Targeting macrophage polarization by Nrf2 agonists for treating various xenobiotics-induced toxic responses.

Macrophages can polarize into different phenotypes in response to different microenvironmental stimuli. Macrophage polarization has been assigned to two extreme states, namely proinflammatory M1 and anti-inflammatory M2. Accumulating evidences have demonstrated that M1 polarized macrophages contribute to various toxicants-induced deleterious effects. Switching macrophages from proinflammatory M1 phenotype toward anti-inflammatory M2 phenotype could be a promising approach for treating various inflammatory diseases. Studies in the past few decades have revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) can modulate the polarization of macrophages. Specifically, activation of Nrf2 could block M1 stimuli-induced production of proinflammatory cytokines and chemokines, and shift the polarization of macrophages toward M2 by cross-talking with nuclear factor kappa-B (NF-κB), mitogen-activated protein kinases (MAPKs), peroxisome proliferator-activated receptor γ (PPARγ), and autophagy. Importantly, a great number of studies have confirmed the beneficial effects of natural and synthesized Nrf2 agonists on various inflammatory diseases; however, most of these compounds are far away from clinical application due to lack of characterization and defects of study designs. Interestingly, some endogenous Nrf2 inducers and compounds with dual activities (such as the Nrf2 inducing and CO releasing effects) exhibit potent anti-inflammatory effects, which points out an important direction for future researches.

Transformed ALDH2-/- hepatocytes by ethanol could serve as a useful tool for studying alcoholic hepatocarcinogenesis.

Alcohol is a well-recognized hepatic carcinogen. Alcohol is metabolized into genotoxic acetaldehyde in hepatocytes, which is catalyzed by aldehyde dehydrogenase 2 (ALDH2). The detailed underlying mechanisms of alcohol-related hepatocellular carcinoma (HCC) remains unclear, at least partially, due to the absence of appropriate experimental models. Current studies suggest that rodents are not good models of the most common liver diseases that trigger HCC including alcoholic liver injury. We hypothesize that ethanol could induce transformation of immortalized normal liver cells, which may serve as a versatile tool for studying alcoholic HCC. Besides, we believe that knockout of ALDH2 will help to shorten the time course of transformation, as ALDH2 deficiency will significantly increase the accumulation of acetaldehyde in hepatocytes. Using this model, the dynamic changes of carcinogenesis-related molecular events could be easily examined. Furthermore, the transformed cells isolated from soft agar could be inoculated to mice for studying invasion, metastasis, and also for screening prophylactics.

Roles of peroxisome proliferator-activated receptor α in the pathogenesis of ethanol-induced liver disease.

Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.