Quercetin and resveratrol are known to have beneficial effects on the diabetes and diabetic complication, however, the effects of combined treatment of these compounds on diabetes are not fully revealed. Therefore, the present study was designed to investigate the combined antidiabetic action of quercetin (QE) and resveratrol (RS) in streptozotocin (STZ)-induced diabetic rats. To test the effects of co-treated with these compounds on diabetes, serum glucose, insulin, lipid profiles, oxidative stress biomarkers, and ions were determined. Additionally, the activities of hepatic glucose metabolic enzymes and histological analyses of pancreatic tissues were evaluated. 50 male Sprague-Dawley rats were divided into five groups; normal control, 50 mg/kg STZ-induced diabetic, and three (30 mg/kg QE, 10 mg/kg RS, and combined) compound-treated diabetic groups. The elevated serum blood glucose levels, insulin levels, and dyslipidemia in diabetic rats were significantly improved by QE, RS, and combined treatments. Oxidative stress and tissue injury biomarkers were dramatically inhibited by these compounds. They also shown to improve the hematological parameters which were shown to the hyperlactatemia and ketoacidosis as main causes of diabetic complications. The compounds treatment maintained the activities of hepatic glucose metabolic enzymes and structure of pancreatic β-cells from the diabetes, and it is noteworthy that cotreatment with QE and RS showed the most preventive effect on the diabetic rats. Therefore, our study suggests that cotreatment with QE and RS has beneficial effects against diabetes. We further suggest that cotreatment with QE and RS has the potential for use as an alternative therapeutic strategy for diabetes.

Growing evidence has indicated that supplementation with probiotics improves lipid metabolism. We aimed to investigate the beneficial effects of a probiotics mixture (PM) of three strains belonging to the species Bifidobacterium (B. longum, B. lactis, and B. breve) and two strains belonging to the species Lactobacillus (L. reuteri and L. plantarum) on cholesterol-lowering efficacy in hypercholesterolemic rats. A hypercholesterolemic rat model was established by feeding a high-cholesterol diet for eight weeks. To test the effects of PM on hypercholesterolemia, hypercholesterolemic rats were assigned to four groups, which were treated daily with low (1.65 × 10⁹ cfu/kg), medium (5.5 × 10⁹ cfu/kg), or high (1.65 × 10¹⁰ cfu/kg) doses of probiotic mixture or simvastatin for eight weeks. Significant reductions of serum total cholesterol (TC), triacylglycerol (TG), and low-density lipoprotein (LDL)-cholesterol levels, but increases of high-density lipoprotein (HDL)-cholesterol were observed after supplementation of PM in hypercholesterolemic rats. In PM-supplemented hypercholesterolemic rats, hepatic tissue contents of TC and TG also significantly decreased. Notably, the histological evaluation of liver tissues demonstrated that PM dramatically decreased lipid accumulation. For their underlying mechanisms, we demonstrated that PM reduced expressions of cholesterol synthesis-related proteins such as sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) in the liver. Taken together, these findings suggest that PM has beneficial effects against hypercholesterolemia. Accordingly, our PM might be utilized as a novel therapeutic agent for the management of hypercholesterolemia.

Multiple signaling pathways involving protein kinase C (PKC) have been implicated in the development of cardiac hypertrophy. We observed that a putative PKC inhibitor, PICOT ( P KC- I nteracting C ousin O f T hioredoxin) was upregulated in response to hypertrophic stimuli both in vitro and in vivo. This suggested that PICOT may act as an endogenous negative feedback regulator of cardiac hypertrophy through its ability to inhibit PKC activity, which is elevated during cardiac hypertrophy. Adenovirus-mediated gene transfer of PICOT completely blocked the hypertrophic response of neonatal rat cardiomyocytes to enthothelin-1 and phenylephrine, as demonstrated by cell size, sarcomere rearrangement, atrial natriuretic factor expression, and rates of protein synthesis. Transgenic mice with cardiac-specific overexpression of PICOT showed that PICOT is a potent inhibitor of cardiac hypertrophy induced by pressure overload. In addition, PICOT overexpression dramatically increased the ventricular function and cardiomyocyte contractility as measured by ejection fraction and end-systolic pressure of transgenic hearts and peak shortening of isolated cardiomyocytes, respectively. Intracellular Ca ²⁺ handing analysis revealed that increases in myofilament Ca ²⁺ responsiveness, together with increased rate of sarcoplasmic reticulum Ca ²⁺ reuptake, are associated with the enhanced contractility in PICOT-overexpressing cardiomyocytes. The inhibition of cardiac remodeling by of PICOT with a concomitant increase in ventricular function and cardiomyocyte contractility suggests that PICOT may provide an efficient modality for treatment of cardiac hypertrophy and heart failure.

Notch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of its ligands results in the proteolytic cleavage of Notch by the γ-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription. Here we show that activation of Notch modulates ischemic neuronal cell death in vitro and in vivo. Specifically, our findings from the use of Notch-1 siRNA or the overexpression of NICD indicate that Notch activation contributes to cell death. Using modified NICD, we demonstrate an apoptosis-inducing function of NICD in both the nucleus and the cytosol. NICD transfection-induced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, γ-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-κB (NF-κB), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a γ-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, γ-secretase inhibition reduced NICD, p-p65, and Bim levels in vivo. These findings suggest that Notch signaling endangers neurons after ischemic stroke by modulating the NF-κB, pro-death protein Bim, and caspase pathways.