gyy-4137 and Disease-Models--Animal

In prolonged complete unilateral ureteral obstruction, reduced renal blood flow places the kidney in a state of ischemia, which can cause tubular injury and inflammation. Infiltrating inflammatory cells release transforming growth factor beta 1, which is a cytokine that initiates fibrosis through the epithelial-mesenchymal-transition pathway. Persistent fibrosis can lead to irreversible renal injury and loss of function. While surgical intervention can remove the obstruction, relief of obstruction may not fully reverse renal injury. Additionally, patients often encounter long wait-times between initial consultation and medical intervention, resulting in the accumulation of renal injury that may cause permanent dysfunction. Currently, accepted pharmacological therapies to mitigate the symptoms of ureteral obstruction include acetaminophen, cyclooxygenase-inhibitors, non-steroidal anti-inflammatory medications, opioids and alpha-receptor blockers. However, there is no evidence that they mitigate renal injury. Therefore, identifying potential therapies that could be administered during obstruction may help to improve renal function following decompression. Evidence suggests that endogenously produced gasotransmitters can exhibit anti-inflammatory and antioxidant effects. Nitric oxide, carbon monoxide, and hydrogen sulfide have been identified as gasotransmitters and have been shown to have cytoprotective effects in various models of tissue injury. Studies have shown that treatment with sodium hydrogen sulfide (a hydrogen sulfide donor salt) mitigated transforming growth factor beta 1 expression, oxidative stress, fibrosis, and inflammation associated with urinary obstruction. More recently, the use of more directed hydrogen sulfide donor molecules, such as GYY4137, has led to significant decreases in inflammation, fibrosis, and expression of epithelial mesenchymal transition markers following urinary obstruction. Taken together, these findings suggest that hydrogen sulfide may be a novel potential therapy against renal injury caused by urinary obstruction. This review will highlight the existing literature about the pathogenesis and treatment of renal damage caused by chronic urinary obstruction and propose novel upcoming strategies that could improve patient outcomes.

Topics: Animals; Carbon Monoxide; Disease Models, Animal; Fibrosis; Gasotransmitters; Humans; Hydrogen Sulfide; Kidney; Male; Morpholines; Nitric Oxide; Organothiophosphorus Compounds; Ureteral Obstruction

Rheumatoid arthritis (RA) and osteoarthritis (OA) are widespread rheumatic diseases characterized by persistent inflammation and joint destruction. Hydrogen sulfide (H2S) is an endogenous gas with important physiologic functions in the brain, vasculature and other organs. Recent studies have found H2S to be a mediator in inflammatory joint diseases.. This review summarizes the recent literature in this area highlighting relevant developments.. Several authors have found that H2S exhibited anti-inflammatory, anti-catabolic and/or anti-oxidant effects in rodent models of acute arthritis and in in vitro models using human synoviocytes and articular chondrocytes from RA and OA tissues. The earliest studies used fast-dissolving salts, such as NaSH, but GYY4137, which produces H2S more physiologically, shortly appeared. More recently still, new H2S-forming compounds that target mitochondria have been synthesized. These compounds open exciting opportunities for investigating the role of H2S in cell bioenergetics, typically altered in arthritides. Positive results have also been obtained when H2S is administered as a sulphurous water bath, an option meriting further study. These findings suggest that exogenous supplementation of H2S may provide a viable therapeutic option for these diseases, particularly in OA.

Topics: Animals; Arthritis, Rheumatoid; Cells, Cultured; Clinical Trials as Topic; Disease Models, Animal; Humans; Hydrogen Sulfide; Morpholines; Organothiophosphorus Compounds; Osteoarthritis; Sulfides; Treatment Outcome

Hydrogen sulfide (H. In WT mice, the administration of GYY4137 significantly improved clinical sickness scores, attenuated intestinal and lung injury, and improved mesenteric perfusion compared to vehicle (p < 0.05). In eNOS. GYY4137 administration improves clinical outcomes, attenuates intestinal and lung injury, and improves perfusion in a murine model of necrotizing enterocolitis. The beneficial effects of GYY4137 are dependent on the Cys440 residue of eNOS.

Topics: Animals; Disease Models, Animal; Enterocolitis, Necrotizing; Humans; Hydrogen Sulfide; Infant, Newborn; Infant, Newborn, Diseases; Lung Injury; Mice; Nitric Oxide; Nitric Oxide Synthase Type III

Sepsis often leads to multiple organ failure or even death and is a significant health problem that contributes to a heavy economic burden. The lung is the first organ to be affected by sepsis. Presently, there is no specific drug or method to treat sepsis and sepsis-induced acute lung injury (ALI). H2S, along with CO and NO, is a physiological gas that acts as a signaling molecule and plays an active role in fighting various lung infections. GYY4137 is a novel H2S donor that is stable in vivo and in vitro. However, particularly in the context of ferroptosis, GYY4137 affects cecal ligation and puncture (CLP)-induced ALI by a mechanism that is not understood. Ferroptosis is a new form of cell necrosis. The primary mechanism is the accumulation of cellular lipid ROS in an iron-dependent manner. The principal objective of this project was to investigate the effects of GYY4137 on ferroptosis and autophagy in a mouse model of sepsis-induced ALI. We divided the experimental mice randomly into 5 groups: (1) sham group; (2) CLP group; (3) CLP + DMSO group: (4) CLP + GYY4137 (25 mg/kg) group; and (5) CLP + GYY4137 (50 mg/kg) group. (6) CLP + Rapamycin (2.0 mg/Kg) group. (7) CLP + Chloroquine (80 mg/Kg) group. (8) the Chloroquine (80 mg/Kg) + GYY (50 mg/Kg) group. The findings showed that GYY4137 significantly protected against CLP-induced ALI by improving sepsis-induced lung histopathological changes, diminishing lung tissue damage, ameliorating oxidative stress, and attenuating the severity of lung injury in mice. In this study, we found that GYY4137 could alleviate septicemia-induced ferroptosis in ALI by increasing the expression of GPx4 and SLC7A11 in lung tissue after CLP. One unexpected finding was the extent to which the levels of ferritin and ferritin light chain increased after CLP, which may be a compensatory mechanism for storing abnormally increased iron. We also found that the expression of p-mTOR, P62, and Beclin1 was significantly increased and that LC3II/LC3I declined after LPS stimulation, but the effect was inhibited by treatment with GYY4137, indicating that GYY4137 could inhibit the activation of autophagy in sepsis-induced ALI by blocking mTOR signaling.

Topics: Acute Lung Injury; Animals; Autophagy; Cecum; Cell Line; Disease Models, Animal; Ferroptosis; Hydrogen Sulfide; Ligation; Lung; Male; Mice; Mice, Inbred C57BL; Morpholines; Multiple Organ Failure; Organothiophosphorus Compounds; RAW 264.7 Cells; Sepsis; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; Apoptosis; Biological Transport; Blood-Brain Barrier; Brain; Disease Models, Animal; Hydrogen Sulfide; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; Morpholines; NF-E2-Related Factor 2; Organothiophosphorus Compounds; Oxidative Stress; Sepsis; Signal Transduction

Neointima formation is closely linked to vascular stenosis and occurs after endothelial damage. Hydrogen sulfide is an endogenous pleiotropic mediator with numerous positive effects on the cardio vascular system.. This study evaluates the effect of the slow releasing hydrogen sulfide donor GYY4137 (GYY) on neointimal formation in vivo.. The effect of GYY on neointimal formation in the carotid artery was studied in the FeCl3 injury model in GYY- or vehicle-treated mice. The carotid arteries were studied at days 7 and 21 after treatment by means of histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and alpha smooth muscle actin (α-SMA).. GYY treatment significantly reduced the maximal diameter and the area of the newly formed neointima on both days 7 and 21 when compared to vehicle treatment. GYY additionally reduced the number of PCNA- and α-SMA-positive cells within the neointima on day 21 after FeCl3 injury of the carotid artery.. Summarizing, single treatment with the slow releasing hydrogen sulfide donor GYY reduced the extent of the newly formed neointima by affecting the cellular proliferation at the site of vascular injury.

Topics: Animals; Carotid Arteries; Carotid Artery, Common; Disease Models, Animal; Hydrogen Sulfide; Male; Mice; Morpholines; Neointima; Organothiophosphorus Compounds

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

The efficacy of intraperitoneal GYY4137 therapy and intratesticular GYY4137 therapy in an experimental rat model was investigated. Four groups were set up as the sham-operation group, torsion/detorsion (T/D) group, T/D plus intraperitoneal GYY4137 (G-IP) group, and T/D plus intratesticular GYY4137 (G-IT) group. In order to establish a testicular T/D model, the left testis was operated and the rotation reached 720° clockwise which lasted 1 h before reperfusion. The G-IP group accepted 100 µmol/kg of GYY4137 intraperitoneally 30 min after testicular rotation, while the G-IT group was treated with the same dose by intratesticular injection. Six h after detorsion, the testis was collected and subsequently assessed. The T/D group showed significant changes in histology and an enhancement in the level of oxidative stress and apoptosis compared to the sham-operation group. The expression of Caspase-3 and Bax turned out to be strengthened by T/ D and relatively decreased with GYY4137 treatment in both the G-IP and G-IT groups. Moreover, the Bcl-2 expression was inhibited in the T/D group, and promoted by GYY4137 in the G-IP and G-IT groups. GYY4137, moderating these observed changes, displayed a more protective effect with G-IT therapy than G-IP therapy.This study indicated that the efficacy of intratesticular therapy with GYY4137 is better than that of intraperitoneal therapy, which may provide a more valuable approach for testicular torsion therapy.

Topics: Animals; bcl-2-Associated X Protein; Caspase 3; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Injections, Intralesional; Injections, Intraperitoneal; Male; Morpholines; Organothiophosphorus Compounds; Oxidative Stress; Rats; Spermatic Cord Torsion; Treatment Outcome

Osteoarthritis (OA) is the most common articular chronic disease. However, its current treatment is limited and mostly symptomatic. Hydrogen sulfide (H

Topics: Animals; Arthralgia; Cartilage, Articular; Cyclooxygenase 2; Disease Models, Animal; Female; Gene Expression Regulation; Hydrogen Sulfide; Injections, Intra-Articular; Matrix Metalloproteinase 13; Morpholines; Motor Activity; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Organothiophosphorus Compounds; Osteoarthritis; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Rotarod Performance Test; Signal Transduction; Treatment Outcome

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

We have recently shown that endogenous hydrogen sulfide (H₂S), an important cellular gaseous mediator, exerts an antiviral and anti-inflammatory activity in vitro and in vivo, and that exogenous H₂S delivered via the synthetic H₂S-releasing compound GYY4137 also has similar properties. In this study, we sought to extend our findings to a novel class of H₂S donors, thiol-activated gem-dithiol-based (TAGDDs). In an in vitro model of human respiratory syncytial virus (RSV) infection, TAGDD-1 treatment significantly reduced viral replication, even when added up to six hours after infection. Using a mouse model of RSV infection, intranasal delivery of TAGDD-1 to infected mice significantly reduced viral replication and lung inflammation, markedly improving clinical disease parameters and pulmonary dysfunction, compared to vehicle treated controls. Overall our results indicate that this novel synthetic class of H₂S-releasing compounds exerts antiviral and anti-inflammatory activity in the context of RSV infection and represents a potential novel pharmacological approach to ameliorate viral-induced lung disease.

Topics: A549 Cells; Administration, Intranasal; Animals; Antiviral Agents; Cytokines; Disease Models, Animal; Female; Humans; Hydrogen Sulfide; Lung; Mice; Mice, Inbred BALB C; Morpholines; Organothiophosphorus Compounds; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Sulfhydryl Compounds; Virus Replication

Evidence has shown that endogenous H. The OVX osteoporosis model was established in female Sprague-Dawley rats by full bilateral ovariectomy. The rats were randomly divided into four groups, with the two experimental groups receiving an intraperitoneal injection of GYY4137 or sodium alendronate. The level of H. The OVX osteoporosis model was successfully established. GYY4137 was injected to increase the level of H. Through the slow release of H

Topics: Animals; Biomechanical Phenomena; Bone and Bones; Bone Density; Calcium; Disease Models, Animal; Female; Hormones; Morpholines; Organothiophosphorus Compounds; Osteoporosis; Ovariectomy; Phosphorus; Rats, Sprague-Dawley

The relationship between hydrogen sulfide (H

Topics: Animals; Collagen; Diabetic Nephropathies; Disease Models, Animal; Endothelial Cells; Hydrogen Sulfide; Matrix Metalloproteinases; Mice; MicroRNAs; Morpholines; Organothiophosphorus Compounds; Poly (ADP-Ribose) Polymerase-1; Treatment Outcome

Autophagy plays an important role in cellular homeostasis through the disposal and recycling of cellular components. Hydrogen sulphide (H2S) is the third endogenous gas that has been shown to confer cardiac protective effects. Given the regulation of autophagy in cardioprotection, this study aimed to investigate the protective effects of H2S via autophagy during high glucose treatment.. This study investigated the content of H2S in the plasma as well as myocardial, ultrastructural changes in mitochondria and autophagosomes. This study also investigated the apoptotic rate using Hoechst/PI as well as expression of autophagy-associated proteins and mitochondrial apoptotic proteins in H9C2 cells treated with or without GYY4137. Mitochondria of cardiac tissues were isolated and RCR and ADP/O were also detected. AMPK knockdown was performed with siRNA transfection.. In a STZ-induced diabetic model, NaHS treatment not only increased the expression of p-AMPK in diabetic group but further activated cell autophagy. Following 48h high glucose, autophagosomes and cell viability were reduced. The present results showed that autophagy could be induced by H2S, which was verified by autophagic ultrastructural observation and LC3-I/LC3-II conversion. In addition, the mitochondrial membrane potential (MMP) was significantly decreased. The expressions levels of autophagic-related proteins were significantly elevated. Moreover, H2S activated the AMPK/rapamycin (mTOR) signalling pathway.. Our findings demonstrated that H2S decreases oxidative stress and protects against mitochondria injury, activates autophagy, and eventually leads to cardiac protection via the AMPK/mTOR pathway.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Blood Glucose; Cardiotonic Agents; Cell Line; Cell Survival; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Glucose; Male; Membrane Potential, Mitochondrial; Mitochondria; Morpholines; Organothiophosphorus Compounds; Oxidative Stress; Rats; Rats, Wistar; Signal Transduction; Streptozocin; Sulfides; TOR Serine-Threonine Kinases; Ventricular Function

Hydrogen sulfide (H2S) is recognized as a novel third signaling molecule and gaseous neurotransmitter. Recently, cell protective properties within the central nervous and cardiovascular system have been proposed. Our purpose was to analyze the expression and neuroprotective effects of H2S in experimental models of glaucoma.. Elevated IOP was induced in Sprague-Dawley rats by means of episcleral vein cauterization. After 7 weeks, animals were killed and the retina was analyzed with label-free mass spectrometry. In vitro, retinal explants were exposed to elevated hydrostatic pressure or oxidative stress (H2O2), with and without addition of a slow-releasing H2S donor Morpholin-4-ium-methoxyphenyl-morpholino-phosphinodithioate (GYY4137). In vivo, GYY4137 was injected intravitreally in animals with acute ischemic injury or optic nerve crush. Brn3a+ retinal ganglion cells (RGCs) were counted in retinal flat mounts and compared. Optical coherence tomography (OCT) was performed to examine the vessels. Comparisons were made by t-test and ANOVA (P < 0.05).. IOP elevation caused significant RGC loss (P < 0.001); 3-mercaptosulfurtransferase, an H2S producing enzyme, showed a 3-fold upregulation within the retina after IOP elevation. GYY4137 protected RGCs against elevated pressure and oxidative stress in vitro depending on the concentration used (P < 0.005). In vivo, intravitreal administration of GYY4137 preserved RGCs from acute ischemic injury and optic nerve crush (P < 0.0001). Retinal vessel diameters enlarged after intravitreal GYY4137 injection (P < 0.0001).. H2S is specifically regulated in experimental glaucoma. By scavenging reactive oxygen species and dilating retinal vessels, H2S may protect RGCs from pressure and oxidative stress-induced RGC loss in vitro and in vivo. Therefore, H2S might be a novel neuroprotectant in glaucoma.

Topics: Animals; Disease Models, Animal; Female; Glaucoma; Hydrogen Peroxide; Hydrogen Sulfide; Hydrostatic Pressure; Intraocular Pressure; Morpholines; Nerve Crush; Neuroprotective Agents; Optic Nerve Injuries; Organothiophosphorus Compounds; Oxidative Stress; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells

Infrarenal aortic cross-clamping (IAC) is a common procedure during infrarenal vascular operations. It often causes ischemia-reperfusion injury to lower limbs, resulting in systemic inflammation response and damage to remote organs (particularly lungs). Hydrogen sulfide (H. Wistar rats underwent IAC for 2 hours, followed by 4 hours of reperfusion. GYY4137 (a slow-releasing H. IAC induced a significant increase in plasma levels of H. The study indicates that H

Topics: Acute Lung Injury; Alkynes; Angiopoietin-2; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Constriction; Cystathionine gamma-Lyase; Cytoprotection; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Glycine; Hydrogen Sulfide; Lung; Lyases; Male; Morpholines; Organothiophosphorus Compounds; Pneumonia; Proto-Oncogene Proteins c-akt; Rats, Wistar

Decreased levels of endogenous hydrogen sulfide (H2S) contribute to atherosclerosis, whereas equivocal data are available on H2S effects during sepsis. Moreover, H2S improved glucose utilization in anaesthetized, ventilated, hypothermic mice, but normothermia and/or sepsis blunted this effect. The metabolic effects of H2S in large animals are controversial. Therefore, we investigated the effects of the H2S donor GYY4137 during resuscitated, fecal peritonitis-induced septic shock in swine with genetically and diet-induced coronary artery disease (CAD). Twelve and 18 h after peritonitis induction, pigs received either GYY4137 (10 mg kg, n = 9) or vehicle (n = 8). Before, at 12 and 24 h of sepsis, we assessed left ventricular (pressure-conductance catheters) and renal (creatinine clearance, blood NGAL levels) function. Endogenous glucose production and glucose oxidation were derived from the plasma glucose isotope and the expiratory CO2/CO2 enrichment during continuous i.v. 1,2,3,4,5,6-C6-glucose infusion. GYY4137 significantly increased aerobic glucose oxidation, which coincided with higher requirements of exogenous glucose to maintain normoglycemia, as well as significantly lower arterial pH and decreased base excess. Apart from significantly lower cardiac eNOS expression and higher troponin levels, GYY4137 did not significantly influence cardiac and kidney function or the systemic inflammatory response. During resuscitated septic shock in swine with CAD, GYY4137 shifted metabolism to preferential carbohydrate utilization. Increased troponin levels are possibly due to reduced local NO availability. Cautious dosing, the timing of GYY4137 administration, and interspecies differences most likely account for the absence of any previously described anti-inflammatory or organ-protective effects of GYY4137 in this model.

Topics: Animals; Coronary Artery Disease; Delayed-Action Preparations; Disease Models, Animal; Heart; Hydrogen Sulfide; Kidney; Morpholines; Organothiophosphorus Compounds; Resuscitation; Shock, Septic; Swine

Structural remodeling of the microvasculature occurs during obesity. Based on observations that impaired H2S signaling is associated with cardiovascular pathologies, the current study was designed to test the hypothesis that altered H2S homeostasis is involved in driving the remodeling process in a diet-induced mouse model of obesity. The structural and passive mechanical properties of mesenteric resistance arterioles isolated from 30-wk-old lean and obese mice were assessed using pressure myography, and vessel H2S levels were quantified using the H2S indicator sulfidefluor 7-AM. Remodeling gene expression was assessed using quantitative RT-PCR, and histological staining was used to quantify vessel collagen and elastin. Obesity was found to be associated with decreased vessel H2S concentration, inward hypertrophic remodeling, altered collagen-to-elastin ratio, and reduced vessel stiffness. In addition, mRNA levels of fibronectin, collagen types I and III, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 1 were increased and elastin was decreased by obesity. Evidence that decreased H2S was responsible for the genetic changes was provided by experiments in which H2S levels were manipulated, either by inhibition of the H2S-generating enzyme cystathionine γ-lyase with dl-propargylglycine or by incubation with the H2S donor GYY4137. These data suggest that, during obesity, depletion of H2S is involved in orchestrating the genetic changes underpinning inward hypertrophic remodeling in the microvasculature.

Topics: Alkynes; Animals; Arterioles; Cells, Cultured; Collagen; Collagenases; Cystathionine gamma-Lyase; Diet, High-Fat; Disease Models, Animal; Elastin; Enzyme Inhibitors; Fibronectins; Gene Expression Regulation; Glycine; Hydrogen Sulfide; Hypertrophy; Male; Mesentery; Mice, Inbred C57BL; Morpholines; Obesity; Organothiophosphorus Compounds; Signal Transduction; Vascular Remodeling; Vascular Stiffness

Exogenous hydrogen sulfide (H2S) protects against myocardial ischemia/reperfusion injury but the mechanism of action is unclear. The present study investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial infarction given specifically at reperfusion and the signalling pathway involved. Thiobutabarbital-anesthetised rats were subjected to 30min of left coronary artery occlusion and 2h reperfusion. Infarct size was assessed by tetrazolium staining. In the first study, animals randomly received either no treatment or GYY4137 (26.6, 133 or 266μmolkg(-1)) by intravenous injection 10min before reperfusion. In a second series, involvement of PI3K and NO signalling were interrogated by concomitant administration of LY294002 or L-NAME respectively and the effects on the phosphorylation of Akt, eNOS, GSK-3β and ERK1/2 during early reperfusion were assessed by immunoblotting. GYY4137 266μmolkg(-1) significantly limited infarct size by 47% compared to control hearts (P<0.01). In GYY4137-treated hearts, phosphorylation of Akt, eNOS and GSK-3β was increased 2.8, 2.2 and 2.2 fold respectively at early reperfusion. Co-administration of L-NAME and GYY4137 attenuated the cardioprotection afforded by GYY4137, associated with attenuated phosphorylation of eNOS. LY294002 totally abrogated the infarct-limiting effect of GYY4137 and inhibited Akt, eNOS and GSK-3β phosphorylation. These data are the first to demonstrate that GYY4137 protects the heart against lethal reperfusion injury through activation of PI3K/Akt signalling, with partial dependency on NO signalling and inhibition of GSK-3β during early reperfusion. H2S-based therapeutic approaches may have value as adjuncts to reperfusion in the treatment of acute myocardial infarction.

Topics: Animals; Cytoprotection; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Glycogen Synthase Kinase 3 beta; Hemodynamics; Hydrogen Sulfide; Male; Morpholines; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Organothiophosphorus Compounds; Phosphatidylinositol 3-Kinase; Phosphorylation; Protective Agents; Rats, Sprague-Dawley; Signal Transduction; Time Factors

Topics: Animals; Apoptosis; Caco-2 Cells; Cell Membrane Permeability; Disease Models, Animal; Electric Impedance; Endotoxemia; Enterocytes; Gastrointestinal Agents; Gene Expression Regulation; Humans; Interferon-gamma; Intestinal Mucosa; Lipopolysaccharides; Male; Mice, Inbred C57BL; Morpholines; Organothiophosphorus Compounds; Protective Agents; Random Allocation; Tight Junction Proteins; Tight Junctions; Tumor Necrosis Factor-alpha

Arrested alveolarization is the pathological hallmark of bronchopulmonary dysplasia (BPD), a complication of premature birth. Here, the impact of systemic application of hydrogen sulfide (H2S) on postnatal alveolarization was assessed in a mouse BPD model. Exposure of newborn mice to 85% O2 for 10 days reduced the total lung alveoli number by 56% and increased alveolar septal wall thickness by 29%, as assessed by state-of-the-art stereological analysis. Systemic application of H2S via the slow-release H2S donor GYY4137 for 10 days resulted in pronounced improvement in lung alveolarization in pups breathing 85% O2, compared with vehicle-treated littermates. Although without impact on lung oxidative status, systemic H2S blunted leukocyte infiltration into alveolar air spaces provoked by hyperoxia, and restored normal lung interleukin 10 levels that were otherwise depressed by 85% O2. Treatment of primary mouse alveolar type II (ATII) cells with the rapid-release H2S donor NaHS had no impact on cell viability; however, NaHS promoted ATII cell migration. Although exposure of ATII cells to 85% O2 caused dramatic changes in mRNA expression, exposure to either GYY4137 or NaHS had no impact on ATII cell mRNA expression, as assessed by microarray, suggesting that the effects observed were independent of changes in gene expression. The impact of NaHS on ATII cell migration was attenuated by glibenclamide, implicating ion channels, and was accompanied by activation of Akt, hinting at two possible mechanisms of H2S action. These data support further investigation of H2S as a candidate interventional strategy to limit the arrested alveolarization associated with BPD.

Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Cytokines; Disease Models, Animal; Hydrogen Sulfide; Hyperoxia; Lung; Mice; Morpholines; Organothiophosphorus Compounds; Oxygen; Proto-Oncogene Proteins c-akt; Pulmonary Alveoli; Sulfides; Wound Healing

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, remains a major health problem. BPD is characterized by impaired alveolar development and complicated by pulmonary hypertension (PHT). Currently there is no specific treatment for BPD. Hydrogen sulfide (H2S), carbon monoxide and nitric oxide (NO), belong to a class of endogenously synthesized gaseous molecules referred to as gasotransmitters. While inhaled NO is already used for the treatment of neonatal PHT and currently tested for the prevention of BPD, H2S has until recently been regarded exclusively as a toxic gas. Recent evidence suggests that endogenous H2S exerts beneficial biological effects, including cytoprotection and vasodilatation. We hypothesized that H2S preserves normal alveolar development and prevents PHT in experimental BPD.. We took advantage of a recently described slow-releasing H2S donor, GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) to study its lung protective potential in vitro and in vivo.. In vitro, GYY4137 promoted capillary-like network formation, viability and reduced reactive oxygen species in hyperoxia-exposed human pulmonary artery endothelial cells. GYY4137 also protected mitochondrial function in alveolar epithelial cells. In vivo, GYY4137 preserved and restored normal alveolar growth in rat pups exposed from birth for 2 weeks to hyperoxia. GYY4137 also attenuated PHT as determined by improved pulmonary arterial acceleration time on echo-Doppler, pulmonary artery remodeling and right ventricular hypertrophy. GYY4137 also prevented pulmonary artery smooth muscle cell proliferation.. H2S protects from impaired alveolar growth and PHT in experimental O2-induced lung injury. H2S warrants further investigation as a new therapeutic target for alveolar damage and PHT.

Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Disease Models, Animal; Endothelial Cells; Humans; Hydrogen Sulfide; Hyperoxia; Infant, Newborn; Lung; Lung Injury; Mitochondria; Morpholines; Organothiophosphorus Compounds; Oxygen; Prodrugs; Protective Agents; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension.. Plasma levels of H2S were significantly decreased in women with preeclampsia (P<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine reduced placental growth factorproduction from first-trimester (8-12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H2S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL-propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H2S production.. These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia.

Topics: Adolescent; Adult; Alkynes; Animals; Antigens, CD; Cells, Cultured; Cystathionine gamma-Lyase; Disease Models, Animal; Endoglin; Endothelium, Vascular; Female; Fetal Development; Glycine; Humans; Hydrogen Sulfide; Hypertension; Mice; Mice, Inbred C57BL; Morpholines; Neovascularization, Physiologic; Organ Culture Techniques; Organothiophosphorus Compounds; Placenta; Placenta Diseases; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Proteins; Pregnancy, Animal; Receptors, Cell Surface; Vascular Endothelial Growth Factor Receptor-1; Young Adult

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