Selenium modifies glutathione peroxidase activity and glutathione concentration in mice exposed to ozone-provoked oxidative stress

The aim of this study was to show the direct effect of selenium on glutathione peroxidase (GSH-Px) activity and GSH/GSSG concentrations in 3- and 6-month-old mice. An ozone-oxygen mixture was used to provoke an oxygen stress. To measure the Se-effect mice were gavaged with sodium selenite. GSH-Px activity and total glutathione concentrations were determined in serum and in the postnuclear fraction of liver and lungs. Additionally glutathione concentrations were determined in whole blood. Both ozone and selenium, administered separately, reduced GSH-Px activity in lungs of 6-month-old animals, while in young mice an opposite effect of Se was observed. Ozone administered jointly with Se did not influence GSH-Px activity in 6-month-old mice, while in young, 3-month-old mice, a stimulatory effect in lungs was observed. There were no significant changes in GSH-Px activity in the liver of 6-month-old mice, but the stimulatory effect occurred in young mice treated with Se and Se & ozone jointly. In young mice, ozone (also ozone with Se) augmented glutathione concentrations. The response to ozone and selenium strictly depended on age and the antagonism between selenium and ozone was observed only in a few cases.     

Salvianolate ameliorates oxidative stress and podocyte injury through modulation of NOX4 activity in db/db mice

Podocyte injury is associated with albuminuria and the progression of diabetic nephropathy (DN). NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and NOX4 is up-regulated in podocytes in response to high glucose. In the present study, the effects of Salvianolate on DN and its underlying mechanisms were investigated in diabetic db/db mice and human podocytes. We confirmed that the Salvianolate administration exhibited similar beneficial effects as the NOX1/NOX4 inhibitor GKT137831 treated diabetic mice, as reflected by attenuated albuminuria, reduced podocyte loss and mesangial matrix accumulation. We further observed that Salvianolate attenuated the increase of Nox4 protein, NOX4-based NADPH oxidase activity and restored podocyte loss in the diabetic kidney. In human podocytes, NOX4 was predominantly localized to mitochondria and Sal B treatment blocked HG-induced mitochondrial NOX4 derived superoxide generation and thereby ameliorating podocyte apoptosis, which can be abrogated by AMPK knockdown. Therefore, our results suggest that Sal B possesses the reno-protective capabilities in part through AMPK-mediated control of NOX4 expression. Taken together, our results identify that Salvianolate could prevent glucose-induced oxidative podocyte injury through modulation of NOX4 activity in DN and have a novel therapeutic potential for DN.     

Tertiary butylhydroquinone alleviates gestational diabetes mellitus in C57BL/KsJ-Lep db/+ mice by suppression of oxidative stress

Gestational diabetes mellitus (GDM) is a common disorder characterized by abnormal glucose metabolism during pregnancy, affecting 2% to 5% of pregnant women. Currently, clinical treatment for GDM is very limited. The present study was designed to investigate the effect and underlying molecular mechanism of tertiary butylhydroquinone (TBHQ) in a pregnant C57BL/KsJ-Lep db/+ (referred to as db+) GDM mouse model. The results showed that nonpregnant db/+ mice did not show a diabetic phenotype, and TBHQ had no effect on glucose and insulin tolerance in these mice. Moreover, in db/+ pregnant mice exhibiting typical diabetes symptoms, such as hyperglycemia and hypoinsulinemia, TBHQ could remarkably decrease the blood glucose level, increase insulin level, and improve glucose and insulin intolerance. The results also revealed that TBHQ could inhibit oxidative stress in pregnant db/+ mice. Furthermore, TBHQ greatly improved offspring survival rate, glucose metabolism, and insulin tolerance. In addition, TBHQ inhibited oxidative stress by reducing malondialdehyde (MDA) and reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Moreover, we found that TBHQ activated the nuclear factor erythroid 2-related factor 2 (Nrf2), thereby increasing the levels of Nrf2, and ultimately upregulating the expression of heme oxygenase 1 (NO-1) and superoxide dismutase 2 (SOD2). In conclusion, our findings demonstrated that TBHQ alleviated GDM via Nrf2 activation.     

Osmotic stress induces loss of glutathione and increases the sensitivity to oxidative stress in H9c2 cardiac myocytes

It has been observed that H9c2 cardiac cells cultured in physiologic solutions exhibit delayed cell death after repeated medium replacements, of which the cause was the relatively mild osmotic challenges during the renewal of the culture medium. Interestingly, the cell damage was associated with altered intracellular GSH homeostasis. Therefore, this study attempted to elucidate the effects of osmotic stress on GSH metabolism. In cells subjected to osmotic stress by lowering the NaCl concentration of the medium, the cell swelling was rapidly counterbalanced, but the intracellular GSH content was significantly lower in 3 h. Meanwhile, the ratio of GSH-to-GSSG was not affected. As expected, osmotic stress also increased the sensitivity to H₂O₂, which was attributable to the decrease of GSH content. The decrease of GSH content was similarly evident when the synthetic pathways of GSH were blocked by BSO or acivicin. It was concluded that osmotic stress induced the decrease of intracellular GSH content by increased consumption and this loss of GSH rendered the cells susceptible to a subsequent oxidative stress.     

Reversibility of established diabetic glomerulopathy by anti-TGF-beta antibodies in db/db mice

Treatment with a neutralizing anti-transforming growth factor-beta (TGF-beta) antibody can prevent the development of diabetic nephropathy in the db/db mouse, a model of type 2 diabetes. However, it is unknown whether anti-TGF-beta therapy can reverse the histological lesions of diabetic glomerulopathy once they are established. Diabetic db/db mice and their non-diabetic db/m littermates were allowed to grow until 16 weeks of age, by which time the db/db mice had developed glomerular basement membrane (GBM) thickening and mesangial matrix expansion. The mice were then treated with an irrelevant control IgG or a panselective, neutralizing anti-TGF-beta antibody for eight more weeks. Compared with control db/m mice, the db/db mice treated with IgG had developed increased GBM width (16.64+/-0.80 nm vs. 21.55+/-0.78 nm, P<0.05) and increased mesangial matrix fraction (4.01+/-0.81% of total glomerular area vs. 9.55+/-1.04%, P<0.05). However, the db/db mice treated with anti-TGF-beta antibody showed amelioration of GBM thickening (18.40+/-0.72 nm, P<0.05 vs. db/db-IgG) and mesangial matrix accumulation (6.32+/-1.79%, P<0.05 vs. db/db-IgG). Our results demonstrate that inhibiting renal TGF-beta activity can partially reverse the GBM thickening and mesangial matrix expansion in this mouse model of type 2 diabetes. Anti-TGF-beta regimens would be useful in the treatment of diabetic nephropathy.     

Mitochondrial glutathione protects against cell death induced by oxidative and nitrative stress in astrocytes

The major cellular antioxidant, glutathione, is mostly localized in the cytosol but a small portion is found in mitochondria. We have recently shown that highly selective depletion of mitochondrial glutathione in astrocytes in culture markedly increased cell death induced by the peroxynitrite donor, 3-morpholino-syndnonimine. The present study was aimed at characterizing the increase in susceptibility arising from mitochondrial glutathione loss and testing the possibility that elevating this metabolite pool above normal values could be protective. The increased vulnerability of astrocytes with depleted mitochondrial glutathione to Sin-1 was confirmed. Furthermore, these cells showed marked increases in sensitivity to hydrogen peroxide and also to high concentrations of the nitric oxide donor, S-nitroso-N-acetyl-penicillamine. The increase in cell death was mostly due to necrosis as indicated by substantially increased release of lactate dehydrogenase and staining of nuclei with propidium iodide but little change in annexin V staining and caspase 3 activation. The enhanced cell loss was blocked by prior restoration of the mitochondrial glutathione content. It was also essentially fully inhibited by treatment with cyclosporin A, consistent with a role for the mitochondrial permeability transition in the development of cell death. Susceptibility to the classical apoptosis inducer, staurosporine, was only affected to a small extent in contrast to the response to the other substances tested. Incubation of normal astrocytes with glutathione monoethylester produced large and long-lasting increases in mitochondrial glutathione content with much smaller effects on the cytosolic glutathione pool. This treatment reduced cell death on exposure to 3-morpholino-syndnonimine or hydrogen peroxide but not S-nitroso-N-acetyl-pencillamine or staurosporine. These findings provide evidence for an important role for mitochondrial glutathione in preserving cell viability during periods of oxidative or nitrative stress and indicate that increases in this glutathione pool can confer protection against some of these stressors.     

Quantitative proteomics study of protective effects of grape seed procyanidin B2 on diabetic cardiomyopathy in db/db mice

Diabetic cardiomyopathy is one of the major complications of diabetes mellitus. Oxidative stress appears to play a substantial role in cardiomyopathy. Grape seed procyanidin B2 (GSPB2) has been known as an anti-oxidant in treating diabetes mellitus; however, little is known about its effects and underlying mechanisms on diabetic cardiomyopathy. The present study is to explore the molecular targets of GSPB2 responsible for the anti-oxidative effects in db/db mice by quantitative proteomics. GSPB2 (30?mg/kg body weight/day) were intragastric administrated to db/db mice for 10?weeks. Proteomics of the heart tissue extracts by isobaric tags for relative and absolute quantification analysis was obtained from db/db mice. Our study provides important evidence that GSPB2 protect against cardiomyopathy in diabetes mellitus, which are believed to result from regulating the expression of key proteins involving cardiac fibrosis and proliferation. GSPB2 could be expected to become novel clinical application in fighting against diabetic cardiomyopathy.     

Biochanin-A alleviates fibrosis and inflammation in cardiac injury in mice

Biochanin-A (BCA), is an isoflavonoid, exhibits protective effects against various diseases. This study was conducted to observe the effect of BCA on isoprenaline (ISP)-induced cardiac fibrosis and explore the underlying mechanism. The curative effect of BCA was investigated with oral administration for 14 days in ISP-induced cardiac fibrosis in mice. The fibrotic biomarkers, like collagen I and III, were estimated by ELISA. Commercial kits were used to estimate cholesterol, triglycerides, and creatine kinase-myocardial band (CK-MB) levels. The messenger ribonucleic acid (mRNA) expression studies were performed by quantitative real-time polymerase chain reaction. Gelatin zymography was used to study the expression of matrix metalloproteinases-2 (MMP-2). BCA co-administration significantly improved the morphometric parameters; including heart weight, heart weight to body weight, heart weight to tibial length, and lipid profile. BCA treatment showed a reduction in inflammatory cells and collagen deposition as depicted in the histopathology of heart tissues. The enhanced levels of collagen-I, III, and hydroxyproline were significantly decreased by BCA co-treatment, whereas CK-MB level was reduced slightly. BCA co-administration increased the activity of reduced glutathione enzyme, showing the antioxidative effects of BCA. BCA treatment significantly reduced interleukin-6 (Il6) inflammatory cytokine along with partially decreased mRNA expression of fibrotic signaling markers such as natriuretic peptide type B (Nppb), α-smooth muscle actin (Acta2), connective tissue growth factor (Ctgf), transforming growth factor β (Tgfb), small mothers against decapentaplegic homolog-3 (Smad-3). However, BCA did not modify Mmp-2 expression, which was significantly increased by ISP. In conclusion, BCA exerts an antifibrotic effect by modulating lipid profile, enhancing antioxidant enzyme, and reducing collagen content and inflammation.     

Maternal voluntary exercise mitigates oxidative stress and incidence of congenital heart defects in pre‐gestational diabetes

Women with pre‐gestational diabetes have a higher risk of producing children with congenital heart defects (CHDs), caused predominantly by hyperglycemia‐induced oxidative stress. In this study, we evaluated if exercise during pregnancy could mitigate oxidative stress and reduce the incidence of CHDs in the offspring of diabetic mice. Female mice were treated with streptozotocin to induce pre‐gestational diabetes, then mated with healthy males to produce offspring. They were also given access to running wheels 1 week before mating and allowed to exercise voluntarily until E18.5. Heart morphology, gene expression, and oxidative stress were assessed in foetal hearts. Maternal voluntary exercise results in a significantly lower incidence of CHDs from 59.5% to 25%. Additionally, diabetes‐induced defects in coronary artery and capillary morphogenesis were also lower with exercise. Myocardial cell proliferation and epithelial‐mesenchymal transition at E12.5 was significantly lower with pre‐gestational diabetes which was mitigated with maternal exercise. Cardiac gene expression of Notch1, Snail1, Gata4 and Cyclin D1 was significantly higher in the embryos of diabetic mice that exercised compared to the non‐exercised group. Furthermore, maternal exercise produced lower reactive oxygen species (ROS) and oxidative stress in the foetal heart. In conclusion, maternal exercise mitigates ROS and oxidative damage in the foetal heart, and results in a lower incidence of CHDs in the offspring of pre‐gestational diabetes. Exercise may be an effective intervention to compliment clinical management and further minimize CHD risk in mothers with diabetes.     

Effects of aerobic and resistance exercise on cardiac remodelling and skeletal muscle oxidative stress of infarcted rats

We compared the influence of aerobic and resistance exercise on cardiac remodelling, physical capacity and skeletal muscle oxidative stress in rats with MI‐induced heart failure. Three months after MI induction, Wistar rats were divided into four groups: Sham; sedentary MI (S‐MI); aerobic exercised MI (A‐MI); and resistance exercised MI (R‐MI). Exercised rats trained three times a week for 12 weeks on a treadmill or ladder. Statistical analysis was performed by ANOVA or Kruskal‐Wallis test. Functional aerobic capacity was greater in A‐MI and strength gain higher in R‐MI. Echocardiographic parameters did not differ between infarct groups. Reactive oxygen species production, evaluated by fluorescence, was higher in S‐MI than Sham, and lipid hydroperoxide concentration was lower in A‐MI than the other groups. Glutathione peroxidase activity was higher in A‐MI than S‐MI and R‐MI. Superoxide dismutase was lower in S‐MI than Sham and R‐MI. Gastrocnemius cross‐sectional area, satellite cell activation and expression of the ubiquitin‐proteasome system proteins did not differ between groups. In conclusion, aerobic exercise and resistance exercise improve functional capacity and maximum load carrying, respectively, without changing cardiac remodelling in infarcted rats. In the gastrocnemius, infarction increases oxidative stress and changes antioxidant enzyme activities. Aerobic exercise reduces oxidative stress and attenuates superoxide dismutase and glutathione peroxidase changes.     

Up-regulation of P-glycoprotein expression by glutathione depletion-induced oxidative stress in rat brain microvessel endothelial cells

Glutathione (GSH) depletion has been implicated in the pathogenesis of neurological diseases. During GSH depletion, cells of the blood-brain barrier (BBB) are subjected to chronic oxidative stress. In this study, we investigated the effect of such stress, produced with the GSH synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO), on expression of P-glycoprotein (Pgp) in primary cultured rat brain microvessel endothelial cells that comprise the blood-brain barrier (BBB). Application of BSO to cell monolayers at concentrations up to 800 microm caused increases in expression of Pgp. Concentrations >or= 400 microm BSO decreased cell viability. Application of 200 microm BSO caused a significant increase in Pgp function activity, as assessed by rhodamine 123 (Rh123) accumulation experiments. At this concentration, BSO produced time-dependent decreases in levels of intracellular GSH and increases in levels of intracellular reactive oxygen species (iROS). The increases were also observed within 48 h following BSO treatment in mdr1a and mdr1b mRNA. Exposure of cells to BSO for 24 h produced maximal effects in the accumulation of iROS, and in expression and function of Pgp. The ROS scavenger N-acetylcysteine prevented ROS generation and attenuated the changes of both expression and activity of Pgp induced by BSO. Therefore, the transport of Pgp substrates may be affected by changing Pgp expression under conditions of chronic oxidative stress induced by GSH depletion.     

Tributyltin induces oxidative stress and neuronal injury by inhibiting glutathione S-transferase in rat organotypic hippocampal slice cultures

Tributyltin (TBT) has been used as a heat stabilizer, agricultural pesticide and antifouling agents on ships, boats and fish-farming nets; however, the neurotoxicity of TBT has recently become a concern. TBT is suggested to stimulate the generation of reactive oxygen species (ROS) inside cells. The aim of this study was to determine the mechanism of neuronal oxidative injury induced by TBT using rat organotypic hippocampal slice cultures. The treatment of rat hippocampal slices with TBT induced ROS production, lipid peroxidation and cell death. Pretreatment with antioxidants such as superoxide dismutase, catalase or trolox, suppressed the above phenomena induced by TBT, indicating that TBT elicits oxidative stress in hippocampal slices, which causes neuronal cell death. TBT dose-dependently inhibited glutathione S-transferase (GST), but not glutathione peroxidase or glutathione reductase in the cytosol of rat hippocampus. The treatment of hippocampal slices with TBT decreased the GST activity. Pretreatment with reduced glutathione attenuated the reduction of GST activity and cell death induced by TBT, indicating that the decrease in GST activity by TBT is involved in hippocampal cell death. When hippocampal slices were treated with sulforaphane, the expression and activity of GST were increased. Notably, TBT-induced oxidative stress and cell death were significantly suppressed by pretreatment with sulforaphane. These results indicate that GST inhibition could contribute, at least in part, to the neuronal cell death induced by TBT in hippocampal slices. This study is the first report to show the link between neuronal oxidative injury and the GST inhibition elicited by TBT.     

Foc4 2个谷胱甘肽S-转移酶基因的克隆、鉴定及其在外源氧化胁迫下的表达

为鉴定香蕉枯萎病菌(尖孢镰刀菌古巴专化型4号生理小种,Fusarium oxysporum f.sp.cubense race 4,Foc4)中的2个假想谷胱甘肽S转移酶(GSTs),采用RT-PCR方法克隆了这2个GSTs基因cDNA编码序列,随后分别将2个基因定名为Fogst1和Fogst2。其中,Fogst1的开放阅读框长609 bp,编码202个氨基酸残基,Fogst2的开放阅读框长693 bp,编码230个氨基酸残基。进化树分析表明:Fogst1属于GSTs超家族的sigma(σ)亚型成员,Fogst2属于GSTs超家族中目前未知的亚家族成员。为了验证Fogst1和Fogst2的表达,分别构建了Fogst1和Fogst2的原核表达重组载体pET28a-Fogst1和pET28a-Fogst2,并将pET28a-Fogst1和pET28a-Fogst2转化到大肠杆菌表达菌株BL21,经IPTG诱导后获得以可溶形式表达的重组蛋白Fogst1和Fogst2。GSTs活性分析表明,以CDNB为底物检测,2个重组蛋白均具有GSTs酶活性。分别取外源氧化胁迫处理后1、5、12、24 h菌丝样品进行相对荧光定量PCR分析,结果表明:Fogst1和Fogst2在前5 h表达量均大幅上调,表达量随后下调并恢复正常水平。这些结果均暗示Fogst1和Fogst2可能参与了Foc4抗外源氧化胁迫过程。     

Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress

Long-term poorly controlled myocardial hypertrophy often leads to heart failure and sudden death. Activation of ras-related C3 botulinum toxin substrate 1 (RAC1) by angiotensin II (Ang II) plays a pivotal role in myocardial hypertrophy. Previous studies have demonstrated that scoparone (SCO) has beneficial effects on hypertension and extracellular matrix remodelling. However, the function of SCO on Ang II-mediated myocardial hypertrophy remains unknown. In our study, a mouse model of myocardial hypertrophy was established by Ang II infusion (2 mg/kg/day) for 4 weeks, and SCO (60 mg/kg bodyweight) was administered by gavage daily. In vitro experiments were also performed. Our results showed that SCO could alleviate Ang II infusion-induced cardiac hypertrophy and fibrosis in mice. In vitro, SCO treatment blocks Ang II-induced cardiomyocyte hypertrophy, cardiac fibroblast collagen synthesis and differentiation to myofibroblasts. Meanwhile, we found that SCO treatment blocked Ang II-induced oxidative stress in cardiomyocytes and cardiac fibroblasts by inhibiting RAC1-GTP and total RAC1 in vivo and in vitro. Furthermore, reactive oxygen species (ROS) burst by overexpression of RAC1 completely abolished SCO-mediated protection in cardiomyocytes and cardiac fibroblasts in vitro. In conclusion, SCO, an antioxidant, may attenuate Ang II-induced myocardial hypertrophy by suppressing of RAC1 mediated oxidative stress.     

Modulation of adriamycin-induced changes in serum free fatty acids,albumin and cardiac oxidative stress

Adriamycin-induced cardiomyopathic changes are prevented by combination therapy with probucol. These beneficial effects are suggested to be due to a combination of antioxidant as well as lipid-lowering effects of probucol. In the present study, we compared the effects of probucol (PROB) with that of lovastatin (LOV), a lipid-lowering drug, and trolox (TRO), an antioxidant, on adriamycin (ADR)-induced subchronic in vivo changes in serum free fatty acids (FFA), serum albumin and myocardial reduced (GSH) and oxidized (GSSG) glutathione in rats. ADR caused a significant increase in FFA, decrease in albumin, and an increase in FFA/albumin. PROB and LOV modulated the increases in FFA and FFA/albumin, while TRO was without any effect. ADR reduced myocardial GSH, increased GSSG and decreased GSH/GSSG. Only PROB caused significant improvement in GSH and normalized GSSG levels. It is suggested that these modulatory effects of probucol may also contribute in the beneficial effects of this drug against adriamycininduced cardiomyopathy and congestive heart failure.     

Anti-diabetic properties of genistein-chromium (III) complex in db/db diabetic mice and its sub-acute toxicity evaluation in normal mice

BackgroundIn this study, chromium (III) complex was synthesized from genistein (GEN) which had good hypoglycemic activity and inorganic chromium (III) element, and its hypoglycemic activity and sub-acute toxicity were studied.MethodsThe genistein-chromium (III) complex was synthesized by chelating chromium with genistein in ethanol and its structure was determined by LC–MS, atomic absorption spectroscopy, UV–vis spectroscopy, infrared spectroscopy, elemental and thermodynamic analysis. The anti-diabetic activity of the complex was assessed in db/db mice and C57 mice by daily oral gavage for 4 weeks. The sub-acute toxicity test was carried out on KM mice with this complex.ResultsThe molecular structure of this complex was inferred as a complex [CrGEN₃] formed by three ligands and one chromium element. The complex could significantly improve the body weight of db/db mice, fasting blood glucose, random blood glucose, organ index, glycogen levels and the performance of OGTT (Oral Glucose Tolerance Test) and ITT (Insulin Tolerance Test) in db/db mice (p < 0.05). The morphology of liver, kidney, pancreas and skeletal muscle also had obviously improvement and repairment. Effects on serum indices and antioxidant enzymes activities of db/db mice showed that the serum profiles and antioxidant ability of complex group had significant improvement compared with the diabetic control group (p < 0.05 or p < 0.01), and some indices even returned to normal levels. In addition, this complex did not produce any hazardous symptoms or deaths in sub-acute toxicity test. High dose of [CrGEN₃] had no significant influence on serum indices and antioxidant capacity in normal mice, and the organ tissues maintained organized and integrity in the sub-acute toxicity study.ConclusionThe study of the genistein-chromium (III) complex showed that the complex had good hypoglycemic activity in vivo, and did not have the potential toxicity. These results would provide an important reference for the development of functional hypoglycemic foods or pharmaceuticals.     

Inflammation,oxidative stress,and cardiovascular disease risk factors in adults with cystic fibrosis

Cystic fibrosis (CF) represents one of a number of localized lung and non-lung diseases with an intense chronic inflammatory component associated with evidence of systemic oxidative stress. Many of these chronic inflammatory diseases are accompanied by an array of atherosclerotic processes and cardiovascular disease (CVD), another condition strongly related to inflammation and oxidative stress. As a consequence of a dramatic increase in long-lived patients with CF in recent decades, the specter of CVD must be considered in these patients who are now reaching middle age and beyond. Buttressed by recent data documenting that CF patients exhibit evidence of endothelial dysfunction, a recognized precursor of atherosclerosis and CVD, the spectrum of risk factors for CVD in CF is reviewed here. Epidemiological data further characterizing the presence and extent of atherogenic processes in CF patients would seem important to obtain. Such studies should further inform and offer mechanistic insights into how other chronic inflammatory diseases potentiate the processes leading to CVDs.     

Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis,fibrosis, and oxidative stress in high-fat diet-fed mice

Obesity is associated with chronic diseases such as fatty liver, type 2 diabetes, cardiovascular disease, and severe metabolic syndrome. Obesity causes metabolic impairment including excessive lipid accumulation and fibrosis in the hepatic tissue as well as the increase in oxidative stress. In order to investigate the effect of mulberry leaf (Morus alba L.) extract (MLE) on obesity-induced oxidative stress, lipogenesis, and fibrosis in liver, MLE has been gavaged for 12 weeks in high-fat diet (HFD)-induced obese mice. MLE treatment significantly ameliorated LXRα-mediated lipogenesis and hepatic fibrosis markers such as α-smooth muscle actin, while MLE up-regulated lipolysis-associated markers such as lipoprotein lipase in the HFD-fed mice. Moreover, MLE normalized the activities of antioxidant enzymes including heme oxygenase-1 and glutathione peroxidase in accordance with protein levels of 4-hydroxynonenal in the HFD-fed mice. MLE has beneficial effects on obesity-related fatty liver disease by regulation of hepatic lipid metabolism, fibrosis, and antioxidant defense system. MLE supplementation might be a potential therapeutic approach for obesity-related disease including non-alcoholic fatty liver disease.