gyy-4137 and Reperfusion-Injury

Hydrogen sulfide (H

Topics: Animals; Creatinine; Hydrogen Sulfide; Kidney; Reperfusion Injury

Hydrogen sulfide (H2S) is considered to be the third most important endogenous gasotransmitter in organisms. GYY4137 is a long-acting donor for H2S, a gas transmitter that has been shown to prevent multi-organ damage in animal studies. We previously reported the effect of GYY4137 on cardiac ischaemia reperfusion injury (IRI) in diabetic mice. However, the role and mechanism of GYY4137 in renal IRI are poorly understood. The aims of this study were to determine whether GYY4137 can effectively alleviate the injury induced by renal ischaemia reperfusion and to explore its possible mechanism.. Mice received right nephrectomy and clipping of the left renal pedicle for 45 min. GYY4137 was administered by intraperitoneal injection for 2 consecutive days before the operation. The model of hypoxia/reoxygenation injury was established in HK-2 cells, which were pre-treated with or without GYY4137. Renal histology, function, apoptosis, and oxidative stress were measured. Western blot was used to measure the target -protein after renal IRI.. The results indicated that GYY4137 had a clear protective effect on renal IRI as reflected by the attenuation of renal dysfunction, renal tubule injury, and apoptosis. Moreover, GYY4137 remarkably reduced renal IRI-induced oxidative stress. GYY4137 significantly elevated the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2) and the expression of antioxidant enzymes regulated by Nrf2, including SOD, HO-1, and NQO-1.. GYY4137 alleviates ischaemia reperfusion-induced renal injury through activating the antioxidant effect mediated by Nrf2 signalling.

Topics: Animals; Antioxidants; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Morpholines; NF-E2-Related Factor 2; Organothiophosphorus Compounds; Oxidative Stress; Reperfusion Injury

The present study aimed to clarify the protective effects of p‑methoxyphenyl morpholino‑phosphinodithioic acid (GYY4137), a water‑soluble hydrogen sulfide‑releasing molecule, on a rat model of intestinal ischemia‑reperfusion (IIR). A total of 40 healthy male Sprague Dawley (SD) rats were randomly divided into four groups (n=10/group): Group A, a sham‑surgery group; Group B, the IIR group; group C, rats with IIR that were administered an abdominal injection of low‑dose GYY4137 (40 mg/kg); and group D, rats with IIR that were administered high‑dose GYY4137 (80 mg/kg). Intestinal histomorphology was observed using hematoxylin and eosin staining, and the concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Apoptotic index (AI) was determined by terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling. Reverse transcription‑quantitative PCR analysis was performed to assess the expression levels of intestinal caspase‑3, Bax and Bcl‑2. Notably, disordered arrangement of intestinal villi and mucosal necrosis were detected in group B, which was substantially improved by GYY4137 treatment (groups C and D). MDA content (nmol/mg) was 2.83±0.36, 9.23±0.78, 4.97±0.45 and 3.51±1.05 nmol/mg in groups A, B, C and D, respectively. In addition, SOD concentration (U/mg) was 135.37±3.34, 76.45±1.39, 95.13±1.64 and 115.13±2.54 in groups A, B, C and D, respectively. Furthermore, AI in group B (21.73±1.17%) was markedly higher than that in group A (4.53±0.28%) and in the GYY4137 intervention groups (9.53±0.96 and 6.53±0.76% in groups C and D, respectively). Compared with in group A, the mRNA expression levels of Bax and caspase‑3 were markedly higher in group B (P<0.05), whereas the expression of Bcl‑2 was significantly lower (P<0.05). Furthermore, compared with in group B, Bcl‑2 expression was higher, and Bax and caspase‑3 expression was lower in groups C and D (P<0.05). In conclusion, GYY4137 may alleviate IIR‑induced damage in SD rats.

Topics: Animals; Apoptosis; Biomarkers; Disease Models, Animal; Gene Expression; Hydrogen Sulfide; Immunohistochemistry; Intestinal Mucosa; Intestines; Male; Malondialdehyde; Morpholines; Organothiophosphorus Compounds; Oxidative Stress; Protective Agents; Rats; Reperfusion Injury; Superoxide Dismutase

Necrotizing enterocolitis (NEC) in premature infants is often a devastating surgical condition with poor outcomes. GYY4137 is a long-acting donor of hydrogen sulfide, a gasotransmitter that is protective against intestinal injury in experimental NEC, likely through protection against injury secondary to ischemia. We hypothesized that administration of GYY4137 would improve mesenteric perfusion, reduce intestinal injury, and reduce inflammatory responses in experimental NEC and ischemia-reperfusion injury, and that these benefits would be mediated through endothelial nitric oxide synthase-dependent pathways.. NEC was induced in C57BL/6 wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (eNOSKO) pups via maternal separation, formula feeding, enteral lipopolysaccharide, and intermittent hypoxic and hypothermic stress. Pups received daily intraperitoneal injections of 50 mg/kg GYY4137 or phosphate buffered saline vehicle. In separate groups, adult male WT and eNOSKO mice underwent superior mesenteric artery occlusion for 60 min. Before abdominal closure, 50 mg/kg GYY4137 or phosphate buffered saline vehicle was administered into the peritoneal cavity. Laser doppler imaging was used to assess mesenteric perfusion of pups at baseline and on postnatal day 9, and the adult mice at baseline and 24 h after ischemic insult. After euthanasia, the terminal ileum of each animal was fixed, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Sections were blindly graded using published injury scores. Intestinal tissue was homogenized and cytokines measured by ELISA. Data were compared using Mann-Whitney U test, and P-values <0.05 were significant.. After NEC and ischemia reperfusion (I/R) injury, GYY4137 improved perfusion in WT mice compared to vehicle, but this effect was lost in the eNOSKO animals. Histologic injury followed a similar pattern with reduced intestinal injury in WT mice treated with GYY4137, and no significant improvement in the eNOSKO group. Cytokine expression after GYY4137 administration was altered by the ablation of eNOS in both NEC and I/R injury groups, with significant differences noted in Interleukin 6 and vascular endothelial growth factor.. GYY4137, a long-acting donor of hydrogen sulfide, has potential as a therapeutic compound for NEC. It improves mesenteric perfusion and intestinal injury in experimental NEC and intestinal I/R injury, and these benefits appear to be mediated through eNOS-dependent pathways.

Topics: Animals; Biomarkers; Cytokines; Drug Administration Schedule; Endothelium, Vascular; Enterocolitis, Necrotizing; Hydrogen Sulfide; Injections, Intraperitoneal; Intestinal Mucosa; Male; Mesenteric Ischemia; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Nitric Oxide; Nitric Oxide Synthase; Organothiophosphorus Compounds; Protective Agents; Reperfusion Injury; Treatment Outcome

Lung ischemia-reperfusion injury is a complex pathophysiologic process associated with high morbidity and mortality. We have demonstrated elsewhere that diabetes mellitus aggravated ischemia-induced lung injury. Oxidative stress and mitochondrial dysfunction are drivers of diabetic lung ischemia-reperfusion injury; however, the pathways that mediate these events are unexplored. In this study using a high-fat diet-fed model of streptozotocin-induced type 2 diabetes in rats, we determined the effect of hydrogen sulfide on lung ischemia-reperfusion injury with a focus on Sirtuin3 signaling.. Rats with type 2 diabetes were exposed to GYY4137, a slow release donor of hydrogen sulfide with or without administration of the Sirtuin3 short hairpin ribonucleic acid plasmid, and then subjected to a surgical model of ischemia-reperfusion injury of the lung (n = 8). Lung function, oxidative stress, inflammation, cell apoptosis, and mitochondrial function were measured.. Compared with nondiabetic rats, animals with type 2 diabetes at baseline exhibited significantly decreased Sirtuin3 signaling in lung tissue and increased oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction (P < .05 each). In addition, further impairment in Sirtuin3 signaling was found in diabetic rats subjected to this model of lung ischemia-reperfusion. Simultaneously, the indexes showed further aggravation. Treatment with hydrogen sulfide restored Sirtuin3 expression and decreased lung ischemia-reperfusion injury in animals with type 2 diabetes mellitus by improving lung functional recovery, decreasing oxidative damage, suppressing inflammation, ameliorating cell apoptosis, and preserving mitochondrial function (P < .05). Conversely, these protective effects were largely reversed in Sirtuin3 knockdown rats.. Impaired lung Sirtuin3 signaling associated with type 2 diabetic conditions was further attenuated by an ischemia-reperfusion insult. Hydrogen sulfide ameliorated reperfusion-induced oxidative stress and mitochondrial dysfunction via activation of Sirtuin3 signaling, thereby decreasing lung ischemia-reperfusion damage in rats with a model of type II diabetes.

Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Evaluation, Preclinical; Humans; Hydrogen Sulfide; Lung; Lung Injury; Male; Mitochondria; Morpholines; Organothiophosphorus Compounds; Oxidative Stress; Rats; Reperfusion Injury; RNA, Small Interfering; Signal Transduction; Sirtuins; Streptozocin

Carbon monoxide (CO)- and hydrogen sulphide-releasing molecules (CORM-3 and GYY4137, respectively) have been shown to be potent antioxidant and antiinflammatory agents at the tissue and systemic level. We hypothesized that both CORM-3 and GYY4137 would reduce the significant organ dysfunction associated with abdominal compartment syndrome (ACS).. Randomized trial was conducted where ACS was maintained for 2 hours in 27 rats using an abdominal plaster cast and intraperitoneal CO. Hepatocellular death and the number of activated leukocytes within postsinusoidal venules were significantly increased in rats with ACS (16-fold increase, 17-fold leukocyte activation, respectively, P < 0.05). Administration of CORM-3 or GYY4137 resulted in a significant decrease of both parameters (P = 0.03 and P = 0.009). ACS resulted in an increase in markers of renal and liver injury; CORM-3 or GYY4137 partially restored levels to those seen in sham animals. Myeloperoxidase was significantly elevated in the ACS group in lung, liver, and small intestine (P = 0.0002, P = 0.01, and P = 0.08, respectively). CORM-3 treatment, but not GYY4137, was able to completely block the response (65 ± 11 U/ml and 92 ± 18 U/ml, respectively versus 110 ± 10U/ml in the ACS group, lung tissue).. We have demonstrated the effect of two molecules, CO and hydrogen sulphide, on tempering the reperfusion-associated metabolic and organ derangements in ACS. CORM-3 demonstrated a greater effect than GYY4137 and was able to restore most of the measured parameters to levels comparable to sham.

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Intra-Abdominal Hypertension; Male; Morpholines; Organometallic Compounds; Organothiophosphorus Compounds; Random Allocation; Rats, Wistar; Reperfusion Injury

Hydrogen sulfide (H

Topics: A549 Cells; Cell Line; Coordination Complexes; Crystallography, X-Ray; Humans; Hydrogen Sulfide; Morpholines; Myocytes, Cardiac; Organothiophosphorus Compounds; Photochemical Processes; Prodrugs; Reperfusion Injury; Ruthenium