Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure

Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure.Mesothelial cell loss is an initiating event for peritoneal fibrosis.We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E,driving downstream inflammatory responses,including the activation of macrophages.Moreover,pyroptosis is associated with elevated vascular endothelial growth factor A and C,two key factors in vascular angiogenesis and lymphatic vessel formation.GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure.Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action,and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy.Mechanistically,melatonin treatment maintains mitochondrial integrity in mesothelial cells,meanwhile activating m TOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate.These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress.Thus,Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.

Detailed approach toward the anti-hyperglycemic potential of Sterculia diversifolia G.Don against alloxan-induced in vivo hyperglycemia model

OBJECTIVE:To investigate Sterculia diversifolia G.Don for potential anti-diabetic activity in the in vivo mouse model of alloxan-induced hyperglycemia.METHODS:Sterculia diversifolia(S.diversifolia)was subjected to extraction and isolation techniques and structural characterization of the isolated compounds were performed using spectroscopic methods.The acute toxicity test was performed by orally administering S.diversifolia in doses of 500-2000 mg/kg.For the assessment of anti-hyperglycemic activity,S.diversifolia bark and leaves extracts were administered orally in doses of 50,100,and 200 mg/kg,along with metformin(150 mg/kg,i.p)as positive control,after confirmation of alloxan(150 mg/kg,i.p.)induced hyperglycemia in BALB/c mice.Serum biochemical parameters were monitored for the period of study.RESULTS:The phytochemical studies showed the presence of quercetin and kaempferol in S.diversifolia.The IC50 values in the in vivo acute toxicity study revealed the safety margin of S.diversifolia bark(1166.66 mg/kg)and leaves(683.34 mg/kg)extracts.A significant attenuation of alloxan induced hyperglycemia was produced by S.diversifolia extracts at 50 mg/kg(P<0.05),100 mg/kg(P<0.05,<0.01),and 150 mg/kg(P<0.05,<0.01,<0.001)during 1-4 h,which was comparable to metformin(P<0.001).Significant(P<0.001)improvement appeared in blood hemoglobin,protein,cholesterol,triglycerides,urea,creatinine,HDL,and LDL of the stem bark and leaves extracts treated diabetic mice.CONCLUSION:These findings connote the usefulness of S.diversifolia as an anti-diabetic in traditional medicine and this might be attributed to the presence of quercetin and kaempferol,among other phytochemicals.