Telmisartan ameliorates carbon tetrachloride‐induced acute hepatotoxicity in rats

This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT₁) receptor blocker, on carbon tetrachloride (CCl₄)‐induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl₄ 1 mL kg^?1, 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl₄ group. Rats receiving CCl₄ and co‐treated with TLM (3 and 10 mg kg^?1, orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg^?1) didn't show any significant changes compared to CCl₄ intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl₄ intoxication. Interestingly, TLM protected against CCl₄‐induced expressions of nuclear factor‐κB, inducible nitric oxide synthase and cyclooxygenase‐II, in a dose related manner. Moreover, TLM (3 and 10 mg kg^?1) significantly modified CCl₄‐induced elevation in tumor necrosis factor‐α and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl₄‐intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg^?1) showed significant hepato‐protective effects. However, TLM at a dose of 10 mg kg^?1 didn't show significant efficacy above 3 mg kg^?1 which is nearly equivalent to the human anti‐hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti‐inflammatory activities. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359–370, 2017.     

Modulatory effects of gentisic acid against genotoxicity and hepatotoxicity induced by cyclophosphamide in Swiss albino mice

Objectives This study evaluated the protective effects of gentisic acid (GA) against genotoxicity and hepatotoxicity induced by cyclophosphamide (CP) in Swiss albino mice. Methods Mice were pretreated with GA orally at doses of 50 and 100 mg/kg for 14 consecutive days before the administration of a single intraperitoneal dose of 50 mg/kg CP. The ameliorative effect of GA on genotoxicity was studied using the in‐vivo bone marrow micronuclei induction test, DNA integrity and alkaline unwinding assay. The activity of various oxidative stress enzymes were estimated in hepatic tissue. Key findings A single intraperitoneal administration of CP in mice increased the malondialdehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione reductase, catalase and quinone reductase), and induced DNA strand breaks and micronuclei induction. Oral pretreatment with GA at both doses caused a significant reduction in malondialdehyde and glutathione levels, restoration of antioxidant enzyme activity, reduction in micronuclei formation and DNA fragmentation. Serum toxicity marker enzymes such as aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase were increased after CP treatment but restored in GA pretreated groups. Conclusion The results support the protective effect of GA against CP induced genotoxicity and hepatotoxicity.     

丙戊酸钠及其代谢产物的体外肝毒性研究

目的 研究丙戊酸钠及3个代谢产物（2-丙基-4-五烯酸、3-羟基丙戊酸、5-羟基丙戊酸）对体外人正常肝细胞L02增殖活性及对肝细胞损伤相关指标的影响。方法 实验分为对照组和实验组,对照组细胞常规培养,实验组加入丙戊酸钠及3个代谢产物,采用CCK-8法检测细胞增殖活性,PCR法检测CYP1A1、CYP1A2、PCNA、Bax及Bcl-2的mRNA相对含量,Western Blotting法检测蛋白表达,同时检测细胞上清液中谷草转氨酶（AST）、谷丙转氨酶（ALT）、乳酸脱氢酶（LDH）的含量。结果 与对照组相比,随着丙戊酸钠及3个代谢产物浓度和时间的增加,对 L02细胞增殖活性的抑制逐渐增强,CYP1A1、CYP1A2及Bax的mRNA相对含量和蛋白表达量升高,PCNA及Bcl-2的 mRNA相对含量和蛋白表达量均有下降,AST、ALT、LDH含量升高。结论 丙戊酸钠及3个代谢产物与肝毒性有关。     

Protection against paracetamol-induced hepatotoxicity by acetylsalicylic acid in rats

Acetylsalicylic acid (ASA) given simultaneously with paracetamol decreased paracetamol-induced hepatotoxicity (measured by plasma transaminase activities as well as histology) without any effect on glutathione depletion, indicating that ASA prevents a process (or processes) subsequent to the metabolic activation of paracetamol. Delayed treatment with ASA also reduced paracetamol-induced liver toxicity, suggesting that reduction of the absorption rate of paracetamol does not contribute essentially to the protection by ASA. Combinations of paracetamol and ASA may have potential use in the development of safer analgesic combinations containing paracetamol (or ASA).     

Ellagic acid attenuates beryllium sulphate-induced oxidative stress and histopathological alterations of spleen in rats

ContextEllagic acid (EA) is a phenolic constituent in certain fruits and has largely been recognized for its role as an antioxidant compound.ObjectiveTo evaluate the effect of EA on beryllium sulphate-induced splenic toxicity in rats.Materials and methodsMale Sprague-Dawley rats were divided into four groups. The first group was used as control. Group 2 was exposed to BeSO₄ (12 mg/kg, b.w.). Groups 3 and 4 were treated with EA (100 and 300 mg/kg, b.w.) daily for 6 weeks after exposing to BeSO₄ (12 mg/kg, b.w.). Various biochemical and molecular biomarkers were assessed in blood and spleen.ResultsBeSO₄-intoxicated rats showed significant higher WBC (6.74 ± 0.20 × 10⁹/L vs. 11.02 ± 1.31 × 10⁹/L, p < 0.05), Neu (1.14 ± 0.11 × 10⁹/L vs. 2.45 ± 0.42 × 10⁹/L, p < 0.05), Lym (3.80 ± 0.83 × 10⁹/L vs. 9.64 ± 1.99 × 10⁹/L, p < 0.05), and PLT (868.4 ± 43.2 × 10⁹/L vs. 1408 ± 77.57 × 10⁹/L, p < 0.05) than normal control animals. Moreover, an increase in MDA with depletion of GSH and SOD activity (all p < 0.05) occurred in the spleen of rats treated with BeSO₄. Furthermore, BeSO₄-treated rats displayed significantly higher levels of apoptotic markers (Bax, Caspase-3, PARP) (all p < 0.05). EA administration resulted in a significant reversal of hematological and apoptotic markers in beryllium sulphate-intoxicated rats.Discussion and conclusionsOur results suggest EA treatment exerts a significant protective effect on BeSO₄-induced splenic toxicity in rats.     

Ellagic acid ameliorates isoproterenol induced oxidative stress: Evidence from electrocardiological, biochemical and histological study

The present study was designed to evaluate the cardioprotective effects of ellagic acid against isoproterenol induced myocardial infarction in rats by studying electrocardiography, blood pressure, cardiac markers, lipid peroxidation, antioxidant defense system and histological changes. Male Wistar rats were treated orally with ellagic acid (7.5 and 15 mg/kg) daily for a period of 10 days. After 10 days of pretreatment, isoproterenol (100 mg/kg) was injected subcutaneously to rats at an interval of 24 h for 2 days to induce myocardial infarction. Isoproterenol administered rats showed significant changes in the electrocardiogram pattern, arterial pressure, and heart rate. Isoproterenol-induced rats also showed significant (P < 0.05) increase in the levels of serum troponin-I, creatine kinase, lactate dehydrogenase, C-reactive protein, plasma homocysteine, heart tissue thiobarbituric acid reactive substances and lipid hydro peroxides. The activities/levels of antioxidant system were decreased in isoproterenol-induced rats. The histopathological findings of the myocardial tissue evidenced myocardial damage in isoproterenol induced rats. The oral pretreatment of ellagic acid restored the pathological electrocardiographic patterns, regulated the arterial blood pressures and heart rate in the isoproterenol induced myocardial infarcted rats. The ellagic acid pretreatment significantly reduced the levels of biochemical markers, lipid peroxidation and significantly increased the activities/levels of the antioxidant system in the isoproterenol induced rats. An inhibited myocardial necrosis was evidenced by the histopathological findings in ellagic acid pretreated isoproterenol induced rats. Our study shows that oral pretreatment of ellagic acid prevents isoproterenol induced oxidative stress in myocardial infarction.     

Effect of goat milk on hepatotoxicity induced by antitubercular drugs in rats

Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg) along with antitubercular drugs (Group III) reversed the levels of serum alanine aminotransferase (82 ± 25.1 vs. 128.8 ± 8.9 units/L) and aspartate aminotransferase (174.7 ± 31.5 vs. 296.4 ± 56.4 units/L, p < 0.01) compared with antitubercular drug treatment Group II. There was a significant decrease in serum alanine aminotransferase (41.8 ± 4.1 vs. 128.8 ± 8.9 units/L, p < 0.01) and aspartate aminotransferase (128.8 ± 8.54 vs. 296.4 ± 56.4 units/L, p < 0.001) levels in Group IV (goat milk 40 mL/kg) compared with antitubercular drug treatment Group II. Goat milk (20 mL/kg and 40 mL/kg) was effective in reversing the rise in malondialdehyde level compared with the antitubercular drug suspension groups (58.5 ± 2 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p < 0.001 and 69.7 ± 0.78 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p < 0.001, respectively). Similarly, both doses of milk significantly prevented a fall in superoxide dismutase level (6.23 ± 0.29 vs. 3.1 ± 0.288 units/mL, p < 0.001 and 7.8 ± 0.392 vs. 3.1 ± 0.288 units/mL, p < 0.001) compared with the group receiving antitubercular drugs alone. Histological examination indicated that goat milk reduced inflammation and necrotic changes in hepatocytes in the treatment groups. The results indicated that goat milk prevented the antitubercular drug-induced hepatotoxicity and is an effective hepatoprotective agent.     

Triptolide‐induced hepatotoxicity via apoptosis and autophagy in zebrafish

Previous research about the development of triptolide (TP) as a natural active compound has often focused on hepatotoxicity. Among its various mechanisms, autophagy and apoptosis are two important signaling pathways. In this study, we used zebrafish to establish a TP‐induced hepatotoxicity model, and investigated the roles of autophagy and apoptosis in the progress of liver injury. Zebrafish exposed to TP showed increased mortality and malformation because of the increased drug dose and duration of exposure. Meanwhile, we found that TP induced liver injury in a time‐ and dose‐dependent manner, which was observed as a reduction in liver area, slow yolk absorption, upregulation of transaminase and local neurosis. With the application of the high‐content imaging system (HCIS) technique in liver 3D imaging in vivo, clear imaging of the zebrafish liver was achieved. The results showed a decrease in volume and location of necrosis in the liver after TP exposure. Increased expression of inflammatory cytokines genes tumor necrosis factor (Tnf)α, Il1β and Il6 were shown, particularly Tnfα. The Fas‐Caspase8 signaling pathway was activated. The apoptosis‐related gene Bcl‐2 was increased, and Bax, Caspase9 and Caspase3 were increased. However, autophagy related genes Beclin1, Atg5, Atg3 and Lc3 were increased more significantly, and the changes of Beclin1 and Atg5 were the most severe. This study successfully established a TP‐induced zebrafish hepatotoxicity model and applied the HCIS technique in a zebrafish hepatotoxicity study. The result indicated Fas might be the main target of TP‐induced hepatotoxicity. Autophagy played a more important role than apoptosis and was characterized by the overexpression of Beclin1 and Atg5.     

Ellagic acid prevents rat colon carcinogenesis induced by 1, 2 dimethyl hydrazine through inhibition of AKT-phosphoinositide-3 kinase pathway

Colon cancer is the third most malignant neoplasm in the world and chemoprevention through dietary intervention is an emerging option to reduce its mortality. Ellagic acid (EA) a major component of berries possesses attractive biological deeds. This study is aimed to investigate the effect of ellagic acid in fostering apoptosis in 1,2-dimethyl hydrazine (DMH) mediated experimental colon carcinogenesis model. Wistar male rats were segregated into four groups: group I-control rats, group II-rats received ellagic acid (60 mg/kg body weight p.o. every day), rats in group III-induced with DMH (20 mg/kg body weight, s.c.) for 15 weeks, DMH-induced group IV rats were initiated with ellagic acid treatment. The present study is designed to explore the significance of phosphoinositide-3-kinase (PI3K)/Akt molecular pathway as well as ellagic acid's chemopreventive effect in colon cancer. DMH-induced rats exhibited elevated expressions of PI3K and Akt as confirmed by immunofluorescence, immunoblot and confocal microscopic analysis. Mechanistically, ellagic acid was found to prevent PI3K/Akt activation that in turn, results in modulation of its downstream Bcl-2 family proteins. Bax expression and caspase-3 activation was noted after ellagic acid supplementation leading to elevation of cytochrome c (cyt c) levels and finally cell death. These observations were supported by the DNA fragmentation results, which showed the occurrence of apoptosis. This study reveals the involvement of PI3K-Akt signaling through which ellagic acid induces apoptosis and subsequently suppresses colon cancer during DMH-induced rat colon carcinogenesis. In conclusion, our findings demonstrate that ellagic acid begets apoptosis in DMH-induced colon carcinoma.     

十全大补丸对环孢菌素A肝毒性的作用

目的观察十全大补丸对环孢菌素A(CsA)所致大鼠肝毒性的作用。方法大鼠分为4组 :ⅠCsA组(50mg/kg) ,ⅡCsA 十全大补丸高剂量组(50mg/kg 0.6g/kg) ,ⅢCsA 大补丸低剂量组(50mg/kg 0.3g/kg) ,Ⅳ空白对照组(等量2 %羧甲基纤维素CMC)。灌胃给药 ,每日1次 ,连续7天后取血 ,测定血清谷丙转氨酶(GPT)、硷性磷酸酶(AKP)及血清超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽s_转移酶(GST)。取肝组织作病理检查。结果用药7天后 ,CsA 十全大补丸高、低剂量组 ,均有明显降低血清GPT、AKP的作用 ,与单用CsA相比 ,有显著性差异。各用药组SOD活力与对照组比都有所下降 ,差异显著 :但合并用药组与单用CsA组比 ,无显著性差异。各用药组GST活力与对照组比也有所下降 ,但无显著性差异 ;合并用药组MDA均高于对照组 ,单用CsA组低于对照组。结论十全大补丸对CsA所致大鼠肝毒性有保肝降酶作用 ,其抗氧化清除自由基作用不明显。     

丙戊酸钠及其代谢产物与肝损伤的相关性分析

目的研究丙戊酸钠及3个代谢产物(2-丙基-4-五烯酸、3-羟基丙戊酸、5-羟基丙戊酸)对肝损伤参考指标的相关性分析。方法共收集328例癫痫患者血样,其中,123例肝功能异常癫痫患者血样为试验组,205例肝功能正常癫痫患者血样为对照组,采用LC-MS/MS方法测定两组血样(丙戊酸钠及代谢产物)的血药浓度,通过ROC曲线分析丙戊酸及其代谢产物浓度对肝功能异常的诊断价值。结果肝功能异常组患者丙戊酸钠及其3个代谢产物平均血药浓度均高于对照组,差异有统计学意义(P<0.05)。丙戊酸钠及其代谢产物的血药浓度均可作为诊断肝损伤的参考指标,5-羟基丙戊酸比丙戊酸钠有更好的诊断价值。结论丙戊酸钠代谢产物与肝毒性有关,能够作为肝损伤的诊断指标,可将其应用于临床,为丙戊酸钠有效给药提供参考。     

(E)‐2‐Benzylidene‐4‐phenyl‐1,3‐diselenole ameliorates signals of renal injury induced by cisplatin in rats

The present study investigated the protective role of antioxidant (E)‐2‐benzylidene‐4‐phenyl‐1,3‐diselenole (BPD), an organoselenium compound, against the renal injury induced by cisplatin in rats. Canola oil or BPD (50 mg kg^?1) was administered orally by gavage once a day for 6 days to rats. The first dose of BPD was given 24 h before a single intraperitoneal injection of saline or cisplatin (7 mg kg^?1). At day 7, animals were killed and parameters related to renal injury were determined. The histological analysis showed that cisplatin caused renal injury in rats, which was accompanied by an increase in urea and creatinine levels in plasma. The increase of plasma creatinine levels negatively correlated with renal antioxidant defenses including ascorbic acid (AA) and reduced glutathione (GSH) content as well as glutathione S‐transferase (GST), glutathione peroxidase (GPx) and catalase (CAT) activities. As revealed by histological analysis, BPD ameliorated tubular injury in rat kidney and reduced plasma markers altered by cisplatin. The administration of BPD to rats attenuated the reduction of renal AA and GSH content in animals exposed to cisplatin. The decrease of GST activity, but not GPx and CAT activities, in rats exposed to cisplatin was totally reversed by BPD administration. BPD was also effective in attenuating the inhibition of a sulfhydryl enzyme sensitive to oxidative stress, δ‐aminolevulinic dehydratase, in kidneys of rats exposed to cisplatin. The present study demonstrated that BPD reduced renal injury induced by cisplatin in rats and this effect seems to be related to antioxidant mechanisms. Copyright © 2012 John Wiley & Sons, Ltd.     

藏药石榴莲花散中鞣花酸和胡椒碱含量测定方法研究

目的:建立藏药石榴莲花散中鞣花酸和胡椒碱含量测定方法,以完善其质量标准。方法:采用高效液相色谱法测定制剂中石榴子和诃子的鞣花酸含量,采用ODS-2 HYPERSIL C₁₈色谱柱(4.6 mm×250mm,5μm),以乙腈-0.2%磷酸(15∶85)为流动相,流速1.0 mL·min^-1,检测波长254 nm,柱温30℃;采用高效液相色谱法测定制剂中荜茇的胡椒碱含量,采用ODS-2 HYPERSIL C₁₈色谱柱(4.6mm×250 mm,5μm),以乙腈-水(40∶60)为流动相,流速1.0 mL·min^-1,检测波长343 nm,柱温30℃。结果:鞣花酸进样量在5.065～25.325μg范围内呈良好线性关系(r=0.9999),平均回收率为97.5%,RSD=1.5%(n=6);胡椒碱进样量在10.414～52.071μg范围内呈良好线性关系(r=1.0000),平均回收率为99.6%,RSD=0.6%(n=6)。结论:该方法可准确测定石榴莲花散中鞣花酸和胡椒碱的含量,有助于提高石榴莲花散的质...     

HPLC同时测定珠子草中没食子酸、短叶苏木酚和鞣花酸的含量

目的 建立同时测定珠子草中没食子酸、短叶苏木酚和鞣花酸的HPLC法,并对珠子草该3种成分进行含量测定。方法 色谱柱：Shimazu C₁₈(150 mm×4.6 mm,5 μm);流动相：0.1%磷酸(A)-乙腈(B)梯度洗脱,流速为0.8 mL·min^-1;柱温：室温;检测波长：270 nm;进样量10 μL。结果 没食子酸、短叶苏木酚和鞣花酸含量分别在0.6~9.6 μg、0.525~8.4 μg、0.475~7.6 μg内与峰面积呈良好的线性关系。没食子酸的平均含量为0.196 2%,短叶苏木酚为0.518 2%,鞣花酸为0.411 0%。结论 本方法操作简便,准确度高,可用于珠子草中没食子酸、短叶苏木酚和鞣花酸3种成分含量的测定。     

丙戊酸肝毒性的早期预警及预防研究状况

丙戊酸是临床上主要的一线抗癫痫药,还广泛用于其他神经疾病的治疗,治疗范围广,但肝毒性是丙戊酸较严重的不良反应,2岁以下且联合用药的癫痫患者肝毒性风险显著增大,严重时甚至发生致死性、急性肝坏死。因此,临床上选择合适的生物标志物预警丙戊酸肝毒性的发生以及早期实施药物干预进行预防显得尤为重要。本文就近几年丙戊酸肝毒性的预警和预防方面的研究进展做一综述。     

Role of glutathione conjugation in the hepatotoxicity and immunotoxicity induced by 1-bromopropane in female BALB/c mice

1-Bromopropane (1-BP) is used as a cleaning agent or adhesive solvent in the workplace. In the present study, the hepatotoxic and immunotoxic effects of 1-bromopropane and its conjugation with glutathione (GSH) were investigated in female BALB/c mice. The animals were treated orally with 200, 500 and 1000 mg kg(-1) of 1-BP in corn oil for a dose response study or treated orally with 1000 mg kg(-1) of 1-BP for 6, 12, 24 and 48 h for a time course study. The hepatic and splenic contents of GSH were significantly decreased by 1-BP in a dose-dependent manner. S-propyl GSH was identified in livers following treatment with 1-BP by liquid chromatography-electrospray ionization tandem mass spectrometry. When the production of conjugates from 1-BP was investigated in livers following oral treatment with 1000 mg kg(-1) of 1-BP for 6, 12, 24 and 48 h, the GSH conjugates were detected maximally 6 h after treatment. Treatment of mice with 1-BP increased the serum activity of alanine aminotransferase dose-dependently. The oral 1-BP treatment significantly suppressed the antibody response to a T-dependent antigen and the production of splenic intracellular IL-2 in response to Con A in a dose-dependent manner. The present results suggested that 1-BP could cause hepatotoxicity and immunotoxicity as well as depletion of GSH content due to the formation of GSH conjugates.     

Effects of quercetin and chrysin on 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin induced hepatotoxicity in rats

The objective of current study is to investigate the effects of the administration of chrysin (CH) and quercetin (Q) on rat liver in which oxidative and histological damage had been induced by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD). Rats were randomly divided into six equal groups. TCDD was orally administered at the dose of 2 μg/kg/week, and Q and CH were orally administered at the doses of 20 mg/kg day and 50 mg/kg/day, respectively, by gavages dissolved in corn oil. The liver samples to be analyzed for the determination of oxidative and histological alternations were taken from rats at 60 days. The results indicated that although 2,3,7,8‐TCDD significantly induced (P ≤ 0.01) lipid peroxidation (increase of MDA levels), it positively affected oxidant/antioxidant system (a decline in the levels of GSH, CAT, GSH‐Px, and CuZn‐SOD) in rats significantly. The histological changes observed in the liver correlated with the biochemical findings. However, these effects of TCDD on oxidative and histological changes were eliminated by Q and CH treatment. In conclusion, TCDD caused an adverse effect on rat's liver. When Q and CH were given together with TCDD, they prevented hepatotoxicty induced by TCDD. Thus, it is thought that Q and CH may be useful as a new category of anti‐TCDD toxicity agent. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013.     

Rifampicin induced hepatotoxicity in rats: Protective effect of picrolive effect of picroliv

Rifampicin, an anti-tubercular drug, at 100 mg/kg (122 μmol) body weight (daily single ip injection for 6 days) caused changes in most of the biochemical parameters of the liver and serum in rats, 24 h after the last injection. These included significant increase in the activities of hepatic γ-glutamyl transpeptidase, acid ribonuclease, acid phosphatase and decrease in the activity of succinate dehydrogenase. The levels of RNA, total proteins, bilirubin, total lipids, phospholipids, cholesterol, lipid peroxides in liver and bilirubin in serum increased while hepatic glycogen and serum proteins decreased. At a lower dose (50 mg/kg; 61 μmol/kg) the changes were less as compared to 100 mg/kg dose. When Picroliv (12 mg/kg body weight), a standardized iridoid glycoside mixture of Picrorhiza kurroa was administered simultaneously with rifampicin, most of the biochemical changes in liver and serum were prevented. These results indicate protective effect of Picroliv against rifampicin-induced hepatotoxicity in rats. © 1994 Wiley-Liss, Inc.