Rosmarinic acid protects mice from lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting MAPKs/NF-κB and activating Nrf2/HO-1 signaling pathways

Rosmarinic acid (RA) has antioxidation, anticancer, antibacterial, anti-inflammatory and various biological functions. In our study, we aim to evaluate effects of RA on acute liver injury caused by LPS and d-galactosamine (d-GalN) and its underlying molecular mechanism in mice. Our findings showed that RA could protect C57BL/6 mice from LPS/d-GalN-induced acute liver injury, which not only reflected on declining aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of the serum, but also restrained the phosphorylation of nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK1/2) and p38 protein expression and the content of tissue myeloperoxidase (MPO) elevation. Moreover, RA could enhance the level of glutathione-dependent peroxidase (GSH-PX). Furthermore, RA promoted that nuclear factor erythroid-2-related factor 2 (Nrf2) transported into nucleus, and then up-regulated heme oxygenase 1 (HO-1), glutamate-cysteine ligase catalytic (GCLC), glutamate cysteine ligase modifier (GCLM) and quinone oxidoreductase (NQO1). These results indicated that RA could protect the mice from acute liver injury induced by LPS/d-GalN.     

黄芪提取物对小鼠急性化学性肝损伤的保护作用

目的探讨黄芪提取物（AE）对CCl4致小鼠急性化学性肝损伤模型的保护作用。方法采用CCl4诱导小鼠急性肝损伤模型,检测血清中丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）和肝匀浆中丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）含量,HE染色法对肝脏作病理检查。结果AE能显著降低小鼠血清ALT、AST、肝匀浆MDA水平,升高SOD和GSH-Px酶活性,减轻肝细胞损伤。结论AE对CCl4致小鼠急性化学性肝损伤模型具有保护作用。     

6,7-二乙酰黄芩素对四氯化碳和D-氨基半乳糖所致的急性肝损伤的保护作用

目的:研究6,7-二乙酰黄芩素对四氯化碳(CCl4)和D-氨基半乳糖(D-GalN)所致急性肝损伤的保护作用。方法:分别用CCl4和D-GalN诱导化学性急性肝损伤模型,测定血清中丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)水平;并用苏木素-伊红(HE)染色处理肝脏组织切片,光镜观察病理学改变;用试剂盒测定肝线粒体中AST,SOD和GSH-PX的活性及脂质过氧化产物MDA含量。结果:在CCl4和D-GalN诱导和的小鼠肝急性损伤模型中,6,7-二乙酰黄芩素给药(50,100 mg.kg-1,ig)明显降低血清ALT,AST水平;明显改善肝脏病理组织状况;6,7-二乙酰黄芩素给药(25,50,100 mg.kg-1,ig)明显降低CCl4诱导的肝急性损伤小鼠的肝线粒体中AST活性和MDA的含量,显著增加SOD和GSH-PX的活性。结论:6,7-二乙酰黄芩对CCl4和D-GalN诱导和的小鼠肝急性损伤均具有保护作用,该作用与其增加线粒体中抗氧化酶的酶的活性、降低脂质过氧化水平有关。     

复方护肝颗粒对D-半乳糖胺诱导小鼠化学性肝损伤的保护作用

目的探讨复方护肝颗粒对D-半乳糖胺（D-GalN）致小鼠急性化学性肝损伤的保护作用及可能机制。方法建立D-GalN诱导小鼠化学性肝损伤模型，分光光度法检测血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）水平和肝匀浆丙二醛（MDA）、一氧化氮（NO）含量。结果复方护肝颗粒（20、40和80mg／kg）灌胃给药均能降低血清中升高的转氨酶水平，使升高的肝脾指数降低；同时发现复方护肝颗粒可降低肝匀浆中升高的MDA和NO水平。结论复方护肝颗粒对D-GalN致小鼠急性化学性肝损伤具有保护作用，其机制与其抗氧化活性等有关。     

黄花远志根和叶提取物对急性肝损伤小鼠的保护作用

目的：研究黄花远志根和叶提取物对四氯化碳（CCl4）所致急性肝损伤小鼠的保护作用。方法：采用 CCl4诱导化学性急性肝损伤模型,测定小鼠肝脏指数、血清丙氨酸氨基转移酶（ALT）和天门冬氨酸氨基转移酶（AST）,观察小鼠肝脏病理学变化。结果：黄花远志根（4 g、2 g 生药／ kg）和叶（4 g、2 g 生药／ kg）提取物能显著降低 CCl4致小鼠急性肝损伤ALT 和 AST 的升高,明显改善 CCl4对肝组织的病理损伤。结论：黄花远志根和叶对 CCl4致小鼠急性肝损伤具有保护作用。     

虎杖提取物对小鼠急性肝损伤的保护作用

目的观察虎杖提取物对cch诱导的小鼠急性肝损伤的保护作用。方法采用CCl4诱导小鼠急性肝损伤模型,测定血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AsT）、肝组织超氧化物歧化酶（S（）D）活性及丙二醛（MDA）含量。结果cch诱导的小鼠急性肝损伤摸型,血清ALT、AST明显升高,肝组织SOD活性明显降低,MDA含量显著升高（P〈0．01）;虎杖提取物能显著降低血清ALT,AST,明显提高肝组织SOD活性,降低肝组织MDA含量（P〈0．01）。结论虎杖提取物具有降酶及抗氧化的作用。对CCh诱导的小鼠急性肝损伤具有一定的保护作用。     

高良姜对小鼠急性酒精性肝损伤的保护作用

目的:研究高良姜对小鼠急性酒精性肝损伤的保护作用。方法:连续灌胃35%二锅头白酒15ml/kg,10天建立酒精性肝损伤模型,测定肝脏系数、血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)活性。结果:高良姜可降低急性酒精性肝损伤小鼠肝脏系数,并降低急性酒精性肝损伤小鼠血清中ALT、AST含量的升高。结论:高良姜对小鼠急性酒精性肝损伤有较好的保护作用,其机制有待进一步研究。     

尼美舒利致成人斯蒂尔病患者肝肾功能损害

1例22岁初诊成人斯蒂尔病女性患者经甲泼尼龙抗炎以及护肝、护胃等治疗1周,关节痛及体温控制不理想,遂加用尼美舒利100 mg口服,2次/d。用该药前天冬氨酸转氨酶（AST）60 U/L,丙氨酸转氨酶（ALT）50 U/L,肾功能正常。9 d后复查,AST 458 U/L,ALT 450 U/L,怀疑为尼美舒利引起的药物性肝损害,故停用该药并加强护肝治疗。11 d后复查,AST 221 U/L,ALT 97 U/L。因病情需要,再次给予尼美舒利100 mg口服,2次/d。再次用药的第4天晨患者出现排尿困难,血清尿素11.2 mmol/L,肌酐109μmol/L,尿酸435μmol/L;第5天AST 542 U/L,ALT 104 U/L。考虑为尼美舒利引起的肝肾功能损害,停用该药。4 d后患者肾功能指标恢复正常;2周后AST 47 U/L,ALT32 U/L。     

灵芝益寿胶囊致肝损害

1例53岁女性患者,为滋补强身自行服用灵芝益寿胶囊4粒,3次/d.2个月后出现尿色深黄.约4个月后出现皮肤、巩膜黄染,上腹部不适,伴有恶心、乏力、倦怠.实验室检查：丙氨酸转氨酶（ALT）1114 U/L,天冬氨酸转氨酶（AST）611 U/L,γ-L-谷氨酰转移酶（γ-GT）235 U/L,碱性磷酸酶（ALP） 158 U/L,总胆红素（TBil） 104.5 μmol/L,直接胆红素（DBil） 63.2 μmol/L,间接胆红素（IBil）41.3 μmol/L,总胆汁酸（TBA） 165.3 μmol/L.诊断：药物性肝损害.停用灵芝益寿胶囊,给予还原型谷胱甘肽、异甘草酸镁及丁二磺酸腺苷蛋氨酸治疗.2周后复查肝功能：ALT 69 U/L,AST 35 U/L,γ-GT 100 U/L,ALP 137 U/L,TBil 30.1 μmol/L,DBil 14.4 μmol/L,IBil 15.7 μmol/L,TBA 70.2 μmol/L.     

柴胡乳剂对急性化学性肝损伤的保护作用

目的研究中药柴胡乳剂对急性化学性肝损伤的保护作用。方法经预防给药7 d后,采用四氯化碳(CCl4)、扑热息痛两种肝毒剂复制小鼠急性肝损伤模型,采用四氯化碳复制大鼠急性肝损伤模型,16 h后眼眶取血,测定大鼠、小鼠血清中丙氨酸氨基转移酶(ALT)、门冬氨酸氨基转移酶(AST)含量及血清蛋白的变化,观察柴胡乳剂对四氯化碳、扑热息痛所致小鼠及大鼠急性化学性肝损伤的保护作用。结果柴胡乳剂大、中剂量组均能明显降低四氯化碳、扑热息痛所致急性肝损伤后小鼠血清ALT、AST含量(P<0.01);柴胡乳剂大剂量组能明显降低四氯化碳所致急性肝损伤大鼠血清ALT、AST(P<0.05)含量,增加血清白蛋白(Alb)含量(P<0.05),改善肝功能。结论柴胡乳剂对四氯化碳、扑热息痛所致化学性急性肝损伤有一定的保护作用。     

Protection of Flos Lonicerae against acetaminophen-induced liver injury and its mechanism

This study aims to observe the protective action of Flos Lonicerae (FL) aqueous extract against acetaminophen (AP)-induced liver injury and its mechanism. Results show that FL decreases AP-increased serum alanine/aspartate transaminases (ALT/AST) activity, as well as total bilirubin (TB) amount, in mice. Histological evaluation of the liver further confirms the protection of FL against AP-induced hepatotoxicity. TdT-mediated biotin-dUTP nick-end labeling (TUNEL) assay shows that FL reduces AP-increased apoptotic cells. Furthermore, AP-decreased liver glutamate-cysteine ligase (GCL) enzymatic activity and glutathione (GSH) amount are both reversed by FL because of the increased expression of the catalytic subunit of GCL (GCLC) protein. The amount of chlorogenic acid (CGA), caffeic acid, and luteolin, the main active compounds in FL, is detected by high-performance liquid chromatography (HPLC). In addition, cell viability assay demonstrates that polyphenols in FL, such as CGA, caffeic acid, as well as isochlorogenic acids A, B, and C, can reverse AP-induced cytotoxicity. In conclusion, FL can prevent AP-induced liver injury by inhibiting apoptosis. The cellular antioxidant enzyme GCL is also involved in such protection. Polyphenols may be the main active hepato-protective ingredients in FL.     

清开灵注射液对四氯化碳致小鼠急性肝损伤的保护机制研究

目的：观察清开灵注射液对小鼠急性肝损伤的保护作用,并阐明其可能机制.方法：建立小鼠CCl4急性肝损伤模型,观察清开灵注射液对CCl4诱导升高的小鼠血清ALT、AST活性影响,及对肝脏病理损伤的保护作用;测定肝组织中丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性.结果：与阴性对照组比较,模型组小鼠ALT和AST均显著升高（P＜0.01）,MDA明显增加（P＜0.01）,SOD显著降低（P＜0.01）,组织病理损伤明显.与模型组比较,清开灵注射液中剂量组（10 ml·kg^-1）和高剂量组（20 ml·kg^-1）均能显著降低肝损伤小鼠的ALT和AST（P ＜0.05 或0.01）,并明显减轻了肝脏组织的病理损伤.清开灵注射液低剂量组（5 ml· kg^-1）、中剂量组和高剂量组的MDA均较模型组显著降低（P＜O.05或0.01）,SOD水平则显著升高（P＜0.05或0.01）.结论：清开灵注射液对小鼠CCl4致急性肝损伤的保护作用可能与其抗脂质过氧化作用有关.     

In vitro hepatotoxicity of alachlor and its by-products.

During water treatment, potentially hazardous chemical by-products may be formed. Alachlor (2-chloro-N-(2, 6-diethylphenyl)-N-(methoxymethyl) acetamide) is a widely used pre-emergence herbicide. The present study investigated the toxicity of alachlor and its disinfection by-products on freshly isolated rat hepatocytes. Hepatocytes were harvested by a collagenase perfusion technique and were exposed to different concentrations of alachlor and its by-products for up to 2 h. Cell viability, the leakage of aspartate transaminase (AST) and alanine transaminase (ALT) and glutathione (GSH) depletion were determined throughout the incubation period. The cell viability of the hepatocytes exposed to 100 microg ml(-1) alachlor was decreased by 20% compared with the control after 60 min of incubation. At the same concentration of alachlor the leakage of ALT and AST was increased by 56% and 45%, respectively. Cell viability of the hepatocytes was decreased upon exposure to 2-chloro-N-(3-chloro-2,6-diethylphenyl)-N-(methoxymethyl) acetamide (CCDMA) and 2-chloro-N-(3-chloro-2,6-diethylphenyl) acetamide (CCDA)--the by-products of alachlor and chlorine--after 60 min of exposure. At 100 microg ml(-1) CCDMA the AST leakage was increased significantly (73%) after 30 min of incubation. The reaction mixture of alachlor (100 microg ml(-1)) and chlorine dioxide (1 ppm) caused significant increases in cell loss and ALT and AST levels by 22%, 40% and 34%, respectively, as early as 15 min incubation. Alachlor (100 and 200 microg ml(-1)) caused significant decreases in GSH contents (62%) in isolated hepatocytes. The reaction mixture of alachlor and chlorine dioxide led to significant glutathione depletion (44%) after 60 min of incubation. The by-products of alachlor and chlorine--CCDMA and CCDA--depleted GSH almost completely (93%). This investigation suggested that the by-products formed from the reaction of alachlor and chlorine decreased GSH and increased the leakage of liver enzymes, especially AST.     

二至丸水提物对体外肝细胞损伤的保护作用

目的研究二至丸水提物（aqueous extract of Erzhi Pill,AEEP）对体外肝细胞损伤的保护作用及其机制。方法培养L-O2型肝细胞,采用H2O2和CCl4体外分别诱导肝细胞损伤,检测培养上清液中天门冬氨酸转换酶（AST）和丙氨酸氨基转换酶（ALT）水平,测定上清液中丙二醛（MDA）的含量和过氧化物岐化酶（SOD）活力,MTT法检测细胞存活和增殖活性。结果①AEEP（0.32~40μg/ml）剂量组可明显降低由H2O2升高的肝细胞培养上清液中AST和ALT水平及MDA含量,还可提高H2O2降低的肝细胞存活率和SOD活力;②AEEP（0.32~40μg/ml）剂量组可使CCl4升高的肝细胞培养上清液中ALT和ALT水平及MDA含量明显降低或恢复,还可提高CCl4降低的肝细胞存活率和SOD活力。结论提示AEEP对体外肝细胞损伤有直接保护作用,该作用可能与其抗氧化作用有关。     

Hepatoprotective activity of Terminalia catappa L. leaves and its two triterpenoids

The aim of this study was to evaluate the effect of the chloroform extract of Terminalia catappa L. leaves (TCCE) on carbon tetrachloride (CCl(4))-induced acute liver damage and D-galactosamine (D-GalN)-induced hepatocyte injury. Moreover, the effects of ursolic acid and asiatic acid, two isolated components of TCCE, on mitochondria and free radicals were investigated to determine the mechanism underlying the action of TCCE on hepatotoxicity. In the acute hepatic damage test, remarkable rises in the activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (5.7- and 2.0-fold) induced by CCl(4) were reversed and significant morphological changes were lessened with pre-treatment with 50 and 100 mg kg(-1) TCCE. In the hepatocyte injury experiment, the increases in ALT and AST levels (1.9- and 2.1-fold) in the medium of primary cultured hepatocytes induced by D-GalN were blocked by pre-treatment with 0.05, 0.1, 0.5 g L(-1) TCCE. In addition, Ca(2+)-induced mitochondrial swelling was dose-dependently inhibited by 50-500 microM ursolic acid and asiatic acid. Both ursolic acid and asiatic acid, at concentrations ranging from 50 to 500 microM, showed dose-dependent superoxide anion and hydroxyl radical scavenging activity. It can be concluded that TCCE has hepatoprotective activity and the mechanism is related to protection of liver mitochondria and the scavenging action on free radicals.     

Pretreatment of Albino Rats with Methanolic Fruit Extract of Randia Dumetorum (L.) Protects against Alcohol Induced Liver Damage

Alcohol abuse and its medical and social consequences are a major health problem in many areas of the world. The present study was conducted to evaluate the protective effect of methanolic fruit extract of Randia dumetorum (L.) on alcohol-induced liver damage in rats. Rats were divided into five different groups (n=6), group I served as a control, group II received ethanol (3 ml/100 g/day p.o.), group III served as standard group and received silymarin (50 mg/kg p.o.), group IV and V served as extract treatment groups and received 50 & 100 mg/kg methanolic extract of R. dumetorum. All the treatment protocols followed 30 days and after rats were sacrificed blood and liver were used for biochemical and histological studies, respectively. The activities serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), direct bilirubin (DB), total bilirubin (TB) and lipid peroxidation were statistically increased in rats exposed to alcohol while total protein and glutathione decreased compared to control rats. Treatment with R. dumetorum significantly decreased the elevated levels of ALT, AST, TG, DB, TB and lipid peroxidation compared to the group exposed to alcohol only. R. dumetorum significantly resulted in increased levels of total protein and reduced glutathione compared to the group that received alcohol only. Histology of the liver section of the animals treated with R. dumetorum improved the hepatotoxicity caused by alcohol. Hence the study concluded that R. dumetorum has potential hepatoprotective activity.     

痔血胶囊组方对原代培养大鼠肝细胞和小鼠肝脏的毒性

目的研究痔血胶囊组方白鲜皮和苦参对原代大鼠肝细胞和小鼠肝脏的毒性。方法二步灌流法分离原代大鼠肝细胞并接种于96孔板,培养贴壁后加入一系列浓度的苦参醇提物（ESF）、白鲜皮醇提物（ECD）、苦参自鲜皮复方醇提物（ECF）、苦参素及苦参碱,利用噻唑蓝（MTT）方法检测细胞存活率。另将30只小鼠随机分为溶剂对照组、潜在肝毒性组（50mg·ks^-1）,连续7d尾静脉注射,测定血清丙氨酸氨基转移酶（ALT）和门冬氨酸氨基转移酶（AST）水平。结果体外实验中,孵育24h后,苦参组250、500mg·L^-1的肝细胞活力降至15％以下,与对照组相比活力显著降低（P〈0．01）。ECD、ECF在质量浓度62．5-500mg·L^-1内未见肝细胞活力抑制作用。苦参素（0．05～5mol·L^1）、苦参碱（0．05-5mol·L^-1）对肝细胞活力均未见抑制作用。静脉注射7d后,苦参组小鼠血清ALT水平与对照组相比显著升高（17．05 vs 12．81U·L^-1,P〈0．05）。结论痔血胶囊的肝毒性很可能源于ESF。     

虎杖提取物对CCl_4诱导的小鼠急性肝损伤的保护作用

目的观察虎杖提取物对CCl4诱导的小鼠急性肝损伤的保护作用。方法采用CCl4诱导小鼠急性肝损伤模型,测定血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、肝组织超氧化物歧化酶（SOD）活性及丙二醛（MDA）含量。结果 CCl4诱导的小鼠急性肝损伤模型,血清ALT、AST明显升高,肝组织SOD活性明显降低,MDA含量显著升高（P〈0.01）;虎杖提取物能显著降低血清ALT,AST,明显提高肝组织SOD活性,降低肝组织MDA含量（P〈0.01）。结论虎杖提取物具有降酶及抗氧化的作用,对CCl4诱导的小鼠急性肝损伤具有一定的保护作用。     

降脂利肝颗粒对小鼠急性肝损伤的保护作用

目的：研究降脂利肝颗粒对急性肝损伤小鼠的保护作用。方法：以四氯化碳（CCl4）诱导急性肝损伤制作肝损伤小鼠模型，分别给予低（100mg／kg）、中（300mg／kg）、高（900mg／kg）3个剂量的降脂利肝颗粒浸膏，以联苯双酯（200mg／kg）为阳性对照药物，检测血清中丙氨酸氨基转移酶（ALT）和门冬氨酸氨基转移酶（AST）的水平，并进行病理学检查。结果：与模型对照组比较，降脂利肝颗粒浸膏低、中、高3个剂量组ALT和AST水平显著降低（P〈0．05）。降脂利肝颗粒浸膏低剂量组降低ALT水平的作用不如阳性对照联苯双酯组明显，中、高剂量组作用与联苯双酯组相似。降脂利肝颗粒浸膏低、中、高3个剂量组均能减轻肝组织病理损伤程度。结论：降脂利肝颗粒对小鼠急性肝损伤具有较好的保护作用。     

l-Theanine prevents alcoholic liver injury through enhancing the antioxidant capability of hepatocytes

l-Theanine is a unique amino acid in green tea. We here evaluated the protective effects of l-theanine on ethanol-induced liver injury in vitro and in vivo. Our results revealed that l-theanine significantly protected hepatocytes against ethanol-induced cell cytotoxicity which displayed by decrease of viability and increase of LDH and AST. Furthermore, the experiments of DAPI staining, pro-caspase3 level and PARP cleavage determination indicated that l-theanine inhibited ethanol-induced L02 cell apoptosis. Mechanically, l-theanine inhibited loss of mitochondrial membrane potential and prevented cytochrome c release from mitochondria in ethanol-treated L02 cells. l-Theanine also prevented ethanol-triggered ROS and MDA generation in L02 cells. l-Theanine restored the antioxidant capability of hepatocytes including GSH content and SOD activity which were reduced by ethanol. In vivo experiments showed that l-theanine significantly inhibited ethanol-stimulated the increase of ALT, AST, TG and MDA in mice. Histopathological examination demonstrated that l-theanine pretreated to mice apparently diminished ethanol-induced fat droplets. In accordance with the in vitro study, l-theanine significantly inhibited ethanol-induced reduction of mouse antioxidant capability which included the activities of SOD, CAT and GR, and level of GSH. These results indicated that l-theanine prevented ethanol-induced liver injury through enhancing hepatocyte antioxidant abilities.