

    2012-01-01

    In a recent paper in Frontiers Cohen et al. (2012) asked “What does galvanic vestibular stimulation actually activate?” and concluded that galvanic vestibular stimulation (GVS) causes predominantly otolithic behavioral responses. In this Perspective paper we show that such a conclusion does not follow from the evidence. The evidence from neurophysiology is very clear: galvanic stimulation activates primary otolithic neurons as well as primary semicircular canal neurons (Kim and Curthoys, 2004). Irregular neurons are activated at lower currents. The answer to what behavior is activated depends on what is measured and how it is measured, including not just technical details, such as the frame rate of video, but the exact experimental context in which the measurement took place (visual fixation vs total darkness). Both canal and otolith dependent responses are activated by GVS. PMID:22833733

  5. Localization of nerve depolarization with magnetic stimulation.

    PubMed

    Odderson, I R; Halar, E M

    1992-06-01

    The specific location on the magnetic stimulation (MS) coil that may correspond to the area of nerve depolarization has not been determined. In order to localize such an area, MS with 9-cm and 5-cm diameter coils was compared with conventional percutaneous electric stimulation (ES). On the 9-cm coil the distribution of points of nerve depolarization corresponded to that quarter of the coil which was placed over and parallel to the median nerve, whereas on the 5-cm coil, this area also extended outside the coil. The points of median nerve depolarization with MS were distributed over a distance of 7 cm on the stimulator head and was nearly identical for the 2 coil sizes at the wrist and elbow. Ulnar nerve costimulation was less frequent with the smaller coil at the wrist. A calculated reference point on the coil is suggested for more accurate NCV determinations. PMID:1508235

  6. 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

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

    PubMed

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

    2015-12-01

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

  8. 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

  9. 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