Renoprotective effect of Caralluma fimbriata against high-fat diet-induced oxidative stress in Wistar rats

The current study was designed to evaluate the renoprotective effect of hydro-alcoholic extract of Caralluma fimbriata (CFE) against high-fat diet-induced oxidative stress in Wistar rats. Male Wistar rats were randomly divided into five groups: control (C), control treated with CFE (C + CFE), high-fat diet fed (HFD), high-fat diet fed treated with CFE (HFD + CFE), and high-fat diet fed treated with metformin (HFD + metformin). CFE was orally administered (200 mg/kg body weight) to Groups C + CFE and HFD + CFE rats for 90 days. Renal functional markers such as, urea, uric acid, and creatinine levels in plasma were quantified during the experimental period. At the end of the experimental period, activities of transaminases and oxidative stress markers, i.e., reduced glutathione (GSH), lipid peroxidation, protein oxidation, and activities of antioxidant enzymes were assayed in renal tissue. Coadministration of CFE along with HF-diet in Group HFD + CFE prevented the rise in the levels of plasma urea, uric acid, and creatinine, and elevated activities of renal transaminases with decreased protein content of Group HFD (p < 0.05). Establishment of oxidative stress in Group HFD, as evident from elevated lipid peroxidation, protein oxidation levels with depleted levels of GSH, and decreased activities of GSH dependent and independent antioxidant enzymes, was prevented in Groups HFD + CFE and HFD + metformin rats. Further, there were no deviations in the studied parameters but there was improved antioxidant status of Group C + CFE from Group C which revealed the nontoxic nature of CFE even under chronic treatment. Thus, CFE treatment effectively alleviated the HF-diet induced renal damage. Hence, this plant could be used as an adjuvant therapy for the prevention and/or management of HF-diet induced renal damage.     

Thymol reduces oxidative stress,aortic intimal thickening,and inflammation-related gene expression in hyperlipidemic rabbits

Atherosclerosis plays a key role in the development of cardiovascular diseases, and is often associated with oxidative stress and local inflammation. Thymol, a major polyphenolic compound in thyme, exhibits antioxidant and anti-inflammatory properties. In this study, we measured the in vitro antioxidant activity of thymol, and investigated the effect of thymol on high-fat-diet-induced hyperlipidemia and atherosclerosis. New Zealand white rabbits were fed with regular chow, high-fat and high-cholesterol diet (HC), T3, or T6 (HC with thymol supplementation at 3 mg/kg/d or 6 mg/kg/d, respectively) for 8 weeks. Aortic intimal thickening, serum lipid parameters, multiple inflammatory markers, proinflammatory cytokines, and atherosclerosis-associated indicators were significantly increased in the HC group but decreased upon thymol supplementation. In summary, thymol exhibits antioxidant activity, and may suppress the progression of high-fat-diet-induced hyperlipidemia and atherosclerosis by reducing aortic intimal lipid lesion, lowering serum lipids and oxidative stress, and alleviating inflammation-related responses.     

Oral administration of alkaloid fraction from Ruta graveolens inhibits oxidative stress and inflammation in hypercholesterolemic rabbits

Abstract

Context: The anti-atherogenic effect of alkaloid fraction from Ruta graveolens Linn (Rutaceae) extract is suspected to be related to its activities of antioxidation and anti-inflammation.

Objective: This study investigated the efficacy of alkaloid fraction isolated from Ruta graveolens (AFR) in reducing oxidative damage and inflammation in hypercholesteremic rabbits.

Materials and methods: The New Zealand white rabbits were randomly divided into three groups: Group I rabbits were fed with normal chow diet for 90?d. Group II rabbits were fed with 1% cholesterol-enriched diet. Group III rabbits were fed with 1% cholesterol-enriched diet together with AFR (10?mg/kg/daily for 90?d).

Results and discussion: The results showed that on treatment with AFR significantly lowered the level of total cholesterol and LDL-C and showed an increment in the level of HDL-C. LD₅₀ of the AFR in rats is greater than 525?mg/kg. Activities of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase and GSH level were decreased in cholesterol-fed rabbit and supplementation of AFR significantly enhanced the activities of these antioxidant enzymes and GSH level. Increased activities of enzymes such as cyclooxygenase-2, 15-lipoxygenase and myeloperoxidase were significantly suppressed by AFR administration. The acute phase proteins, total WBC count and TBARS concentrations were significantly increased by hypercholesteromic diet, which were significantly decreased by AFR treatment. Histopathological studies of aorta in cholesterol-fed rabbit showed plaque formation and significant changes in aortic wall. Administration of AFR showed no changes in aortic wall.

Conclusion: AFR reduces oxidative stress and inflammation and reduces the aortic pathology in hypercholesteromic rabbits.     

茶多酚对实验性动脉粥样硬化兔的血脂及炎症因子的影响

目的：探讨茶多酚（rrP）对实验性动脉粥样硬化兔的血脂、抗氧化系统及炎症因子的影响。方法：通过喂养高脂饲料建立兔的动脉粥样硬化模型,同时连续i．g．给予茶多酚（100mg·kg-1·d-1）或空白溶媒12周,测定兔血浆中TC、TG、高密度脂蛋白胆固醇（HDL．C）、低密度脂蛋白胆固醇（LDL—C）、NO、C反应蛋白（CRP）、IL-6、TNF-α含量及超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH—PX）活力,并观察主动脉病理学形态改变。结果：给予茶多酚可有效减小高脂饲料引起的兔动脉粥样硬化斑块面积,同时降低高脂血症兔血浆TG、TC、LDL．C含量（P〈0．01）,增加HDL-C含量（P〈0．01）及SOD和GsH—P）（活力．而且可引起NO、CRP、IL-6、TNF-α含量下降（P〈0．01）。结论：茶多酚可以通过降低动脉粥样硬化兔血脂水平、防止脂质过氧化及抑制炎性因子的产生,从而起到抗动脉粥样硬化的作用。     

Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins

Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called "pleiotropic". The cholesterol-independent or "pleiotropic" effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.     

头孢曲松治疗小儿支气管肺炎疗效观察及对患儿血清炎性因子水平的影响

目的 探讨头孢曲松治疗小儿支气管肺炎疗效及对患儿血清炎性因子水平的影响.方法 将85例小儿支气管肺炎患儿按照随机数字表分为观察组43例以及对照组42例,两组患儿均采用氨溴索治疗,对照组在此基础上联合应用青霉素（20万u/kg,2次/d）,观察组在此基础上采用头孢曲松（20 mg/kg,1次/d）治疗,7d为1个疗程.对比分析两组患儿临床疗效、症状缓解时间及治疗前、治疗后1d、3d、5d、7d超敏C反应蛋白（CRP）、白细胞介素-6（IL-6）及肿瘤坏死因子-α（TNF-α）水平.结果 观察组总有效率为96.97％,对照组为75.00％,两组总有效率差异有统计学意义（x2=5.236,P=0.000.）.观察组治疗后各症状评分显著低于对照组,差异有统计学意义（t =3.425、3.622、3.712、3.812,均P＜0.05）.观察组治疗后3dCRP（4.28±1.07） mmol/L、IL-6（7.21±2.07） mmol/L、TNF-α（15.36±3.78） mmol/L水平显著低于治疗前及对照组同一时间（7.63±1.28） mmol/L、（12.31±2.42） mmol/L、（22.12±7.55）mmol/L,而对照组治疗5d后CRP、IL-6、TNF-α水平低于治疗前,差异有统计学意义（P＜0.05）.结论 头孢曲松能有效缓解小儿肺炎症状,快速降低炎性因子水平,提高患儿临床治疗效果.     

Obesity-induced testicular oxidative stress,inflammation and apoptosis: Protective and therapeutic effects of orlistat

Obesity has been reported to induce oxidative stress, inflammation and apoptosis in the testis. The objective of this study was to determine the effects of the anti-obesity drug orlistat, on testicular oxidative stress, inflammation and apoptosis in high-fat diet (HFD)-fed rats. Twenty-four adult male Sprague Dawley rats weighing 250−300 g were randomized into four groups (n = 6/group), namely; normal control (NC), high-fat diet (HFD), HFD plus orlistat (10 mg/kg body weight/day administered concurrently for 12 weeks) (HFD + Opr) and HFD plus orlistat (10 mg/kg body weight/day administered 6 weeks after induction of obesity) (HFD + Ot) groups. Antioxidant enzymes activities were significantly decreased, while mRNA levels of pro-apoptotic markers (p53, Bax/BCl-2, caspase-9, caspase-8 and caspase-3) were significantly increased in the testis of HFD group relative to NC group. Furthermore, the mRNA levels of pro-inflammatory markers (nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis factor alpha and interleukin (IL)-1β increased significantly, while anti-inflammatory marker (IL-10) decreased significantly in the testis of the HFD group relative to NC group. However, in both models of orlistat intervention (protective and treatment models) up-regulated antioxidant enzymes, down-regulated inflammation and apoptosis were observed in the testis of HFD-fed rats. Orlistat ameliorated testicular dysfunction by attenuating oxidative stress, inflammation and apoptosis in HFD-fed rats, suggesting its potential protective and therapeutic effects in the testis compromised by obesity.     

Meloxicam inhibits fipronil‐induced apoptosis via modulation of the oxidative stress and inflammatory response in SH‐SY5Y cells

Oxidative stress and inflammatory responses have been identified as key elements of neuronal cell apoptosis. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in human neuroblastoma SH‐SY5Y cells treated with fipronil (FPN). Based on the cytotoxic mechanism of FPN, we examined the neuroprotective effects of meloxicam against FPN‐induced neuronal cell death. Treatment of SH‐SY5Y cells with FPN induced apoptosis via activation of caspase‐9 and ‐3, leading to nuclear condensation. In addition, FPN induced oxidative stress and increased expression of cyclooxygenase‐2 (COX‐2) and tumor necrosis factor‐α (TNF‐α) via inflammatory stimulation. Pretreatment of cells with meloxicam enhanced the viability of FPN‐exposed cells through attenuation of oxidative stress and inflammatory response. FPN activated mitogen activated protein kinase (MAPK) and inhibitors of MAPK abolished FPN‐induced COX‐2 expression. Meloxicam also attenuated FPN‐induced cell death by reducing MAPK‐mediated pro‐inflammatory factors. Furthermore, we observed both nuclear accumulation of p53 and enhanced levels of cytosolic p53 in a concentration‐dependent manner after FPN treatment. Pretreatment of cells with meloxicam blocked the translocation of p53 from the cytosol to the nucleus. Together, these data suggest that meloxicam may exert anti‐apoptotic effects against FPN‐induced cytotoxicity by both attenuating oxidative stress and inhibiting the inflammatory cascade via inactivation of MAPK and p53 signaling. Copyright © 2015 John Wiley & Sons, Ltd.     

Transient oxidative stress and inflammation after intraperitoneal administration of multiwalled carbon nanotubes functionalized with single strand DNA in rats

Multi-walled carbon nanotubes (MWCNTs) are widely used for nanotechnology. Their impact on living organisms is, however, not entirely clarified. Oxidative stress and inflammation seem to be the key mechanisms involved in MWCNTs' cytotoxicity. Until present, pulmonary and skin models were the main tested experimental designs to assess carbon nanotubes' toxicity. The systemic administration of MWCNTs is essential, with respect for future medical applications. Our research is performed on Wistar rats and is focused on the dynamics of oxidative stress parameters in blood and liver and pro-inflammatory cytokines in liver, after single dose (270 mg l^− 1) ip administration of MWCNTs (exterior diameter 15-25 nm, interior diameter 10-15 nm, surface 88 m² g^− 1) functionalized with single strand DNA (ss-DNA). The presence of MWCNTs in blood was assessed by Raman spectroscopy, while in liver histological examination and confocal microscopy were used. It was found that ss-DNA-MWCNTs induce oxidative stress in plasma and liver, with the return of the tested parameters to normal values, 6 h after ip injection of nanotubes, with the exception of reduced glutathione in plasma. The inflammatory cytokines (TNF-α, IL-1β) had a similar pattern of evolution. We also assessed the level of ERK1/2 and the phosphorylation of p65 subunit of NF-kB in liver that had a transient increase and returned to normal at the end of the tested period. Our results demonstrate that ss-DNA-MWCNTs produce oxidative stress and inflammation, but with a transient pattern. Given the fact that antioxidants modify the profile not only for oxidative stress, but also of inflammation, the dynamics of these alterations may be of practical importance for future protective strategies.     

Effect of fruit vinegars on liver damage and oxidative stress in high-fat-fed rats

Context: Vinegar has long been used as a condiment and a traditional medicine worldwide.

Objective: The current study investigates the antioxidant effect of three types of fruit vinegars (FV) namely pomegranate [Punica granatum L. (Punicaceae)], prickly pear [Opuntia ficus-indica (L.) Mill. (Cactaceae)], and apple [Malus domestica Borkh. (Rosaceae)] vinegars in high-fat diet (HFD)-induced hyperlipidemic Wistar rats.

Materials and methods: Fifty male Wistar rats were divided into five groups; HFD (80?cal/d) fed rats were orally dosed with fruit vinegars (7?ml/kg) once daily for 28?weeks. At the end of the experiment, lipid profile, lipid peroxidation products, antioxidant enzymes, and trace elements were assessed in serum. In addition, a liver histopathological study was performed.

Results: HFD showed a significant increase (p?≤?0.05) in lipid profile and TBARS levels when compared with normal control. Daily oral administration of FV normalized various biochemical, metabolic, and histopathological changes. However, pomegranate vinegar exhibited a very significant (p?≤?0.001) reduction in lipid profile levels (total cholesterol: 165%, triglycerides: 68%, LDL-c: 76%, and atherogenic index: 80%), whereas an increase in antioxidant status (SOD: 7-fold, GPx: 4.81-fold, GRx: 1.66-fold, and TAS: 3.45-fold) when compared with hyperlipidemic control. Histopathological examinations also confirmed the protective effects of pomegranate vinegar against lipid accumulation and the improvement of hepatic lesions.

Discussion and conclusion: The fruit vinegars regulate lipid metabolism and decrease liver damage in high-fat fed rats as shown in this study.     

熊果酸对动脉粥样硬化大鼠氧化应激和炎性反应的影响

目的 研究熊果酸(UA)对动脉粥样硬化(AS)大鼠氧化应激和炎性反应的抑制作用,并探讨其机制.方法 采用高脂饲料喂养结合腹腔注射VD3的方法建立早期AS大鼠模型,并分别灌胃给予UA(10、20、40 mg· kg-1· d-1)和辛伐他汀(SV, 1.8 mg· kg-1· d-1)进行干预,作为干预组,另设模型组和健康对照组(喂食正常饲料并腹腔注射生理盐水).采用比色法测定血清中抗氧化酶[超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、过氧化氢酶(CAT)]活性和丙二醛(MDA)、活性氧簇(ROS)含量;酶联免疫法(ELISA)测定血浆中炎性细胞因子[C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)]含量;苏木精-尹红(HE)染色观察主动脉形态结构改变并进行病变分级.结果 UA(20、40 mg· kg -1· d-1)同步干预组大鼠血清中 SOD、CAT 活性较模型组显著升高[(318.3 ±29.4)、(12.3 ±2.4)U· mL-1vs(249.3 ±25.1)、(9.3 ±1.7)U· mL-1],MDA、ROS含量显著降低[(31.2 ±5.1)vs(49.6 ±7.0) mmol· L-1和(291.3 ±31.8)vs(402.9 ±35.7)U· mL-1],且UA 40 mg· kg -1· d-1干预组GSH-Px活性显著升高[(809.3 ± 58.4)vs(676.1 ±48.5)U· mL-1];UA(20、40 mg· kg-1· d-1)同步干预组大鼠血浆中CRP、TNF-α、IL-1β、IL-6含量较模型组均显著降低,且UA 40 mg· kg-1· d-1干预组IL-10含量显著升高[(37.6 ±4.9)vs(23.9 ±3.2)ng· L-1];UA同步干预组大鼠主动脉形态结构改变较模型组明显改善、病变评分显著降低,其中以UA 40 mg· kg-1· d-1干预组效果最为显著.结论UA可能通过抑制氧化应激损伤和炎性反应而对AS大鼠起到一定保护作用.     

白芍总苷对动脉粥样硬化大鼠氧化应激和炎症反应的抑制作用

目的研究白芍总苷(Total glucosides of paeony,TGP)对动脉粥样硬化大鼠氧化应激和炎症反应的抑制作用及其机制。方法应用高脂饲料喂养结合腹腔注射维生素D3建立大鼠动脉粥样硬化(AS)模型,造模过程分别同步灌胃给予TGP 50、100、200 mg/(kg·d)和辛伐他汀(SV)1.8 mg/(kg·d),共12周,并设模型组和正常对照组。采用HE染色法观察主动脉形态结构改变并进行病变分级;比色法测定血清中抗氧化酶活性和丙二醛(MDA)、活性氧簇(ROS)含量;酶联免疫法测定血浆中炎症细胞因子含量。结果与模型组比较,TGP干预组大鼠主动脉病理性形态结构改变呈不同程度改善,其中以TGP 200 mg/(kg·d)组最为显著。TGP 100、200 mg/(kg·d)组病变分级显著降低,血清中抗氧化酶[超氧化物歧化酶(SOD)、过氧化氢酶(CAT)]活性显著升高,MDA、ROS含量均降低。其中,TGP 200 mg/(kg·d)组谷胱甘肽过氧化物酶(GSH-Px)活性升高,TGP 100、200 mg/(kg·d)组大鼠血浆中C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)、IL-6含量降低,且TGP200 mg/(kg·d)组炎症细胞因子(IL-10)含量升高,差异均有统计学意义(P<0.05,P<0.01)。结论 TGP能够通过抑制氧化应激和炎症反应而对动脉粥样硬化表现出一定的保护作用。     

Hypotensive effect of atorvastatin is not related to changes in inflammation and oxidative stress

We sought to determine if atorvastatin lowers blood pressure in patients with previously diagnosed and well-controlled essential arterial hypertension and if this effect could be related to anti-inflammatory and anti-oxidative effects. Among 92 patients with essential arterial hypertension, we studied 56 non-smoking and normolipemic: 39 were randomized to receive 80 mg atorvastatin daily for 3 months (statin-treated patients, ST), and the rest continued a previous hypotensive therapy (statin-free patients, SF). Blood pressure was measured using a 24-h ambulatory blood pressure measurement device. Serum levels of high-sensitivity C-reactive protein (hs-CRP), total antioxidant status (TAS) and plasma peroxides (assessed by Oxystat) were measured in both groups. The mean change in systolic BP (SBP) for atorvastatin was -5.7 mmHg (95% confidence interval CI, -4.1 to -7.2 mmHg), and the mean change in diastolic BP (DBP) was -3.9 mmHg (95% CI, -2.7 to -5.0 mmHg). No change in BP in SF patients was observed. In the ST group, hs-CRP and peroxides did not significantly decrease. In the SF group, concentrations of hs-CRP proceeded to decrease while peroxides increased. In the ST group, changes in hs-CRP correlated with changes in total cholesterol and low-density lipoprotein cholesterol (r = 0.41, p = 0.013 and r = 0.35, p = 0.04, respectively) but did not correlate with changes in BP. The hypotensive statin effect was independent of the hypolipemic effect. During three months of observation, TAS concentrations in both groups remained stable. In this randomized study, additionally administered atorvastatin to non-smoking and normolipemic patients with well-controlled essential arterial hypertension resulted in reduction of BP. This effect was not followed by significant changes in hs-CRP, TAS or Oxystat concentrations. The hypotensive effect of atorvastatin did not depend on anti-inflammatory, anti-oxidative or hypolipemic actions.     

Daphnetin inhibits high glucose-induced extracellular matrix accumulation,oxidative stress and inflammation in human glomerular mesangial cells

Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease (ESRD). Oxidative stress and inflammation have been documented to play important roles in the pathogenesis of DN. Daphnetin, a natural coumarin compound, possesses antioxidant and anti-inflammatory activities. However, the role of daphnetin in DN has not yet been investigated. The aim of the present study was to explore the function of daphnetin in DN and the underlying mechanism in vitro. Our results demonstrated that daphnetin alleviated cell proliferation induced by high glucose (HG) in human mesangial cells (MCs). Daphnetin strikingly reduced reactive oxygen species (ROS) and malonaldehyde (MDA) levels, and induced the superoxide dismutase (SOD) activity in HG-stimulated MCs. Besides, the production of TNF-α, IL-1β, IL-6, fibronectin (FN) and collagen IV (Col IV) was also inhibited by daphnetin in HG-stimulated MCs. In addition, daphnetin enhanced the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) and inhibited the levels of p-Akt and p-p65 in HG-stimulated MCs. The results indicated that daphnetin inhibited HG-induced oxidative stress, inflammatory response, and ECM accumulation in human MCs. The effect is partially mediated by Nrf2/keap1 and Akt/NF-κB pathways. The findings suggested that daphnetin might be a therapeutic or preventive agent for DN.     

Clinacanthus nutans attenuates atherosclerosis progression in rats with type 2 diabetes by reducing vascular oxidative stress and inflammation

ContextAtherosclerosis predisposes individuals to adverse cardiovascular events. Clinacanthus nutans L. (Acanthaceae) is a traditional remedy used for diabetes and inflammatory conditions.ObjectivesTo investigate the anti-atherosclerotic activity of a C. nutans leaf methanol extract (CNME) in a type 2 diabetic (T2D) rat model induced by a high-fat diet (HFD) and low-dose streptozotocin.Materials and methodsSixty male Sprague-Dawley rats were divided into five groups: non-diabetic fed a standard diet (C), C + CNME (500 mg/kg, orally), diabetic fed an HFD (DM), DM + CNME (500 mg/kg), and DM + Metformin (DM + Met; 300 mg/kg). Treatment with oral CNME and metformin was administered for 4 weeks. Fasting blood glucose (FBG), serum lipid profile, atherogenic index (AI), aortic tissue superoxide dismutase levels (SOD), malondialdehyde (MDA), and tumour necrosis factor-alpha (TNF-α) were measured. The rats’ aortas were stained for histological analysis and intima-media thickness (IMT), a marker of subclinical atherosclerosis.ResultsThe CNME-treated diabetic rats had reduced serum total cholesterol (43.74%; p = 0.0031), triglycerides (80.91%; p = 0.0003), low-density lipoprotein cholesterol (56.64%; p = 0.0008), AI (51.32%; p < 0.0001), MDA (60.74%; p = 0.0026), TNF-α (61.78%; p = 0.0002), and IMT (39.35%; p < 0.0001) compared to untreated diabetic rats. SOD level, however, increased (53.36%; p = 0.0326). These CNME effects were comparable to those in the metformin-treated diabetic rats.ConclusionsC. nutans possesses anti-atherosclerotic properties, which may be due to reductions in vascular tissue oxidative stress, inflammation, and serum AI. Continued studies on atherosclerotic animal models are suggested.     

An active metabolite of oltipraz (M2) increases mitochondrial fuel oxidation and inhibits lipogenesis in the liver by dually activating AMPK

Background and Purpose

Oltipraz, a cancer chemopreventive agent, has an anti-steatotic effect via liver X receptor-α (LXRα) inhibition. Here we have assessed the biological activity of a major metabolite of oltipraz (M2) against liver steatosis and steatohepatitis and the underlying mechanism(s).

Experimental Approach

Blood biochemistry and histopathology were assessed in high-fat diet (HFD)-fed mice treated with M2. An in vitroHepG2 cell model was used to study the mechanism of action. Immunoblotting, real-time PCR and luciferase reporter assays were performed to measure target protein or gene expression levels.

Key Results

M2 treatment inhibited HFD-induced steatohepatitis and diminished oxidative stress in liver. It increased expression of genes encoding proteins involved in mitochondrial fuel oxidation. Mitochondrial DNA content and oxygen consumption rate were enhanced. Moreover, M2 treatment repressed activity of LXRα and induction of its target genes, indicating anti-lipogenic effects. M2 activated AMP-activated protein kinase (AMPK). Inhibition of AMPK by over-expression of dominant negative AMPK (DN-AMPK) or by Compound C prevented M2 from inducing genes for fatty acid oxidation and repressed sterol regulatory element binding protein-1c (SREBP-1c) expression. M2 activated liver kinase B1 (LKB1) and increased the AMP/ATP ratio. LKB1 knockdown failed to reverse target protein modulations or AMPK activation by M2, supporting the proposal that both LKB1 and increased AMP/ATP ratio contribute to its anti-steatotic effect.

Conclusion and Implications

M2 inhibited liver steatosis and steatohepatitis by enhancing mitochondrial fuel oxidation and inhibiting lipogenesis. These effects reflected activation of AMPK elicited by increases in LKB1 activity and AMP/ATP ratio.