Hepatoprotective effect of silyamarin in individuals chronically exposed to hydrogen sulfide; modulating influence of TNF-α cytokine genetic polymorphism

Background and the purpose of the study

Silymarin, a standardized extract of the milk thistle (Silybum marianum), is believed to exert some of its hepatoprotective effects though inhibition of free radicals and inflammation. In this study the effect of some pro- and anti-inflammatory cytokines and also antioxidant genes polymorphisms on the hepatoprotective effects of silymarin in the occupationally exposed individuals to hydrogen sulfide (H₂S) in the sour natural gas refinery was investigated.

Methods

We genotyped seven polymorphisms in six genes reported by others as modifiers of oxidative stress (NQO1, mEPXH1, GSTT1 and GSTM1) and inflammation (TNF-α and TGF-β1) for an association in effect of decreasing in liver function tests (LFTs). The LFTs of 77 sour gas refinery workers were measured before and after administration of silymarin (140 mg, three times per day for 1 month).

Results

A significant reduction of blood AST, ALT and ALP was observed after 30 days of consumption (p < 0.001). The decreasing effect of silymarin on ALT in the subjects with high producer genotype (A allele carriers) was less than low producers. There were no significant associations between TGF-β1 and the studied genes of oxidative stress pathway and the effectiveness of silymarin.

Conclusion

This is the first report about the effectiveness of silymarin in the subjects exposed chronically to H₂S. Meanwhile, the modulatory effect of TNF-α on the effectiveness of silymarin might be used for individualize therapy.     

复方茵柏颗粒对四氯化碳肝损伤模型大鼠氧化应激的影响

目的:研究复方茵柏颗粒对四氯化碳(CCl4)肝损伤模型大鼠氧化应激的影响。方法:48只SD大鼠随机分为正常对照(等容生理盐水)组、模型(等容生理盐水)组、复方茵柏合剂(8.65 g/kg)组与复方茵柏颗粒高、中、低剂量(8.64、4.32、2.16 g/kg)组。灌胃给药,每天1次,连续3周。末次给药2 h后一次性腹腔注射40%CCl4的玉米油以复制大鼠急性肝损伤模型。测定大鼠血清中丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)和乳酸脱氢酶(LDH)的活性,总胆红素(TBIL)、直接胆红素(DBIL)的含量;酶联免疫吸附(ELISA)法检测大鼠肝组织匀浆中丙二醛(MDA)和还原型谷胱甘肽(GSH)含量;并对大鼠肝组织作病理学检测。结果:与正常对照组比较,模型组大鼠血清ALT、AST、LDH活性显著增强,TBIL、DBIL含量显著增加,MDA含量显著增加,GSH活性显著减弱(P<0.01);与模型组比较,复方茵柏颗粒高、中、低剂量组大鼠血清ALT、AST、LDH活性显著减弱,TBIL、DBIL含量显著减少,MDA含量显著减少,GSH活性显著增强(P<0.01或P<0.05)。正常对照组大鼠肝小叶结构清晰,肝细胞索排列规则,肝细胞结构及形态正常,核大而圆,居中,核膜清晰;模型组大鼠大部分肝细胞明显水肿,气球样变,肝细胞索排列紊乱,肝小叶内中央静脉和汇管区出现弥漫性的炎细胞浸润;而复方茵柏颗粒高、中、低剂量组大鼠大部分肝细胞结构完整,排列整齐,肝细胞水肿、气球样变及炎细胞浸润均明显减轻。结论:复方茵柏颗粒对CCl4所致的大鼠急性肝损伤有一定的保护作用,其机制可能与其清除自由基、抑制脂质过氧化有关。     

In vitro and in vivo hepatoprotective and antioxidant activity of ethanolic extract from Meconopsis integrifolia (Maxim.) Franch

Ethnopharmacological relevance

Meconopsis integrifolia (Maxim.) Franch is a high mountain endemic species used as a traditional Tibetan and Mongolian herb to treat hepatitis, pneumonia, and edema. This study aims to investigate the hepatoprotective and antioxidant effects of Meconopsis integrifolia ethanolic extract (MIE) in vitro and in vivo.

Materials and methods

The in vitro antioxidant property of MIE was investigated by employing various established systems. Rats with carbon tetrachloride (CCl₄)-induced liver injury were used to assess the hepatoprotective and antioxidant effect of MIE in vivo. The level or activity of alkaline phosphatase (ALP), glutamate pyruvate transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) in the blood serum and thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) in the liver and kidney of the rats were assayed using standard procedures.

Results

MIE exhibited strong antioxidant ability in vitro. In the rats with CCl₄-induced liver injury, the groups treated with MIE and silymarin showed significantly lower levels of ALT, AST, ALP, and TB. MIE demonstrated good antioxidant activities in both the liver and kidney of the rats in vivo.

Conclusions

MIE exhibits excellent hepatoprotective effects and antioxidant activities in vitro and in vivo, supporting the traditional use of Meconopsis integrifolia in the treatment of hepatitis.     

肝硬化肝细胞癌患者行大范围肝切除术后的 护肝药物临床应用分析

目的：分析肝硬化肝细胞癌患者行大范围肝切除术后护肝药物的临床应用情况。 方法：纳入2020年1月 ～ 2022年6月南京大学医学院附属鼓楼医院肝胆胰中心收治入院的肝癌肝硬化并接受大范围肝切除手术的患者,针对用药方案的临床应用进行分析。结果：共纳入128例患者,术后单用护肝药物者67例（52.3%）,联合使用两种护肝药物者58例（45.3%）,联合使用三种护肝药物者3例（2.3%）。联合用药的患者手术时间以及术中肝门阻断时间均较单药治疗组长,腹腔镜手术的比例较低,预计剩余肝脏体积百分比较小,术中输血量较大,术后第1天谷丙转氨酶水平也较高。发生肝切除术后肝功能衰竭者共40例,联合使用护肝药物的患者发生率较高,但B级和C级肝功能衰竭的发生率与单药治疗组相比,差异无统计学意义。单药治疗与联合使用护肝药物治疗的患者相比,虽然胸、腹腔积液的发生率更低,但术后感染性并发症的发生率更高。结论：对于肝硬化肝细胞癌行大范围肝切除的患者,联合用药可能增加胸腹腔积液的发生风险,但是可以减少感染性并发症,改善预后。     

Long-term follow-up of cumulative incidence of hepatocellular carcinoma in hepatitis B virus patients without antiviral therapy

BACKGROUNDChina has a high prevalence of hepatitis B virus (HBV), but most chronic hepatitis B (CHB) patients do not receive standardized antiviral therapy. There are few relevant reports addressing the outcomes of the large number of CHB patients who do not receive antiviral therapy.AIMTo observe the outcomes of long-term follow-up of patients with CHB without antiviral treatment.METHODSThis study included 362 patients with CHB and 96 with hepatitis B cirrhosis without antiviral treatment and with only liver protection and anti-inflammatory treatment from 1993 to 1998. The median follow-up times were 10 and 7 years, respectively. A total of 203 CHB and 129 hepatitis B cirrhosis patients receiving antiviral therapy were selected as the control groups. The median follow-up times were 8 and 7 years, respectively. Kaplan-Meier curves were used to analyze the cumulative incidence of hepatocellular carcinoma (HCC), and the Cox regression model was used to analyze the risk factors for HCC.RESULTSAmong the patients in the non-antiviral group, 16.9% had spontaneous decreases in HBV DNA to undetectable levels, and 32.8% showed hepatitis B e antigen (HBeAg) seroconversion. In the antiviral group, 87.2% of patients had undetectable HBV DNA, and 52% showed HBeAg seroconversion. Among CHB and hepatitis B cirrhosis patients, the cumulative incidence rates of HCC were 14.9% and 53.1%, respectively, in the non-antiviral group and were 10.7% and 31.9%, respectively, in the antiviral group. There was no difference between the two groups regarding the CHB patients (P = 0.842), but there was a difference between the groups regarding the hepatitis B cirrhosis patients (P = 0.026). The cumulative incidence rates of HCC were 1.6% and 22.3% (P = 0.022) in the groups with and without spontaneous HBeAg seroconversion, respectively. The incidence rates of HCC among patients with and without spontaneous declines in HBV DNA to undetectable levels were 1.6% and 19.1%, respectively (P = 0.051). There was no difference in the cumulative incidence of HCC between the two groups regarding the patients with drug-resistant CHB (P = 0.119), but there was a significant difference between the two groups regarding the patients with cirrhosis (P = 0.004). The Cox regression model was used for regression of the corrected REACH-B score, which showed that alanine aminotransferase > 400 U/L, history of diabetes, and family history of liver cancer were risk factors for HCC among men aged > 40 years (P < 0.05). Multifactorial analysis showed that a family history of HCC among men was a risk factor for HCC.CONCLUSIONAntiviral therapy and non-antiviral therapy with liver protection and anti-inflammatory therapy can reduce the risk of HCC. Antiviral therapy may mask the spontaneous serological response of some patients during CHB. Therefore, the effect of early antiviral therapy on reducing the incidence of HCC cannot be overestimated.     

Protective effect of Tritone (Livosone) on oxidative DNA damage and its hepatoprotective potential against various hepatotoxic agent in wistar rats

Aim

To evaluate antioxidant activity, DNA damage inhibition and hepatoprotecitve potential of polyherbal formulation Tritone (Livosone).

异甘草酸镁与多烯磷脂酰胆碱预防化疗药物致非霍奇金淋巴瘤患者肝损伤的药物经济学研究

目的：观察异甘草酸镁与多烯磷脂酰胆碱对化疗药物所致非霍奇金淋巴瘤（NHL）患者急性药物性肝损伤的预防作用,并作药物经济学评价。方法：运用回顾性分析方法,选择2014年1月至2018年10月病理诊断为非霍奇金淋巴瘤的患者184例,分为异甘草酸镁组、多烯磷脂酰胆碱组。化疗方案分别采用CHOP方案、R-CHOP方案。观察患者化疗前后肝功能生化指标,统计患者住院期间保肝药物费用,对两种保肝方案作疗效和药物经济学评价。结果：两种保肝方案在预防NHL患者所致肝损伤疗效上无显著性差异（P>0.05）,最小成本分析结果显示,多烯磷脂酰胆碱的经济性较好。结论：两种保肝方案均能有效地预防化疗所致肝损伤,但多烯磷脂酰胆碱价格便宜,在经济性上具有明显优势。     

中药抗四氯化碳所致急性肝损伤作用研究进展

摘 要肝脏疾病是一种严重危害人类健康的疾病,四氯化碳（CCl4）诱导的肝损伤作为经典的急性肝损伤模型,广泛用于保肝药物的筛选。本文综述了近几年国内外中药及制剂对CCl4所致急性肝损伤保护作用的研究进展,为寻找高效低毒的保肝中药提供依据,也为推进肝病的中药治疗奠定基础。     

Effects of rosmarinic acid on acetaminophen-induced hepatotoxicity in male Wistar rats

Context: Drug-induced liver injury is a significant worldwide clinical problem. Rosmarinic acid (RA), a natural phenol, has antioxidant effects.

Objective: The effects of RA against acetaminophen (N-acetyl-p-amino-phenol (APAP))-induced oxidative damage and hepatotoxicity in rats were investigated.

Materials and methods: Male Wistar rats were pretreated with RA (10, 50 and 100?mg/kg, i.g.) for one week. On day 7, rats received APAP (500?mg/kg, i.p.). Then aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein, malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (TAC), glutathione S-transferase (GST), cytochrome CYP450 and histopathological changes were determined.

Results: APAP-induced oxidative stress in liver by a significant increase in the level of MDA (7.6?±?0.21?nmol/mg) as well as a decrease in the contents of TAC (1.75?±?0.14?μmol/g), GSH (1.9?±?0.22?μmol/g) and GST) 3.2?±?0.28?U/mg). RA treatment decreased MDA (4.32?±?0.35?nmol/mg) but increased the contents of TAC (3.51?±?0.34?μmol/g), GSH (3.42?±?0.16?μmol/g) and GST (5.71?±?0.71?μmol/g) in APAP group. RA 100?mg/kg decreased ALT (91.5?±?1.5?U/L), AST (169?±?8.8?U/L) and CYP450 (3?±?0.2?nmol/min/mg) in APAP group. Histologically RA attenuated hepatic damage by decreasing necrosis, inflammation, and haemorrhage in liver sections of APAP group.

Discussion and conclusions: This is the first report that oral administration of RA dose-dependently elicited significant hepatoprotective effects in rats through inhibition of hepatic CYP2E1 activity and lipid peroxidation. RA-protected hepatic GSH and GST reserves and total tissue antioxidant capacity.     

Hepatoprotective activity of Sapindus mukorossi and Rheum emodi extracts： In vitro and in vivo studies

AIM： To study the hepatoprotective capacity of Sapindus mukorossi （S. mukorossi） and Rheum emodi （R. emodi） extracts in CCl4 treated male rats. METHODS： The dried powder of S. mukorossi and R. emodi was extracted successively with petroleum ether, benzene, chloroform, and ethanol and concentrated in vacuum. Primary rat hepatocyte monolayer cultures were used for in vitro studies. In vivo, the hepatoprotective capacity of the extract of the fruit pericarp of S. mukorossi and the rhizomes of R. emodi was analyzed in liver injured CCl4-treated male rats. RESULTS： In vitro： primary hepatocytes monolayer cultures were treated with CCl4 and extracts of S. mukorossi ＆ R. emodi. A protective activity could be demonstrated in the CCl4 damaged primary monolayer culture. In vivo ： extracts of the fruit pericarp of S. mukorossi （2.5 mg/mL） and rhizomes of R. emodi （3.0 mg/mL） were found to have protective properties in rats with CCl4 induced liver damage as judged from serum marker enzyme activities. CONCLUSION： The extracts of S. mukorossi and R. emodi do have a protective capacity both in vitro on primary hepatocytes cultures and in in vivo in a rat model of CCl4 mediated liver injury.