Antioxidative and hepatoprotective effect of CGX, an herbal medicine, against toxic acute injury in mice

Aim

CGX, a modified traditional Chinese herbal drug whose name means “liver cleaning,” is used to treat various liver disorders. This study investigated the protective effects of CGX and its mechanisms.

Material and methods

After pretreating ICR mice twice daily with CGX (po, 50 or 100 mg/kg) or distilled water for three consecutive days, acute liver injury was induced by a single injection of CCl₄ (ip, 10 mL/kg of 0.2% in olive oil) (n = 8 per group).

Results

Pretreatment with CGX significantly attenuated the elevation in biochemical parameters, such as alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) in serum, and the malondialdehyde concentrations in liver tissue. Pretreatment with CGX significantly restored the reduction of catalase activity and glutathione (GSH) content, but not superoxide dismutase (SOD) activity, and it inhibited the CCl₄-induced high expression of iNOS and TNF-α in hepatic tissue.

Conclusion

This study showed that CGX has hepatoprotective effects against free radical-induced acute injury via primarily antioxidative properties.     

对二氯苯对小鼠肝肾抗氧化功能的影响

目的:评价对二氯苯(p-DCB)亚急性染毒对小鼠的氧化性应激效应.方法:选用36只小鼠,雌雄各半,随机分成3组,每组12只,分别给予0(溶剂对照),450,900 mg/kg,每天灌胃1次,连续染毒1周.以丙二醛(MDA)作为脂质过氧化的产物指标;超氧化物歧化酶(SOD)代表抗氧化酶、还原性谷胱甘肽(GSH)代表非酶性抗氧化物综合评价氧化应激效应.结果:染毒后各组间体质量无显著性差别;染毒组肾体系数显著高于溶剂对照组(P＜0.05).小鼠肝脏及肾脏中SOD水平无显著性变化;高剂量组肾脏中GSH水平均低于对照组和低剂量组,与低剂量组比有显著性差别(P＜0.05);染毒组肝脏和肾脏中MDA水平随着染毒剂量的增加逐渐升高,高剂量组MDA水平明显高于对照组和低剂量组.结论:p-DCB能降低小鼠组织的抗氧化功能,氧化性损伤可能是其重要的毒作用机制.     

Ascorbate transport by primary cultured neurons and its role in neuronal function and protection against excitotoxicity

Neurons maintain relatively high intracellular concentrations of ascorbic acid, which is achieved primarily by the activity of the sodium-dependent vitamin C transporter SVCT2. In this work, we studied the mechanisms by which neuronal cells in culture transport and maintain ascorbate as well as whether this system contributes to maturation of neuronal function and cellular defense against oxidative stress and excitotoxic injury. We found that the SVCT2 helps to maintain high intracellular ascorbate levels, normal ascorbate transport kinetics, and activity-dependent ascorbate recycling. Immunocytochemistry studies revealed that SVCT2 is expressed primarily in the axons of mature hippocampal neurons in culture. In the absence of SVCT2, hippocampal neurons exhibited stunted neurite outgrowth, less glutamate receptor clustering, and reduced spontaneous neuronal activity. Finally, hippocampal cultures from SVCT2-deficient mice showed increased susceptibility to oxidative damage and N-methyl-D-aspartate-induced excitotoxicity. Our results revealed that maintenance of intracellular ascorbate as a result of SVCT2 activity is crucial for neuronal development, functional maturation, and antioxidant responses.     

Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression

The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague–Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16α-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(α)pyrene (B(α)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(α)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity.     

Chemoprevention of liver cancer by plant polyphenols

Primary liver cancer or hepatocellular carcinoma (HCC) is one of the most frequent tumors representing the fifth commonest malignancy worldwide and the third cause of mortality from cancer. Currently, the treatments for HCC are not so effective and new strategies are needed for its fight. Chemoprevention, the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenesis is considered an important way for confronting HCC. Many of the chemopreventive agents are phytochemicals, namely non-nutritive plant chemicals with protective or disease preventive properties. In this review, we focus on plant polyphenols, one of the most important classes of phytochemicals, their chemopreventive properties against HCC and discuss the molecular mechanisms accounting for this activity.     

Kaempferol induces apoptosis in human lung non-small carcinoma cells accompanied by an induction of antioxidant enzymes.

Kaempferol (3, 4',5,7-tetrahydroxyflavone) is one of the most commonly found dietary flavonols. The biological and pharmacological effects of kaempferol may depend upon its behavior as either an antioxidant or a prooxidant. However, the clear biological effects of prooxidant or antioxidant character of kaempferol has not been clarified yet. The overall objective of the present study is to explore the role of prooxidant or antioxidant in kaempferol-induced cell toxicity. In this paper, we have proved that antioxidant pathway may be involved in kaempferol induces H460 cell apoptosis. Kaempferol-induced H460 cell apoptosis is a typical apoptosis that was accompanied by a significant DNA condensation and increasing intracellular ATP levels. Kaempferol-induced apoptosis is related to its ability to change the expression of apoptotic markers, such as caspase-3 (caspase-dependent) and AIF (caspase-independent). The overexpression of antioxidant enzyme Mn SOD protein levels, which was promoted to a new type tumor suppressor gene in several human cancer cells recently, may be an important role in kaempferol-induced H460 cell apoptosis.     

Effects of Epigallocatechin-3-gallate on lead-induced oxidative damage

Recent studies have shown that lead (Pb) could disrupt the prooxidant/antioxidant balance of tissue which leads to biochemical and physiological dysfunction. Epigallocatechin-3-gallate (EGCG), a catechin polyphenols component, is found to be an effective antioxidant. The present study investigated whether EGCG administration could reverse the changes on redox states in rat hippocampus caused by lead exposure. The association between redox status changes and long-term potentiation (LTP) in CA1 area of hippocampus were also examined. Wistar rats exposed to lead from postnatal day 1 were followed by 10 days of EGCG (10, 25 and 50 mg/kg) administration through intraperitoneally (ip), and the rats were sacrificed for experiments at the age of 21–23 days. The experimental results showed that glutathione (GSH) and superoxide dismutase (SOD) activity decreased accompanied with LTP amplitude decrease in CA1 area of hippocampus in the lead-exposed group. EGCG supplementation following lead intoxication resulted in increases in the GSH and SOD levels and increases in the LTP amplitude. Malondialdehyde (MDA) levels, a major lipid peroxidation byproduct, increased following lead exposure and decreased following EGCG treatment. In hippocampal neuron culture model, lead exposure (20 μM) significantly inhibited the viability of neurons which was followed by an accumulation of ROS and a decrease of mitochondrial membrane potential (ΔΨ_m). Treatment by EGCG (10–50 μM) effectively increased cell viability, decreased ROS formation and improved ΔΨ_m in hippocampal neurons exposed to lead. These observations suggest that EGCG is a potential complementary agent in the treatment of chronic lead intoxication through its antioxidative character.     

The changes of antioxidant defense system caused by quercetin administration do not lead to DNA damage and apoptosis in the spleen and bone marrow cells of rats.

Quercetin may have the opposite effect, namely anti- as well as pro-oxidant. The aim of this study was to assess the results of quercetin anti- and/or pro-oxidant activity in the bone marrow and spleen cells of rats. The experimental rats were treated daily, with quercetin in a dose of 8 or 80mg/kg b.w. by gavage for 40 days. The intracellular redox state in cells were assessed by measuring the ferric ion reducing antioxidant power (FRAP) level and malonodialdehyde concentration. HO-1 mRNA expression was examined with real-time PCR. The extent of DNA damage was determined by the alkaline-labile comet assay. A potential pro-apoptotic quercetin action was determined using the FITC-Annexin V kit. The quercetin and isorhamnetin concentrations in serum were analyzed by HPLC-ECD. MDA concentration and FRAP values, were significantly decreased in the spleen and bone marrow cells of rats treated with quercetin, in a dose of 80mg/kg b.w. in comparison with the control rats; no significant changes were observed after quercetin was administered in a dose ten times as low. Treatment with quercetin dose-dependently upregulated the expression of HO-1 mRNA in the bone marrow cells. Quercetin administration to the rats did not induce either DNA damage or apoptosis in the examined cells. The results of our study prove that changes in the antioxidant state, caused by quercetin, do not lead to DNA damage or exert any pro-apoptotic activity in vivo.     

依达拉奉对H2O2致星形胶质细胞损伤的保护作用

目的:观察依达拉奉(EDA)对H2O2损伤后的星形胶质细胞活力的影响及其细胞内谷胱甘肽(GSH)含量、诱导型一氧化氮合酶(iNOS)表达的影响.方法:应用MTT法检测星形胶质细胞活力;Tietze法检测细胞内GSH含量;Western-blot法检测细胞内iNOS的表达.结果:H2O2作用24 h后可呈浓度依赖性地抑制星形胶质活力;EDA可逆转H2O2导致的星形胶质细胞活力的下降,胞内GSH含量的降低以及iNOS表达的增加.结论:EDA可改善H2O2所致的星形胶质细胞的氧化损伤.     

Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats

Adriamycin is a potent anticancer agent, its clinical use is limited for its marked cardiotoxicity and nephrotoxicity. The present study aimed to investigate the possible protective role of the natural antioxidant silymarin on ADR-induced heart and kidney toxicity. Studies were performed on four groups of rats. 1--control group, 2--silymarin group (50 mg/kg), 3--adriamycin group (10 mg/kg), 4--adriamycin+silymarin group. On the third day after ADR injection, plasma was separated for determination of LDH, CPK, cholesterol and total lipids. 30 days after ADR injection, plasma was separated for determination of creatinine and urea levels. Frozen heart specimens (72 h) and frozen kidney specimens (30days) were used for estimation of lipid peroxides and GSH contents. Histopathological examinations of heart and kidney sections were also done. Pretreatment of ADR-treated rats with silymarin resulted in a significant decrease in the plasma CPK, LDH, creatinine and urea. On the other hand silymarin pretreatment did not change ADR-induced hyperlipidemia. Silymarin pretreatment significantly decreased the myocardial MDA contents. In addition, silymarin pretreatment normalized renal tissue contents of MDA and GSH. Histopathological examination of heart and kidney sections revealed that ADR caused only mild myocardial injury in silymarin pretreated rats. Also, silymarin pretreatment inhibited ADR-induced renal tubular damage in rats. These results have suggested that, silymarin ameliorated ADR-induced cardiotoxicity and protected against ADR-induced nephrotoxicity in male albino rats. The mechanisms of silymarin induced protection against ADR-induced toxicities were proved to be due to inhibition of lipid peroxidation and protection against GSH depletion.