Background: Pyroptosis is an inflammatory programmed cell death accompanied by activation of inflammasomes and maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Pyroptosis is closely linked to the development of diabetic cardiomyopathy (DC). Pomegranate peel extract (PPE) exhibits a cardioprotective effect due to its antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanisms of the protective effect of PPE on the myocardium in a rat model of DC and determine the underlying molecular mechanism.Methods: Type 1 diabetes (T1DM) was induced in rats by intraperitoneal injection of streptozotocin. The rats in the treated groups received (150 mg/kg) PPE orally and daily for 8 weeks. The effects on the survival rate, lipid profile, serum cardiac troponin-1, lipid peroxidation, and tissue fibrosis were assessed. Additionally, the expression of pyroptosis-related genes (NLRP3 and caspase-1) and lncRNA-MALAT1 in the heart tissue was determined. The PPE was analyzed using UPLC-MS/MS and NMR for characterizing the phytochemical content.Results: Prophylactic treatment with PPE significantly ameliorated cardiac hypertrophy in the diabetic rats and increased the survival rate. Moreover, prophylactic treatment with PPE in the diabetic rats significantly improved the lipid profile, decreased serum cardiac troponin-1, and decreased lipid peroxidation in the myocardial tissue. Histopathological examination of the cardiac tissues showed a marked reduction in fibrosis (decrease in collagen volume and number of TGF-β-positive cells) and preservation of normal myocardial structures in the diabetic rats treated with PPE. There was a significant decrease in the expression of pyroptosis-related genes (NLRP3 and caspase-1) and lncRNA-MALAT1 in the heart tissue of the diabetic rats treated with PPE. In addition, the concentration of IL-1β and caspase-1 significantly decreased in the heart tissue of the same group. The protective effect of PPE on diabetic cardiomyopathy could be due to the inhibition of pyroptosis and downregulation of lncRNA-MALAT1. The phytochemical analysis of the PPE indicated that the major compounds were hexahydroxydiphenic acid glucoside, caffeoylquinic acid, gluconic acid, citric acid, gallic acid, and punicalagin.Conclusion: PPE exhibited a cardioprotective potential in diabetic rats due to its unique antioxidant, anti-inflammatory, and antifibrotic properties and its ability to improve the lipid profile. The protective effect of PPE on DC could be due to the inhibition of the NLRP3/caspase-1/IL-1β signaling pathway and downregulation of lncRNA-MALAT1. PPE could be a promising therapy to protect against the development of DC, but further clinical studies are recommended.

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Hepatic fibrosis is an outcome of chronic liver injury. Angiotensin II (ANG II) may play a role in the pathogenesis of hepatic fibrosis. Certain drugs such as ACE inhibitors, ANG II antagonists, and even statins could interfere with the renin angiotensin system and modulate its deleterious effects. This study was carried out to investigate the possible role of losartan and atorvastatin in liver fibrosis. Liver fibrosis was induced in rats by i.p. injection of 50% CCl twice per week for 8 weeks. The rats intoxicated with CCl were divided into four groups: fibrosis control; losartan group; atorvastatin group; and co-treated group. A fifth group of normal healthy rats served as a control group. The results showed that losartan and atorvastatin, either alone or in combination, significantly decreased ALT, AST, hyaluronic acid and hydroxyproline levels in their groups compared to those of the fibrosis control group. A significant decrease in TGF-β was found in the losartan and co-treated groups but not in the atorvastatin group. These biochemical data were supported by liver histopathology and α-SMA. The results indicate that the combined treatment with both losartan and atorvastatin produced a greater effect than either drug alone and proved a beneficial role in inhibiting or reversing liver fibrosis.

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Diabetes mellitus is the most common chronic metabolic disorder worldwide. The present study was designed to investigate the potential role of cinnamon bark extract oligomeric proanthocyanidins (OPCs) in controlling streptozotocin (STZ)-induced hyperglycemia and to clarify the underlying molecular mechanisms underlying its effects. For this purpose, 60 male rats were equally divided into six groups as follows: The normal control group; OPC control group (non-diabetic rats treated with OPC at 300 mg/kg orally for 21 days); the untreated diabetic control group; the wortmannin control group [diabetic rats treated with wortmannin at 1 mg/kg, intraperitoneal (i.p.) on the final day of the experiment]; the OPC diabetic group (diabetic rats treated with OPC at 300 mg/kg orally for 21 days); and the OPC diabetic + wortmannin co-treated group (diabetic rats treated with OPC at 300 mg/kg/day for 21 consecutive days and then 24 h after the final OPC dose treated with a single wortmannin injection at 1 mg/kg, i.p.). The results indicated that OPC ameliorated the diabetic state, as evidenced by a significant decrease in serum glucose levels, and a significant increase in the levels of insulin, amylin, insulin receptor phosphorylation, glycogen and glucose transporter-4 translocation; it also improved the lipid profile in STZ-diabetic rats. On the whole, the findings of the present study provide biochemical evidence that OPC treatment is effective as an anti-diabetic and anti-hyperlipidemic agent by enhancing glucose uptake through the activation of insulin receptor kinase activity and the PI3K/Akt pathway.