gyy-4137 and Inflammation

Topics: Endothelial Cells; Humans; Hydrogen Sulfide; Inflammation; PPAR delta; Sodium-Glucose Transporter 2; STAT3 Transcription Factor

Macrophages play a crucial role in inflammation, a defense mechanism of the innate immune system. Metabolic function powered by glucose transporter isoform 1 (Glut1) is necessary for macrophage activity during inflammation. The present study investigated the roles of cystathionine-γ-lyase (CSE) and its byproduct, hydrogen sulfide (H2S), in macrophage glucose metabolism to explore the mechanism by which H2S acts as an inflammatory regulator in lipopolysaccharide- (LPS) induced macrophages. Our results demonstrated that LPS-treated macrophages increased Glut1 expression. LPS-induced Glut1 expression is regulated via nuclear factor (NF)-κB activation and is associated with phosphatidylinositol-3-kinase PI3k activation. Small interfering (si) RNA-mediated silencing of CSE decreased the LPS-induced NF-κB activation and Glut1 expression, suggesting a role for H2S in metabolic function in macrophages during pro-inflammatory response. Confoundingly, treatment with GYY4137, an H2S-donor molecule, also displayed inhibitory effects upon LPS-induced NF-κB activation and Glut1 expression. Moreover, GYY4137 treatment increased Akt activation, suggesting a role in promoting resolution of inflammation. Our study provides evidence that the source of H2S, either endogenous (via CSE) or exogenous (via GYY4137), supports or inhibits the LPS-induced NF-κB activity and Glut1 expression, respectively. Therefore, H2S may influence metabolic programming in immune cells to alter glucose substrate availability that impacts the immune response.

Topics: Cystathionine gamma-Lyase; Glucose Transport Proteins, Facilitative; Humans; Hydrogen Sulfide; Inflammation; Lipopolysaccharides; Macrophages; NF-kappa B; Phosphatidylinositol 3-Kinases; Protein Isoforms; Proto-Oncogene Proteins c-akt

Hydrogen sulfide (H

Topics: Animals; Anti-Inflammatory Agents; Autophagy; Beclin-1; Cells, Cultured; Humans; Hydrogen Sulfide; Inflammation; Lactosylceramides; Male; Models, Animal; Morpholines; Organothiophosphorus Compounds; Periodontitis; Rats; Rats, Sprague-Dawley

Hydrogen sulfide donors reduce inflammatory signaling in vitro and in vivo. The biological effect mediated by H. We investigated the effects of GYY4137 and sodium hydrosulfide on the release of proinflammatory molecules such as ROS, NO and TNF-α from LPS-treated human SH-SY5Y neuroblastoma and the THP-1 promonocytic cell lines. Transcriptomic and RT-qPCR studies using THP-1 cells were performed to monitor the effects of the GYY4137 on multiple signaling pathways, including various immune-related and proinflammatory genes after combined action of LPS and GYY4137.. The GYY4137 and sodium hydrosulfide differed in the ability to reduce the production of the LPS-evoked proinflammatory mediators. The pre-treatment with GYY4137 resulted in a drastic down-regulation of many TNF-α effectors that are induced by LPS treatment in THP-1 cells. Furthermore, GYY4137 pretreatment of LPS-exposed cells ameliorates the LPS-mediated induction of multiple pro-inflammatory genes and decreases expression of immunoproteasome genes. Besides, in these experiments we detected the up-regulation of several important pathways that are inhibited by LPS.. Based on the obtained results we believe that our transcriptomic analysis significantly contributes to the understanding of the molecular mechanisms of anti-inflammatory and cytoprotective activity of hydrogen sulfide donors, and highlights their potential against LPS challenges and other forms of inflammation.

Topics: Anti-Inflammatory Agents; Cell Line; Cytokines; Humans; Hydrogen Sulfide; Inflammation; Lipopolysaccharides; Morpholines; Nitric Oxide; Organothiophosphorus Compounds; Reactive Oxygen Species; Signal Transduction; Sulfides; Transcriptome

GYY4137, a slow-releasing hydrogen sulfide (H

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Cytokines; Heme Oxygenase-1; Inflammation; Lipopolysaccharides; Male; Metalloporphyrins; Mice; Mice, Inbred C57BL; Morpholines; Nitric Oxide Synthase Type II; Organothiophosphorus Compounds; Protoporphyrins; RAW 264.7 Cells

A dual role of hydrogen sulfide (H

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Alkynes; Animals; Cell Differentiation; Gene Expression; Glycine; Hydrogen Sulfide; Inflammation; Mice; Morpholines; Organothiophosphorus Compounds; Sulfides

Accumulating evidence demonstrated that hydrogen sulfide (H2S) is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN) and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1β in circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS) and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

Topics: Animals; Apoptosis; Cisplatin; Hydrogen Sulfide; Inflammation; Kidney; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Morpholines; Organothiophosphorus Compounds; Oxidative Stress; Renal Insufficiency; Thiobarbituric Acid Reactive Substances

Hydrogen sulfide (H2S), known as the third endogenous gaseous transmitter, has received increasing attention because of its diverse effects, including angiogenesis, vascular relaxation and myocardial protection.We aimed to investigate the role of H2S in oxidative/nitrative stress and inflammation in acute lung injury (ALI) induced by endotoxemia.. Male ICR mice were divided in six groups: (1) Control group; (2) GYY4137treatment group; (3) L-NAME treatment group; (4) lipopolysaccharide (LPS) treatment group; (5) LPS with GYY4137 treatment group; and (6) LPS with L-NAME treatment group. The lungs were analysed by histology, NO production in the mouse lungs determined by modified Griess (Sigma-Aldrich) reaction, cytokine levels utilizing commercialkits, and protein abundance by Western blotting.. GYY4137, a slowly-releasing H2S donor, improved the histopathological changes in the lungs of endotoxemic mice. Treatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, increased anti-oxidant biomarkers such as thetotal antioxidant capacity (T-AOC) and theactivities of catalase (CAT) and superoxide dismutase (SOD) but decreased a marker of peroxynitrite (ONOO-) action and 3-nitrotyrosine (3-NT) in endotoxemic lung. L-NAME administration also suppressed inflammation in endotoxemic lung, as evidenced by the decreased pulmonary levels of interleukin (IL)-6, IL-8, and myeloperoxidase (MPO) and the increased level of anti-inflammatory cytokine IL-10. GYY4137 treatment reversed endotoxin-induced oxidative/nitrative stress, as evidenced by a decrease in malondialdehyde (MDA), hydrogenperoxide (H2O2) and 3-NT and an increase in the antioxidant biomarker ratio of reduced/oxidized glutathione(GSH/GSSG ratio) and T-AOC, CAT and SOD activity. GYY4137 also attenuated endotoxin-induced lung inflammation. Moreover, treatment with GYY4137 inhibited inducible NOS (iNOS) expression and nitric oxide (NO) production in the endotoxemia lung.. GYY4137 conferred protection against acute endotoxemia-associated lung injury, which may have beendue to the anti-oxidant, anti-nitrative and anti-inflammatory properties of GYY4137. The present findings warrant further exploration of the clinical applicability of H2S in the prevention and treatment of ALI.

Topics: Acute Lung Injury; Animals; Antioxidants; Endotoxemia; Hydrogen Peroxide; Hydrogen Sulfide; Inflammation; Inflammation Mediators; Lipopolysaccharides; Lung; Male; Malondialdehyde; Mice, Inbred ICR; Morpholines; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrosation; Organothiophosphorus Compounds; Oxidative Stress; Tyrosine

Hydrogen sulfide (H2S), the third gasotransmitter together with NO and CO, is emerging as a regulator of inflammation. To test if it might offer therapeutic value in the treatment of osteoarthritis (OA) we evaluated the effects of two exogenous sources of H2S, NaSH and GYY4137, on inflammation and catabolic markers that characterize OA.. Human chondrocytes (CHs) were isolated from OA tissue. Cells were stimulated with a pro-inflammatory cytokine (interleukin-1β, IL1β, 5 ng/ml) and the ability of the two H2S sources to ameliorate its effects on the cells was tested. Nitric oxide (NO) production was quantified through the Griess reaction. Protein levels of inducible NO synthase (NOS2) and matrix metalloproteinase 13 (MMP13) were visualized through immunocytochemistry (ICC). Relative mRNA expression was quantified with qRT-PCR. Prostaglandin-2 (PGE-2), interleukin 6 (IL6) and MMP13 levels were measured with specific EIAs. NFκB nuclear translocation was visualized with immunofluorescence.. Both H2S sources led to significant reductions in NO, PGE-2, IL6 and MMP13 released by the cells and at the protein level. This was achieved by downregulation of relevant genes involved in the synthesis routes of these molecules, namely NOS2, cyclooxigenase-2 (COX2), prostaglandin E synthase (PTGES), IL6 and MMP13. NFκB nuclear translocation was also reduced.. NaSH and GYY4137 show anti-inflammatory and anti-catabolic properties when added to IL1β activated osteoarthritic CHs. Supplementation with exogenous H2S sources can regulate the expression of relevant genes in OA pathogenesis and progression, counteracting IL1β pro-inflammatory signals that lead to cartilage destruction in part by reducing NFκB activation.

Topics: Aged; Aged, 80 and over; Biomarkers; Cartilage, Articular; Cells, Cultured; Chondrocytes; Dinoprostone; Female; Humans; Hydrogen Sulfide; Inflammation; Interleukin-1beta; Interleukin-6; Male; Matrix Metalloproteinase 13; Metabolism; Morpholines; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Organothiophosphorus Compounds; Osteoarthritis; Sulfides

The role of hydrogen sulfide (H2 S) in inflammation remains unclear with both pro- and anti-inflammatory actions of this gas described. We have now assessed the effect of GYY4137 (a slow-releasing H2 S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro. We have also examined the effect of GYY4137 in a complete Freund's adjuvant (CFA) model of acute joint inflammation in the mouse. GYY4137 (0.1-0.5 mM) decreased LPS-induced production of nitrite (NO2 (-) ), PGE2 , TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro. Using recombinant human enzymes, GYY4137 inhibited the activity of COX-2, iNOS and TNF-α converting enzyme (TACE). In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activity and decreased TNF-α, IL-1β, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA. GYY4137 was also anti-inflammatory when given 18 hrs after CFA. Thus, although GYY4137 consistently reduced the generation of pro-inflammatory mediators from human joint cells in vitro, its effect on acute joint inflammation in vivo depended on the timing of administration.

Topics: Acute Disease; Animals; Arthritis; Cartilage; Cells, Cultured; Chondrocytes; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Humans; Hydrogen Sulfide; Inflammation; Inflammation Mediators; Joints; Lipopolysaccharides; Mice; Morpholines; NF-kappa B; Nitric Oxide Synthase Type II; Organothiophosphorus Compounds; Synovial Membrane; Tumor Necrosis Factor-alpha