gyy-4137 and Sepsis

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

Sepsis-induced cardiomyopathy (SICM) has a poor prognosis, with no effective therapeutic strategy currently. This study aimed to explore the mechanism underlying SICM and investigate the protective role of the hydrogen sulfide (H

Topics: Animals; Cardiomyopathies; Cytokines; Hydrogen Sulfide; Inflammasomes; Lipopolysaccharides; Mice; Morpholines; Myocytes, Cardiac; NLR Family, Pyrin Domain-Containing 3 Protein; Organothiophosphorus Compounds; Reactive Oxygen Species; RNA; Sepsis

The model of CLP-induced ALI was established in vivo. The mice were subsequently treated with GYY4137 (25 μg/g and 50 μg/g) to simulate the realistic conditions of pathogenesis. Western blotting and immunohistochemical staining were used to examine protein expression, hematoxylin and eosin staining was used for the histopathological analysis, and the levels of inflammatory factors were determined using enzyme-linked immunosorbent assays (ELISAs).. GYY4137 significantly increased the 7-day survival of mice with septic peritonitis and protected against CLP-induced ALI, including decreasing neutrophil infiltration, improving sepsis-induced lung histopathological changes, diminishing lung tissue damage, and attenuating the severity of lung injury in mice. The protective effect of GYY4137 was undoubtedly dose-dependent. We discovered that GYY4137 reduced the levels of the p-PDGFRβ, p-NF-κB, ASC, NLRP3, caspase-1, and p-Akt proteins in septic mouse lung tissue. Akt regulates the generation of proinflammatory cytokines in endotoxemia-associated ALI by enhancing the nuclear translocation of NF-κB.. These results indicate a new molecular mechanism explaining the effect of GYY4137 on the treatment of CLP-induced ALI in mice.

Topics: Acute Lung Injury; Animals; Male; Mice; Mice, Inbred C57BL; Morpholines; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Organothiophosphorus Compounds; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Receptor, Platelet-Derived Growth Factor beta; Sepsis; Signal Transduction

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