Anti-inflammatory and anti-oxidant effects of aloe vera in rats with non-alcoholic steatohepatitis

BACKGROUND Aloe vera exerts several biological activities, such as, anti-inflammatory, antioxidant, and antimicrobial effects. It was recently shown to reduce insulin resistance and triglyceride level. We hypothesized that aloe vera would have beneficial effects in alleviating non-alcoholic steatohepatitis(NASH) in rats.AIM To examine the therapeutic effects of aloe vera in NASH rats.METHODS All rats were randomly divided into 3 groups(n = 6 in each group). Rats in the control group were fed ad libitum with a standard diet for 8 wk. Rats in the NASH group were fed ad libitum with a high-fat high-fructose diet(HFHFD) for 8 wk. Rats in the aloe vera group were fed ad libitum with a HFHFD and aloe vera in dimethylsulfoxide(50 mg/kg) by gavage daily for 8 wk. Liver samples were collected at the end of the treatment period.RESULTS Hepatic malondialdehyde(MDA) levels increased significantly in the NASH group as compared with the control group(377 ± 77 nmol/mg vs 129 ± 51 nmol/mg protein, respectively, P 0.001). Glutathione(GSH) levels were significantly lower in the NASH group than the control group(9 ± 2 nmol/mg vs 24 ± 8 nmol/mg protein, respectively, P = 0.001). The expression of interleukin-18(IL-18), nuclear factor-kappa β, and caspase-3 increased, while peroxisome proliferator-activated receptor gamma decreased in the NASH group compared with the controls. Following aloe vera administration, MDA levels decreased(199 ± 35 nmol/mg protein) and GSH increased(18 ± 4 nmol/mg protein) markedly. Steatosis, hepatocyte ballooning, lobular inflammation and increased hepatocyte apoptosis were observed in the NASH group. Aloe vera treatment attenuated these changes in liver histology.CONCLUSION Aloe vera attenuated oxidative stress, hepatic inflammation and hepatocyte apoptosis, thus improving liver pathology in rats with NASH.     

Effects of commercial chlorophenolate, 2,3,7,8-TCDD,and pure phenoxyacetic acids on hepatic peroxisome proliferation,xenobiotic metabolism and sister chromatid exchange in the rat

The induction of hepatic peroxisome proliferation and drug metabolizing enzymes and of sister chromatid exchange (SCE) in lymphocytes was studied in male Han/Wistar rats after exposing them for 2 weeks to a commercial chlorophenolate formulation (Ky-5) (100mg/kg/ day), to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; 0.05–5 g/kg/wk) and to the pure phenoxyacetic acids, 2,4-dichlorophenoxyacetic acid (2,4-D; 100 mg/kg/day) and 2-chloro-4-methylphenoxyacetic acid (MCPA; 100 mg/kg/day). The chlorophenolate formulation and pure 2,4-D and MCPA caused significant increases in the number of peroxisomes in liver cells, although the average size of peroxisomes was not affected, whereas the effect of even the highest dose of 2,3,7,8-TCDD remained small. This finding indicates that dioxin impurities do not account for the peroxisome proliferation induced by chlorophenolate. The relative weight of the liver increased significantly in rats treated with the chlorophenolate formulation and with 2,3,7,8-TCDD (5.0 and 0.5 g/kg). The pattern of induction of xenobiotic metabolizing enzymes showed some differences between chlorophenolate treatment and 2,3,7,8-TCDD treatment. Furthermore, the effects of pure phenoxyacetic acids were different from that seen with chlorophenolate and 2,3,7,8-TCDD. The highest dose of 2,3,7,8-TCDD increased the frequency of SCE in circulating lymphocytes slightly, but significantly.     

Administration of ciprofibrate to lactating mothers induces PPARα-signaling pathway in the liver and kidney of suckling rats

It is well known that the hypolipidemic drug ciprofibrate induces peroxisome proliferation in rodent liver, which in turn leads to the oxidative stress, and modifies some parameters related to cell proliferation and apoptosis. The administration of ciprofibrate to rats during the lactating period determined in their pups significant modifications in hepatic peroxisome enzyme activities, induction of the PPARalpha-target gene, Cyp4a10, and perturbation in cell proliferation and apoptosis, which affected the size of the liver. Moreover, this modification was associated to about two-fold induction of mRNA-PPARalpha. On the contrary, in the kidney, although a similar two-fold up-regulation of PPARalpha was detected, the induction of both peroxisomal enzyme activities and Cyp4a10 were weak, and no alterations were detected, neither in cell cycle nor in the size of the tissue. Our results indicate that the response to ciprofibrate is stronger in the liver than in the kidney of newborn rats.     

PPARγ在不同周龄apoE-/-小鼠主动脉斑块表达及与斑块成份的相互关系

目的:研究PPARγ基因表达与ApoE-/-小鼠主动脉斑块成份的相互关系。方法:以20和40周龄ApoE-/-小鼠(n=10/组)为研究对象,相同基因背景和周龄C57BL/6 J小鼠设为对照。采用RT-PCR和免疫印迹技术检测各组小鼠主动脉PPARγ基因和蛋白表达变化;Movat 5色套染法和油红O染色检测ApoE-/-小鼠主动脉斑块成份;免疫组织化学技术检测斑块内PPARγ、SM-actin、MOMA-2抗原表达。结合免疫荧光技术分析PPARγ基因在主动脉斑块巨噬细胞、平滑肌细胞的表达及与脂质、弹性纤维、胶原和蛋白聚糖的相互关系。结果:20和40周龄C57BL/6 J小鼠主动脉壁有少量PPARγ表达,以20周龄组明显。ApoE-/-小鼠主动脉壁和斑块内PPARγ表达增多,以斑块内表达明显(P<0.05);与20周龄组比较,40周龄组表达最显著;且斑块脂质含量丰富;弹性纤维、胶原和蛋白聚糖含量减少,血管正性重塑明显;MOMA-2表达增加,SM-actin表达降低(P<0.05)。PPARγ在斑块内巨噬细胞、血管中膜平滑肌细胞和斑块内平滑肌细胞都有表达,但以脂质含量丰富处PPARγ表达最明显。结论:PPARγ在C57BL/6 J小鼠动脉壁表达随增龄而减少;在ApoE-/-小鼠主动脉壁和斑块内PPARγ表达随AS病变进程而增加。推测ApoE-/-小鼠主动脉斑块PPARγ表达上调可能是机体一种代偿行为和自我保护机制。     

阿托伐他汀对自发性高血压大鼠心肌组织PPARs表达的影响

目的： 探讨阿托伐他汀对自发性高血压大鼠心肌组织PPARs（peroxisome proliferator-activated receptors, PPARs）表达的影响及其对心肌肥厚的逆转作用与可能机制。方法: 自发性高血压大鼠分为阿托伐他汀灌胃治疗组（SHR-A，30 mg·kg-1·d-1）及模型组（SHR），治疗8周，同周龄Wistar-Kyoto 鼠为正常血压对照组。治疗前及治疗后2、4、8周测量大鼠尾动脉血压。治疗后测血浆血脂水平，以心脏组织病理分析判断心肌肥厚，Western blotting 检测心肌组织PPARα、PPARγ的表达水平。结果: 经过8周治疗， SHR-A组及SHR组血压及血脂水平无明显差异（P＞0.05）。SHR-A组左室重量指数低于SHR组（P＜0.01）。在SHR-A组，PPARα及PPARγ表达高于SHR组（P＜0.01）。结论: 阿托伐他汀显著改善自发性高血压大鼠心肌组织PPARs表达，有效逆转左室肥厚，可能与其降压及降脂作用无关。     

Peroxisome proliferator-activated receptor-α and liver cancer: where do we stand?

The peroxisome proliferator-activated receptor- (PPAR), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPAR is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPAR occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPAR agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPAR also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPAR. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPAR target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPAR in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPAR agonist-induced hepatocarcinogenesis.     

The role of the p33:p33/p92 interaction domain in RNA replication and intracellular localization of p33 and p92 proteins of Cucumber necrosis tombusvirus

Replication of plus-stranded RNA viruses is performed by the viral replicase complex, which, together with the viral RNA, must be targeted to intracellular membranes, where replication takes place in membraneous vesicles/spherules. Tombusviruses code for two overlapping replication proteins, the p33 auxiliary protein and the p92 polymerase. Using replication-competent fluorescent protein-tagged p33 of Cucumber necrosis virus (CNV), we determined that two domains affected p33 targeting to peroxisomal membranes in yeast: an N-proximal hydrophobic trans-membrane sequence and the C-proximal p33:p33/p92 interaction domain. On the contrary, only the deletion of the p33:p33/p92 interaction domain, but not the trans-membrane sequence, altered the intracellular targeting of p92 protein in the presence of wt p33 and DI-72(+) RNA. Moreover, unlike p33, p92 lacking the trans-membrane sequence was still functional in supporting the replication of a replicon RNA in yeast, whereas the p33:p33/p92 interaction domain in both p33 and p92 was essential for replication. In addition, p33 was also shown to facilitate the recruitment of the viral RNA to peroxisomal membranes and that p33 is colocalized with (+) and (-)-stranded viral RNAs. Also, FRET and pull-down analyses confirmed that p33 interacts with other p33 molecules in yeast cells. Based on these data, we propose that p33 facilitates the formation of multimolecular complexes, including p33, p92, viral RNA, and unidentified host factors, which are then targeted to the peroxisomal membranes, the sites of CNV replication.     

Effect of the peroxisome proliferator perfluorodecanoic acid on growth and lipid metabolism in Sprague Dawley rats fed three dietary levels of selenium

The possible interrelationships between the effects of dietary selenium and perfluorodecanoic acid (PFDA) on growth and lipid metabolism were studied in the male Sprague Dawley rat. Rats were divided into groups and placed on diets containing three levels of selenium (0.04, 0.2, and 1.0 ppm as sodium selenite). Two weeks later, half the rats in each group received a single 35 mg/kg IP injection of PFDA in corn oil, while their pair-fed companion received only vehicle. Rats injected with PFDA stopped gaining weight, and weighed less than pair-fed controls, despite equal food intakes. Two weeks following PFDA administration the rats were killed and plasma cholesterol and triglycerides, and liver peroxisomal enzyme activities were quantified. In contrast to other peroxisome proliferators, PFDA increased plasma triglycerides while decreasing plasma cholesterol. The rate of peroxisomal fatty acid -oxidation was decreased, even though the activity of fatty acyl-CoA oxidase, the first enzyme in the peroxisomal fatty acid -oxidation pathway, was increased. Dietary selenium, other than increasing the liver to body weight ratio, did not alter growth or lipid metabolism. This study demonstrates, for the first time, the existence of a non-hypotriglyceridemic peroxisome proliferator-PFDA.     

The Biological Actions of Dehydroepiandrosterone Involves Multiple Receptors

Dehydroepiandrosterone has been thought to have physiological functions other than as an androgen precursor. The previous studies performed have demonstrated a number of biological effects in rodents, such as amelioration of disease in diabetic, chemical carcinogenesis, and obesity models. To date, activation of the peroxisome proliferators activated receptor alpha, pregnane X receptor, and estrogen receptor by DHEA and its metabolites have been demonstrated. Several membrane-associated receptors have also been elucidated leading to additional mechanisms by which DHEA may exert its biological effects. This review will provide an overview of the receptor multiplicity involved in the biological activity of this sterol.