Cardioprotective effect of pioglitazone and curcumin against diabetic cardiomyopathy in type 1 diabetes mellitus: impact on CaMKII/NF-κB/TGF-ß1 and PPAR-γ signaling pathway.

Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients, which is currently without available specific treatment. This study aimed to investigate the potential protective effects of pioglitazone (Pio) and curcumin (Cur) against DCM in type 1 diabetes mellitus (T1DM), with pointing to their role on Ca+2/calmodulin-dependent protein kinase II (CaMKII) and peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. Diabetes was induced in adult male Sprague Dawley rats by administration of single intraperitoneal injection of streptozotocin (STZ) (52.5 mg/kg). Diabetic rats were administered either Pio (20 mg/kg/day) or Cur (100 mg/kg/day) orally for 6 weeks. Treatment with Pio and/or Cur markedly reduced serum cardiac injury markers and lipid profile markers in diabetic animals. Additionally, Pio and/or Cur treatment mitigated oxidative stress and fibrosis in diabetic rats as evident from the significant suppression in myocardial lipid peroxidation and tumor growth factor beta 1 (TGF-ß1) level, with concomitant significant elevation in total antioxidant capacity (TAC) and improvement in histopathological architecture of heart tissue. Pio/Cur treatment protocol accomplished its cardioprotective effect by depressing cardiac CaMKII/NF-κB signaling accompanied by enhancement in PPAR-γ expression. Conclusively, these findings demonstrated the therapeutic potential of Pio/Cur regimen in alleviating DCM in T1DM through modulation of CaMKII and PPAR-γ expression. Graphical Abstract.

New mechanism in the modulation of carbon tetrachloride hepatotoxicity in rats using different natural antioxidants.

Transforming growth factor-ß (TGF-ß1) enhances the expression of apoptosis induced by certain cytokines and oncogenes. Activation of small mother against decapentaplegic (Smads) by TGF-ß results in fibrotic, apoptotic processes. PI-3/AKT focal adhesion kinase-phosphatidylinositol3-kinase (AKT), the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3) pathways are influence in COX-2 and VEGF-stimulating pathways. NF-E2-related factor-2 (Nrf2) is an essential transcription factor that regulates an array of detoxifying and antioxidant defense genes expression in the liver. The objective of this study is to examine whether silymarin alone or in combination with vitamin E and/or curcumin plays a modulatory role against MAPK, STAT3, AKT, Smad-2 and TGF-ß protein expressions that produced apoptotic damage in rat's liver by the administration of carbon tetrachloride (CCl4). The results of the present work revealed that CCl4-induced an elevation of serum alanine aminotransferase (ALT) with concomitant increase in MAPK, STAT3, AKT, Smad-2 and TGF-ß hepatic protein expression, administration of silymarin alone down regulates these expressions. Treatment with vitamin E and/or curcumin along with silymarin produced best results in this concern. On the other hand, Nrf2 protein expression was down regulated by CCl4 whereas concurrent treatment with vitamin E and/or curcumin along with silymarin increased this expression. It was concluded that CCl4-induced protein expression of apoptotic and fibenorgenic factors. Whereas administration of silymarin alone or in combination with vitamin E and/or curcumin plays a modulatory role against the previous aforementioned apoptotic factors expressions. The use of vitamin E and/or curcumin potentiates the anti-apoptotic action of silymarin. So this combination can be used as hepatoprotective agent against other hepatotoxic substances.

Role of quercetin and arginine in ameliorating nano zinc oxide-induced nephrotoxicity in rats.

BACKGROUND: Nanoparticles are small-scale substances (<100 nm) with unique properties. Therefore, nanoparticles pose complex health risk implications. The objective of this study was to detect whether treatment with quercetin (Qur) and/or arginine (Arg) ameliorated nephrotoxicity induced by two different doses of nano zinc oxide (n-ZnO) particles. METHOD: ZnO nanoparticles were administered orally in two doses (either 600 mg or 1 g/Kg body weight/day for 5 conscutive days) to Wister albino rats. In order to detect the protective effects of the studied antioxidants against n-ZnO induced nepherotoxicity, different biochemical parameters were investigated. Moreover, histopathological examination of kidney tissue was performed. RESULTS: Nano zinc oxide-induced nephrotoxicity was confirmed by the elevation in serum inflammatory markers including: tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6); and C-reactive protein (CRP). Moreover, immunoglobulin (IGg), vascular endothelium growth factor (VEGF), and nitric oxide (NO) were significantly increased in rat serum. Serum urea and creatinine levels were also significantly increased in rats intoxicated with n-ZnO particles compared with the control group. Additionally, a significant decrease in the non-enzymatic antioxidant reduced glutathione (GSH) was shown in kidney tissues and serum glucose levels were increased. These biochemical findings were supported by a histopathological examination of kidney tissues, which showed that in the animals that received a high dose of n-ZnO, numerous kidney glomeruli underwent atrophy and fragmentation. Moreover, the renal tubules showed epithelial desquamation, degeneration and necrosis. Some renal tubules showed casts in their lumina. Severe congestion was also observed in renal interstitium. These effects were dose dependent. Cotreatment of rats with Qur and/or Arg along with n-ZnO significantly improved most of the deviated tested parameters. CONCLUSIONS: The data show that Qur has a beneficial effect against n-ZnO oxidative stress and related vascular complications. Also, its combination with Arg proved to be even more effective in ameliorating nano zinc oxide nephrotoxicity.