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Nonalcoholic steatohepatitis (NASH) is the second leading cause of liver transplantation in the US with a high risk of liver-related morbidities and mortality. Given the global burden of NASH, development of appropriate therapeutic strategies is an important clinical need. Where applicable, lifestyle modification remains the primary recommendation for the treatment of NASH, even though such changes are difficult to sustain and even insufficient to cure NASH. Bariatric surgery resolves NASH in such patients where lifestyle modifications have failed, and is recommended for morbidly obese patients with NASH. Thus, pharmacotherapies are of high value for NASH treatment. Though no drug has been approved by the US Food and Drug Administration for treatment of NASH, substantial progress in pharmacological development has been made in the last few years. Agents such as vitamin E and pioglitazone are recommended in patients with NASH, and yet concerns about their side effects remain. Many agents targeting various vital molecules and pathways, including those impacting metabolic perturbations, inflammatory cascades, and oxidative stress, are in clinical trials for the treatment of NASH. Some agents have shown promising results in phase II or III clinical trials, but more studies are required to assess their long-term effects. Herein, we review the potential strategies and challenges in therapeutic approaches to treating NASH. [ABSTRACT FROM AUTHOR]

Kaempferia parviflora (KP), a health-promoting herb, has been traditionally used for treating a variety of diseases. Pharmacological studies have claimed the various benefits from KP and its main effective methoxyflavones, including cellular metabolism-regulating activity, anticancer activity, vascular relaxation and cardioprotective activity, sexual enhancing activity, neuroprotective activity, antiallergic, anti-inflammatory, and antioxidative activity, antiosteoarthritis activity, antimicroorganism activity, and transdermal permeable activity. These might be associated with increased mitochondrial functions and activated cGMP-NO signaling pathway. However, the underlying molecular mechanisms of KP and its methoxyflavones are still under investigation. The clinical applications of KP and its methoxyflavones may be limited due to their low bioavailability. But promising strategies are on the way. This review will comprehensively discuss the biological activities of KP and its methoxyflavones. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 3 ( IRF3) is a transcription factor that plays a central role in the innate immune response, apoptosis, and oncogenesis. Previous studies have shown that endogenous IRF3 does not affect stroke in mice; however, paradoxically, elevated IRF3 expression was observed in the rat brains following cerebral ischemia/reperfusion (I/R) injury, indicating that IRF3 may have different functions during stroke in rats than in mice. A clear and comprehensive study of the effect of IRF3 on stroke in rats has been hampered by the lack of an IRF3-knockout rat strain. In this study, a novel IRF3 knockout rat strain and a transgenic rat strain with neuronal-specific IRF3 over-expression ( IRF3- TG) were created. Subsequently, the generated IRF3-knockout rats, the neuronal-specific IRF3 over-expressing rats and their corresponding controls were subjected to transient middle cerebral artery occlusion and followed by reperfusion, to investigate the exact role of IRF3 in cerebral I/R in rats. In contrast to the results in mice, IRF3 deficiency in rats provided significant protection against cerebral I/R injury and inhibited neuronal apoptosis, inflammation, and oxidative stress after cerebral I/R injury; the opposite patterns were observed in neuronal-specific IRF3 over-expressing rats. Taken together, these data demonstrate that IRF3 plays a negative regulatory role in cerebral I/R in rats, and IRF3 may be an attractive therapeutic target for preventing stroke. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide and is strongly associated with the presence of oxidative stress. Disturbances in lipid metabolism lead to hepatic lipid accumulation, which affects different reactive oxygen species (ROS) generators, including mitochondria, endoplasmic reticulum, and NADPH oxidase. Mitochondrial function adapts to NAFLD mainly through the downregulation of the electron transport chain (ETC) and the preserved or enhanced capacity of mitochondrial fatty acid oxidation, which stimulates ROS overproduction within different ETC components upstream of cytochrome c oxidase. However, non-ETC sources of ROS, in particular, fatty acid β-oxidation, appear to produce more ROS in hepatic metabolic diseases. Endoplasmic reticulum stress and NADPH oxidase alterations are also associated with NAFLD, but the degree of their contribution to oxidative stress in NAFLD remains unclear. Increased ROS generation induces changes in insulin sensitivity and in the expression and activity of key enzymes involved in lipid metabolism. Moreover, the interaction between redox signaling and innate immune signaling forms a complex network that regulates inflammatory responses. Based on the mechanistic view described above, this review summarizes the mechanisms that may account for the excessive production of ROS, the potential mechanistic roles of ROS that drive NAFLD progression, and therapeutic interventions that are related to oxidative stress. Image 1 • Oxidative stress plays a central role in the pathogenesis of NAFLD. • Mechanisms for ROS production include alterations in the mitochondria, ER, and NOX. • Non-ETC sources, especially β-oxidation, are important sources of mitochondrial ROS. • ROS signaling modulates lipid metabolism, insulin signaling, and inflammation. • Targeting hepatic oxidative stress is a promising strategy to treat NAFLD. [ABSTRACT FROM AUTHOR]

Humans are exposed to disinfection by-products through oral, inhalation, and dermal routes, during bathing and swimming, potentially causing skin lesions, asthma, and bladder cancer. Nuclear factor E2-related factor 2 (NRF2) is a master regulator of the adaptive antioxidant response via the antioxidant reaction elements (ARE) orchestrating the transcription of a large group of antioxidant and detoxification genes. Here we used an immortalized human keratinocyte model HaCaT cells to investigate NRF2-ARE as a responder and protector in the acute cytotoxicity of seven haloacetonitriles (HANs), including chloroacetonitrile (CAN), bromoacetonitrile (BAN), iodoacetonitrile (IAN), bromochloroacetonitrile (BCAN), dichloroacetonitrile (DCAN), dibromoacetonitrile (DBAN), and trichloroacetonitrile (TCAN) found in drinking water and swimming pools. The rank order of cytotoxicity among the HANs tested was IAN ≈ BAN ˃ DBAN ˃ BCAN ˃ CAN ˃ TCAN ˃ DCAN based on their LC 50. The HANs induced intracellular reactive oxygen species accumulation and activated cellular antioxidant responses in concentration- and time-dependent fashions, showing elevated NRF2 protein levels and ARE activity, induction of antioxidant genes, and increased glutathione levels. Additionally, knockdown of NRF2 by lentiviral shRNAs sensitized the HaCaT cells to HANs-induced cytotoxicity, emphasizing a protective role of NRF2 against the cytotoxicity of HANs. These results indicate that HANs cause oxidative stress and activate NRF2-ARE-mediated antioxidant response, which in turn protects the cells from HANs-induced cytotoxicity, highlighting that NRF2-ARE activity could be a sensitive indicator to identify and characterize the oxidative stress induced by HANs and other environmental pollutants. [Display omitted] • Haloacetonitriles cause acute cytotoxicity and oxidative stress in HaCaT cells. • Haloacetonitriles induce NRF2-ARE-mediated antioxidant response in HaCaT cells. • NRF2 protects human keratinocytes from HANs-induced acute cell damage. • NRF2-ARE activity is an indicator for the oxidative stress caused by haloacetonitriles. [ABSTRACT FROM AUTHOR]