Protective mechanisms of anthocyanins from purple sweet potato against tert-butyl hydroperoxide-induced hepatotoxicity

Anthocyanins have been shown to exert anti-proliferative, anti-inflammatory effects and anti-carcinogenic activity. In the present work, we investigated the protective effects of anthocyanin fraction (AF) from purple sweet potato on tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in HepG2 cell line and in rat liver. The result showed that the oral pretreatment of AF before t-BHP treatment significantly lowered the serum levels of the hepatic enzyme markers (ALT and AST) and reduced oxidative stress of the liver by evaluation of malondialdehyde and glutathione. Histopathological evaluation of the livers also revealed that AF reduced the incidence of liver lesions. The in vitro result showed that AF significantly reduced t-BHP-induced oxidative injury, as determined by cell cytotoxicity, intracellular glutathione content, lipid peroxidation, reactive oxygen species (ROS) levels, and caspases activation. Also, AF up-regulated antioxidant enzymes including heme oxygenase-1 (HO-1), NAD(P)H:quinone reductase, and glutathione S-transferase. Moreover, AF induced Nrf2 nuclear translocation and Akt and ERK1/2 activation, pathways that are involved in inducing Nrf2 nuclear translocation. Taken together, these results suggest that the protective effects of AF against t-BHP-induced hepatotoxicity may, at least in part, be due to its ability to scavenge ROS and to regulate the antioxidant enzyme HO-1 via the Akt and ERK1/2/Nrf2 signaling pathways.     

Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1.

Curcumin (diferuloymethane), a yellow colouring agent present in the rhizome of Curcuma longa Linn (Zingiberaceae), has been reported to possess anti-inflammatory, antioxidant, antimutagenic and anticarcinogenic activities. Curcumin exerts its chemoprotective and chemopreventive effects via multiple mechanisms. It has been reported to induce expression of the antioxidant enzymes in various cell lines. Heme oxygenase-1 (HO-1) is an important antioxidant enzyme that plays a pivotal role in cytoprotection against noxious stimuli of both endogenous and exogenous origin. In the present study, we found that oral administration of curcumin at 200mg/kg dose for four consecutive days not only protected against dimethylnitrosamine (DMN)-induced hepatic injury, but also resulted in more than three-fold induction of HO-1 protein expression as well as activity in rat liver. Inhibition of HO-1 activity by zinc protoporphyrin-IX abrogated the hepatoprotective effect of curcumin against DMN toxicity. NF-E2-related factor 2 (Nrf2) plays a role in the cellular protection against oxidative stress through antioxidant response element (ARE)-directed induction of several phase-2 detoxifying and antioxidant enzymes including HO-1. Curcumin administration resulted in enhanced nuclear translocation and ARE-binding of Nrf2. Taken together, these findings suggest that curcumin protects against DMN-induced hepatotoxicity, at least in part, through ARE-driven induction of HO-1 expression.     

Anti-fibrotic effects of the anthocyanins isolated from the purple-fleshed sweet potato on hepatic fibrosis induced by dimethylnitrosamine administration in rats

In current study, we investigated the protective effects of the anthocyanin fraction (AF) obtained from the purple-fleshed sweet potato on hepatic fibrosis induced by dimethylnitrosamine (DMN) administration in rats. Treatment with DMN for 4 weeks produced marked liver fibrosis as assessed by increased serum alanine aminotransferase and aspartate aminotransferase activity and hepatic collagen content. These increases were inhibited by treatment with AF prior to the administration of DMN. In addition, AF inhibited DMN-induced reductions in rat body and liver weights in a dose-dependent manner. Histopathological evaluation of the rat livers revealed that AF reduced the incidence of hepatic fibrosis lesions and inhibited DMN-induced increases in α-smooth muscle actin (α-SMA) and collagen type I and III expression levels. AF also decreased DMN-induced expression levels platelet-derived growth factor receptors-beta, tumor necrosis factor-alpha and transforming growth factor-beta. This study demonstrates that AF administration can effectively improve liver fibrosis caused by DMN, and may be used as a therapeutic option and preventive measure against hepatic fibrosis.     

二甲双胍激活Nrf2信号并诱导抗氧化基因的表达

二甲双胍是一个一线抗糖尿病药物,然而其详细作用机制仍在研究中。Nrf2信号在保护细胞免受氧化性损伤中起着重要作用,近年来也成为干预糖尿病及其相关并发症的重要药物靶标。本研究在体内外实验中检测了二甲双胍对Nrf2信号的影响,并探究了其可能的机制。首先,二甲双胍激活AMPK和Nrf2信号,并以类似的浓度-和时间-依赖方式在小鼠骨骼肌细胞C2C12中诱导抗氧化基因NQO1和γ-GCSm的表达。其次,过表达AMPK会显著提高基础的和二甲双胍诱导的ARE–萤光素酶报告基因的活性,说明AMPK参与了二甲双胍对Nrf2信号的激活。最后,二甲双胍激活小鼠肝脏和骨骼肌组织中的Nrf2信号,诱导抗氧化基因HO-1和SOD的表达,导致GSH水平的增加。总之,我们的结果说明二甲双胍可以激活Nrf2信号和增强组织的抗氧化能力,并提供了二甲双胍作用的新机制。     

Purple sweet potato color attenuates oxidative stress and inflammatory response induced by d-galactose in mouse liver

The hepatoprotective effects of purple sweet potato color (PSPC), which is natural anthocyanin food colors, have been well demonstrated in many studies. Nevertheless, little work has been done to clarify the detailed mechanism of hepatoprotective effects of PSPC. This study was designed to explore whether PSPC protected mouse liver from d-gal-induced injury by attenuating oxidative stress or suppressing inflammation. The histology changes of mouse liver was assessed by hematoxylin and eosin staining. The results showed that PSPC could effectively suppress the d-gal-induced histology changes including structure damage and leucocyte infiltration in mouse liver. Oxidative stress and antioxidant status in mouse liver were also analysed. The results showed that PSPC could largely attenuate the d-gal-induced MDA increasing and could markedly renew the activities of Cu, Zn-SOD, CAT and GPx in the livers of d-gal-treated mice. Furthermore, the results of western blot analysis showed that PSPC could inhibit the upregulation of the expression of NF-κB p65, COX-2 and iNOS caused by d-gal. In conclusion, our data suggested that PSPC could protect the mouse liver from d-gal-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and suppressing inflammatory response. This study provided novel insights into the mechanisms of PSPC in the protection of the liver.     

Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet

Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gstα1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities.