Rebamipide protects against experimentally induced intestinal ischemia/reperfusion-promoted liver damage: Impact on SIRT1/ß-catenin/FOXO1and NFκB signaling.

Rebamipide (Reba) is a well-known gastroprotective agent. However, its potential protective efficacy against intestinal ischemia/reperfusion (I/R)-induced liver injury remains elusive. Therefore, this study aimed to assess the modulatory effect of Reba on SIRT1/ß-catenin/FOXO1-NFκB signaling cascade. Thirty-two male Wistar albino rats were randomized into four groups: G1 (sham): rats were subjected to surgical stress without I/R, GII (I/R): rats were subjected to 60 min/4-h I/R, GIII (Reba + I/R): rats received Reba 100 mg/kg/day, p.o. for three weeks, then were subjected to 60 min/4-h I/R, and GIV (Reba + EX527 + I/R): rats received Reba (100 mg/kg/day p.o.) + EX527 (10 mg/kg/day, ip) for three weeks before I/R. Reba pretreatment decreased the serum levels of ALT and AST, improved I/R-induced histological alterations of both intestine and liver, increased hepatic Silent information regulator 1 (SIRT1) expression/content, ß-catenin expression/immunoreactivity, and FOXO1 expression, while suppressed NF-κB p65 expression/protein content. In addition, Reba increased hepatic total antioxidant capacity (TAC), while suppressed malondialdehyde (MDA), tumor necrosis factor (TNFα), and caspase-3 activity. Furthermore, Reba inhibited BAX expression, while upregulated Bcl-2 expression. Reba exhibited a plausible protective effect against intestinal I/R-mediated liver injury by modulating SIRT1/ß-catenin/FOXO1-NFκB signaling mechanisms.

Agomelatine improves streptozotocin-induced diabetic nephropathy through melatonin receptors/SIRT1 signaling pathway.

INTRODUCTION: Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Agomelatine, a melatonin receptor agonist, has a potent anti-inflammatory activity. The current study aimed to determine the ameliorative anti-inflammatory effect of agomelatine against DN. METHODS: We used 10 % fructose with streptozotocin (STZ) to induce DN in male Wistar rats. Diabetic rats were treated with agomelatine in presence or absence of melatonin receptor antagonist (luzindole) or Sirtuin1 (SIRT1) inhibitor (EX527). SIRT1 expression was measured by qRT-PCR and immunohistochemical analysis. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), 5'adenosine monophosphate-activated protein kinase (AMPK), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured using ELISA. Histological assessment was performed using hematoxylin and eosin-stained renal sections. RESULTS: Fructose and STZ treatment induced diabetes, insulin resistance, and renal damage accompanied by reduced SIRT1 expression, increased NFκB activation, and decreased AMPK phosphorylation in the kidney. Agomelatine treatment improved kidney histology and function and upregulated SIRT1 expression (2-fold). Inhibition of melatonin receptors and SIRT1 activity increased NFκB phosphorylation (2.13 and 1.98-folds, respectively), reduced AMPK activation (0.51 and 0.53-folds, respectively), increased inflammatory markers ICAM-1 (2.16 and 2.23-folds, respectively), VCAM-1 (2.19 and 2.26-folds, respectively), and MCP-1(2.84 and 3.12-folds, respectively), and inhibited the ameliorative effect of agomelatine on kidney structure and function. CONCLUSION: Our findings reveal the ameliorative anti-inflammatory activity of agomelatine against STZ-induced DN and this effect is SIRT1- and melatonin receptor-dependent. Therefore, agomelatine may be beneficial to prevent the development of ESRD from diabetes mellitus.

Geraniol protects against cyclosporine A-induced renal injury in rats: Role of Wnt/ß-catenin and PPARγ signaling pathways.

AIMS: The nephrotoxicity of cyclosporine A (CsA) limits its use as an immunosuppressant. Wnt/ß-catenin signaling is involved in the pathogenesis of both acute and chronic kidney disease, and it is inhibited by peroxisome proliferator-activated receptor gamma (PPARγ). We aimed to evaluate if geraniol, which can modulate both PPARγ and Wnt signaling, could protect against CsA-induced nephrotoxicity. MATERIALS AND METHODS: Rats (6 groups) received the vehicle or a combination of CsA (30 mg/kg) with the vehicle, geraniol (50, 100, or 200 mg/kg), or the PPARγ agonist pioglitazone for 4 weeks. Blood pressure (BP), markers of renal injury (serum urea, serum creatinine, blood urea nitrogen, and urinary NAG), oxidative stress (glutathione peroxidase), inflammation (ICAM-1, IL-18, and NF-κB), apoptosis (caspase-3), extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], and fibrosis (TGF-ß1, Smad3, and Smad7) were assessed. Renal histological analysis, Wnt signaling components (Wnt-4/ß-catenin and E-cadherin), and PPARγ expression were evaluated. KEY FINDINGS: CsA group had renal injury, as well as increased BP, renal oxidative stress, inflammation, and fibrosis. The latter changes were associated with altered renal architecture, active Wnt signaling (higher Wnt-4 and ß-catenin expression and E-cadherin down-regulation), and lower PPARγ levels. Geraniol protected against kidney damage and the associated biochemical and histomorphological changes in a dose-dependent manner. The latter effects were comparable or superior to those of pioglitazone. SIGNIFICANCE: The down-regulation of Wnt/ß-catenin and the increase in PPARγ by geraniol suggest that both pathways are involved in its renoprotective potential. The study highlights geraniol as a valuable protective asset against chemically induced nephrotoxicity.

Cilostazol protects against acetic acid-induced colitis in rats: Possible role for cAMP/SIRT1 pathway.

The phosphodiesterase-3 inhibitor, cilostazol has been recently shown to protect against chemically induced colitis in animal models. However, whether cyclic adenosine monophosphate (cAMP) contributes to the anti-inflammatory activity of cilostazol in colitis is still unknown. In the current study, we investigated the role of cAMP/silent information regulator-1 (SIRT-1) pathway in the protective effect of cilostazol using rat model of acetic acid-induced colitis. Upregulation of SIRT1 activity and expression has been recently shown to protect against chemically induced colitis. Our results demonstrated that cilostazol alleviated the histopathological changes associated with acetic acid-induced colitis. Interestingly, pre-administration of cilostazol increased cAMP concentration and SIRT1 expression in colonic mucosa to levels similar to that observed in control animals without induction of colitis. In addition, cilostazol inhibited the SIRT1 targets; NF-κB, Akt and MAPK inflammatory pathways as demonstrated by suppression of acetic acid-induced upregulation of NF-κB activity, p-AKT levels and the expression of p38 MAPK. NF-κB activity and the levels of p-AKT, tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) were similar in rats pretreated with cilostazol prior to induction of colitis and the control rats without colitis. Furthermore, cilostazol reduced acetic acid-induced oxidative stress and apoptosis. In conclusion, the protective effect of cilostazol against acetic acid-induced colitis may be attributed to activation of SIRT1 expression by cAMP. SIRT1 is suggested to contribute to cilostazol-induced suppression of NF-κB, Akt and MAPK inflammatory pathways, oxidative stress and apoptosis.

Canagliflozin protects against non-alcoholic steatohepatitis in type-2 diabetic rats through zinc alpha-2 glycoprotein up-regulation.

Elevated blood glucose and insulin resistance are triggering factors for non-alcoholic steatohepatitis (NASH). We investigated the effects of the Sodium Glucose co-Transporter 2 (SGLT2) inhibitor canagliflozin on NASH development in rats with type 2 diabetes mellitus as well as the possible underlying mechanisms and for the first time the effect of canagliflozin on the hepatic zinc-α2-glycoprotein (ZAG) levels. Rats were treated with nicotinamide and streptozotocin to reduce the insulin secretory capacity then fed high fat diet for 8 weeks. The diabetic high fat diet rats were divided into three groups; untreated group, canagliflozin 10 mg/kg treated group and canagliflozin 20 mg/kg treated group during this period. The elevated blood glucose and glycated haemoglobin (HbA1c) levels in the diabetic high fat diet rats were significantly reduced by canagliflozin. Moreover, the diabetic high fat diet induced NASH development as evidenced by liver weight gain, hepatic lipid accumulation and low hepatic ZAG expression as well as increased serum alanine aminotransferase; all these changes were reversed in rats treated with canagliflozin. Additionally, canagliflozin succeeded to upregulate the hepatic ZAG levels in both normal and diabetic high fat fed rats, lower the serum and hepatic inflammatory cytokines levels as well as lower the serum caspase-3 levels and enhanced hepatic Bcl-2 expression. Also, canagliflozin attenuated hepatic oxidative stress and elevated the antioxidant enzymes activity as well as the total antioxidant capacity. All these effects of canagliflozin were dose dependant. CONCLUSION: SGLT2 inhibitor-canagliflozin- has beneficial effects in treatment of NASH associated with diabetes mellitus.