Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress.

Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pioglitazone (PIO), a PPAR-γ agonist, in fructose/streptozotocin (F/STZ) T2DM model in male Wistar rats. T2DM was induced by maintaining rats on 10% (w/v) fructose in drinking water for 9 weeks with an intraperitoneal injection of sub-diabetogenic dose of STZ (35 mg/kg) by the end of the fourth week. One week after STZ injection, PIO (10 mg/kg/day) alone or with VITD (500 IU/kg/day) was administered orally to diabetic rats till the end of the experiment. Blood samples were collected, livers were homogenized to determine biochemical parameters, and samples of livers were fixed in 10% formalin in saline for histological examination. Administration of PIO alone improved diabetes-induced inflammatory and oxidative states besides controlling hyperglycemia and decreasing apoptosis. Coadministration of VIT D with PIO promoted additional improvement in glycemic and lipid profiles, provided further control on diabetic-induced hepatic inflammation evident by downregulating TLR2, TLR4, and IKK-ß while upregulating IκB-α expression and reducing inflammatory cytokines namely; NF-κB, TNF-α, IL-6, and IL-1ß, decreasing apoptosis and oxidative stress by hampering caspase-3 and MDA contents, respectively, and improved liver histology than PIO alone. These beneficial effects of VIT D may expand its use by diabetics combined with antidiabetic drugs due to its anti-inflammatory, antioxidant, and antiapoptotic properties.

Vitamin D mitigates diabetes-associated metabolic and cognitive dysfunction by modulating gut microbiota and colonic cannabinoid receptor 1.

INTRODUCTION: Obesity is associated with elevated endocannabinoid tone, gut dysbiosis, and inflammation predisposing to diabetes. The endocannabinoid system mediates the effects of gut microbiota and regulates the gut barrier integrity. We examined the effects of vitamin D (VD) on colonic cannabinoid receptor 1(CB1R), tight junction proteins, gut dysbiosis, metabolic and cognitive dysfunction in a model of type 2 diabetes compared with metformin. METHODS: Rats received high-fat, high-sucrose diet (HFSD) and either VD (500 IU/kg/day; p.o.), or metformin (200 mg/kg/day; p.o.) for 8 weeks. After 6 weeks, streptozotocin (STZ) (40 mg/kg; i.p) was injected. Behavioral, cognitive, and metabolic assessments were carried out. Finally, fecal, blood, and tissue samples were collected to examine Bacteroidetes/Firmicutes ratio, colonic CB1R, zonula occludens-1 (ZO-1), occludin, and Toll-like receptor 4 (TLR4); serum lipopolysaccharides (LPS), peptidoglycan (PGN), tumor necrosis factor-alpha (TNF-ɑ), glucagon-like peptide-1 (GLP-1), lipids, and VD; hippocampal brain-derived neurotrophic factor (BDNF) and inflammatory markers. RESULTS: VD ameliorated HFSD/STZ-induced dysbiosis/gut barrier dysfunction as indicated by lower circulating LPS, PGN and TNF-ɑ levels, likely by downregulating colonic CB1R and upregulating ZO-1 and occludin expressions. Additionally, VD suppressed HFSD/STZ-induced hyperglycemia, hyperinsulinemia, dyslipidemia, and hippocampal neuroinflammation. These changes culminated in improved glycemic control and cognitive function. VD was more effective than metformin in decreasing serum LPS and TNF-ɑ levels; whereas metformin resulted in better glycemic control. CONCLUSION: Targeting gut microbiota by VD could be a successful strategy in the treatment of diabetes and associated cognitive deficit. The crosstalk between VD axis and the endocannabinoid system needs further exploration.

Effects of TNF-α antagonist infliximab on fructose-induced metabolic syndrome in rats.

Public health issues have been raised regarding fructose toxicity and its serious metabolic disorders. Deleterious effects of high fructose intake on insulin sensitivity, body weight, lipid homeostasis have been identified. The new millennium has witnessed the emergence of a modern epidemic, the metabolic syndrome (MS), in approximately 25% of the world's adult population. The current study aimed to investigate the effect of the TNF-α antagonist infliximab on fructose-induced MS in rats. Rats were administered fructose (10%) in drinking water for 12 weeks to induce the experimental MS model. infliximab (5 mg/kg) was injected once weekly intraperitoneally starting on the 13th week for 4 weeks. Increase in body weight, blood glucose level, serum triglycerides (TGs), adiponectin level and blood pressure were present in MS rats. They also prompted increases in serum of leptin, TNF-α, and malondialdehyde (MDA) levels. Treatment with infliximab did not affect body weight, hyperglycemia or hypertension, but decreased serum TGs and increased serum HDL-c levels. Infliximab also decreased adiponectin levels. Surprisingly, infliximab increased MDA above its value in the MS group. These results reflect the fact that infliximab affects the manifestations of MS in rats. Though infliximab reduced TGs, increased HDL-c levels, reversed adiponectin resistance occurred by fructose, the drug failed to combat MS-mediated hyperglycemia, hypertension, and elevated MDA above the insult.

Rice Bran Extract Protected against LPS-Induced Neuroinflammation in Mice through Targeting PPAR-γ Nuclear Receptor.

PPAR-γ anti-inflammatory functions have received significant attention since its agonists have been shown to exert a wide range of protective effects in many experimental models of neurologic diseases. Rice bran is very rich in polyunsaturated fatty acids, which are reported to act as PPAR-γ partial agonists. Herein, the anti-inflammatory effect of rice bran extract (RBE) through PPAR-γ activation was evaluated in LPS-induced neuroinflammatory mouse model in comparison to pioglitazone (PG) using 80 Swiss albino mice. RBE (100 mg/kg) and PG (30 mg/kg) were given orally for 21 days and LPS (0.25 mg/kg) was injected intraperitoneally for the last 7 days. TNF-α and COX-2 brain contents were evaluated by real-time PCR and immunohistochemical analysis. In addition, NFκB binding to its response element was evaluated alongside with the effect of treatments on IκB gene expression. Furthermore, PPAR-γ sumoylation was also studied. Finally, histopathological examination was performed for different brain areas. RBE administration was found to protect against the LPS-induced inflammatory effects by decreasing the inflammatory mediator expression in mice brains. It also decreased PPAR-γ sumoylation without significant effect on IκB expression or NFκB binding to its response element. The majority of the effects were attenuated in presence of PPAR-γ antagonist (GW9662). Level of significance was set to P < 0.05. Such findings highlight the agonistic effect of RBE component(s) on PPAR-γ and support the hypothesis of involvement of PPAR-γ activation in its neuroprotective effect.