Telmisartan alleviates alcohol-induced liver injury by activation of PPAR-γ/ Nrf-2 crosstalk in mice.

Excessive consumption of alcohol may induce severe liver damage, in part via oxidative stress and inflammatory responses, which implicates these processes as potential therapeutic approaches. Prior literature has shown that Telmisartan (TEL) may provide protective effects, presumably mediated by its anti-oxidant and anti-inflammatory activities. The purpose of this study was to determine TEL's hepatoprotective effects and to identify its possible curative mechanisms in alcoholic liver disease. A mouse chronic alcohol plus binge feedings model was used in the current study for induction of alcoholic liver disease (ALD). Our results showed that TEL (10 mg/kg/day) has the ability to reduce serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). TEL also increased the activity of superoxide dismutase (SOD) and glutathione (GSH) with concomitant reduction of nitric oxide (NO) malonaldehyde (MDA) in the liver homogenate. Moreover, TEL downregulated nuclear factor kappa B (NF-κB) expression and decreased liver content of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α). These anti-inflammatory and anti-oxidant activities were associated with a significant increase in the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), peroxisome proliferator-activated receptors -γ (PPAR-γ), and heme oxygenase-1 (Hmox-1). In conclusion, TEL's hepatoprotective effects against ALD may be attributable to its anti-inflammatory and anti-oxidant activities which may be in part via the modulation of PPAR-γ/ Nrf-2/ NF-κB crosstalk.

Empagliflozin ameliorates ethanol-induced liver injury by modulating NF-κB/Nrf-2/PPAR-γ interplay in mice.

BACKGROUND: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.

Enhanced in vitro cytotoxicity and anti-tumor activity of vorinostat-loaded pluronic micelles with prolonged release and reduced hepatic and renal toxicities.

Vorinostat is the first histone deacetylase inhibitor approved by US FDA for use in cancer therapy. However, its limited aqueous solubility, low permeability, and suboptimal pharmacokinetics hinder its delivery. Thus, in this study, micelles of vorinostat with each of pluronic F68 (PF68) and pluronic F127 (PF127) were developed and optimized based on drug loading and entrapment. The optimized micelles were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), zeta analyzer, and electron transmission microscopy. Their in vitro release, stability, in vitro cytotoxicity against HepG2, Caco-2, and MCF-7 cell lines, and finally, in vivo antitumor activity in mice bearing Ehrlich Ascites Carcinoma (EAC) were assessed. The highest entrapment efficiency was 99.09±2.16% and 94.19±2.37% for micelles of 1:50 drug to polymer ratio with each of PF127 and PF68, respectively. These micelles were nearly spherical with nanoscopic mean diameters of 72.61±10.66nm for PF68 and 91.88±10.70nm for PF127 with narrow size distribution. The micelles provided prolonged release at phosphate buffer saline pH7.4 up to 24h for PF68 and 72h for PF127. Potentiation of in vitro cytotoxicity of vorinostat was more pronounced with PF127 micelles particularly against MCF-7 cells. Compared with free vorinostat, the micelles with PF127 were more effective in inhibiting tumor growth as well as exhibiting significantly (p<0.05) diminished hepatic and renal toxicities. In conclusion, 1:50 vorinostat-PF127 micelles may facilitate i.v. formulations and can be suggested as a promising stable and safe nanoparticulate delivery system with prolonged release and potentiated cytotoxicity.