Probucol attenuates ethanol‐induced liver fibrosis in rats by inhibiting oxidative stress,extracellular matrix protein accumulation and cytokine production

相似文献   

Naringenin attenuates CCl4‐induced hepatic inflammation by the activation of an Nrf2‐mediated pathway in rats

The possible protective effects of naringenin, a naturally occurring citrus flavonone, on carbon tetrachloride (CCl₄)‐induced liver injury in rats and the mechanism underlying its effects were investigated. Forty rats were divided into five groups. Rats in Groups I and II served as the normal and injured liver groups, respectively; Group III rats were treated with the standard drug silymarin as a positive control; and rats in Groups IV and V (naringenin‐treated groups) were administrated 50 mg/kg, p.o., naringenin for 7 days. Liver samples were collected to evaluate mRNA and protein expression, histological changes and oxidative stress. Naringenin inhibited lipid peroxidation and reduced serum levels of hepatic enzymes induced by CCl₄. In addition, naringenin increased the liver content of reduced glutathione and the activity of anti‐oxidant enzymes in rats treated with CCl₄. Naringenin attenuated liver inflammation by downregulating CCl₄‐induced activation of tumour necrosis factor (TNF)‐α, inducible nitric oxide synthase (iNOS) and cyclo‐oxygenase (COX‐2) at both the protein and mRNA levels. Naringenin treatment significantly increased NF‐E2‐related factor 2 (Nrf2) and heme oxygenase (HO‐1) expression in injured livers. In rats treated with CCl₄ alone, decreases were seen in nuclear Nrf2 expression and in the mRNA levels of its target genes (e.g. HO‐1, NQO1 and glutathione S‐transferase alpha 3 (GST‐a3)). Together, the results suggest that naringenin can protect the liver against oxidative stress, presumably by activating the nuclear translocation of Nrf2 as well as attenuating the TNF‐α pathway to elicit an anti‐inflammatory response in liver tissue.     

Increasing the effectiveness of tyrosine kinase inhibitor (TKI) in combination with a statin in reducing liver fibrosis

It has been shown that both nilotinib as a tyrosine kinase inhibitor, and atorvastatin as a rho‐kinase inhibitor, have antifibrotic effects. Therefore, considering the relationship between these two pathways, this study aimed to investigate the effects of their co‐treatment against hepatic stellate cells (HSCs) activation and liver fibrosis. For this purpose, the activation of HSCs coincided with these therapies. Also, liver fibrosis by carbon tetrachloride (CCl₄) was induced in male Wistar rats and treated simultaneously with these compounds. The expression of alpha‐smooth muscle actin (α‐SMA), connective tissue growth factor (CTGF), Ras homolog gene family, and member A (RhoA)/Rho‐associated protein kinase (ROCK) in HSCs were measured. The expression of transforming growth factor beta‐1 (TGF‐β1), its receptor (TβRII), CTGF, and platelets derived growth factor (PDGF), in the livers, were also investigated, all by real‐time PCR and western blot analysis. Also, histopathologic and immunohistochemical evaluations were performed to evaluate changes in liver fibrosis during treatment. The results indicated the down‐regulation of RhoA/ROCK, CTGF, and α‐SMA, and inhibition of the HSCs activation toward myofibroblasts. The results also showed that the combined use of atorvastatin and nilotinib has significantly higher inhibitory effects. The antifibrotic effects of atorvastatin and nilotinib co‐administration were also observed by histopathologic and immunohistochemical observations, and inhibiting the expression of TGF‐β1, TβRII, CTGF, and PDGF. Taken together, this study revealed that co‐administration of nilotinib–atorvastatin has novel antifibrotic effects, by inhibiting RhoA/ROCK, and CTGF pathway. Therefore, the importance of the common pathway of RhoA/ROCK and CTGF, in reducing fibrosis may almost be concluded.     

Angiotensin-converting enzyme inhibitor prevents oxidative stress,inflammation, and fibrosis in carbon tetrachloride-treated rat liver

Hepatic fibrosis is a common feature of chronic liver injury, and the involvement of angiotensin II in such process has been studied earlier. We hypothesized that anti-angiotensin II agents may be effective in preventing hepatic fibrosis. In this study, Long Evans female rats were used and divided into four groups such as Group-I, Control; Group-II, Control?+?ramipril; Group-III, CCl₄; and Group-IV, CCl_4?+_?ramipril. Group II and IV are treated with ramipril for 14 d. At the end of treatment, the livers were removed, and the level of hepatic marker enzymes (aspartate aminotransferase, Alanine aminotransferase, and alkaline phosphatase), nitric oxide, advanced protein oxidation product , catalase activity, and lipid peroxidation were determined. The degree of fibrosis was evaluated through histopathological staining with Sirius red and trichrome milligan staining. Carbon-tetrachloride (CCl₄) administration in rats developed hepatic dysfunction and raised the hepatic marker enzymes activities significantly. CCl₄ administration in rats also produced oxidative stress, inflammation, and fibrosis in liver. Furthermore, angiotensinogen-inhibitor ramipril normalized the hepatic enzymes activities and improved the antioxidant enzyme catalase activity. Moreover, ramipril treatment ameliorated lipid peroxidation and hepatic inflammation in CCl₄-treated rats. Ramipril treatment also significantly reduced hepatic fibrosis in CCl₄-administered rats. In conclusion, our investigation suggests that the antifibrotic effect of ramipril may be attributed to inhibition of angiotensin-II mediated oxidative stress and inflammation in liver CCl₄-administered rats.     

Antifibrotic effects of D‐limonene (5(1‐methyl‐4‐[1‐methylethenyl]) cyclohexane) in CCl4 induced liver toxicity in Wistar rats

This study was designed to assess the potential antifibrotic effect of D‐Limonene—a component of volatile oils extracted from citrus plants. D‐limonene is reported to have numerous therapeutic properties. CCl₄‐intduced model of liver fibrosis in Wistar rats is most widely used model to study chemopreventive studies. CCl₄‐intoxication significantly increased serum aminotransferases and total cholesterol these effects were prevented by cotreatment with D‐Limonene. Also, CCl₄‐intoxication caused depletion of glutathione and other antioxidant enzymes while D‐Limonene preserved them within normal values. Hydroxyproline and malondialdehyde content was increased markedly by CCl₄ treatment while D‐Limonene prevented these alterations. Levels of TNF‐α, TGF‐β, and α‐SMA were also assessed; CCl₄ increased the expression of α‐SMA, NF‐κB and other downstream inflammatory cascade while D‐Limonene co‐treatment inhibited them. Collectively these findings indicate that D‐Limonene possesses potent antifibrotic effect which may be attributed to its antioxidant and anti‐inflammatory properties.     

Hepatoprotective activity of Feronia limonia root

Objectives The aim of this study was to evaluate the hepatoprotective potential of a methanolic extract and of marmesin isolated from the root bark of Feronia limonia. Methods Activity levels of aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), cell viability and cell death were evaluated in HepG2 cells (human liver hepatoma cells) treated with CCl₄ in the presence or absence of F. limonia extract or marmesin. Plasma activity levels of AST, ALT, bilirubin, alkaline phosphatase, protein, hepatic antioxidants, lipid peroxidation and histopathological evaluations were carried out in rats treated with CCl₄ alone or co‐supplemented with F. limonia extract or marmesin in a dose‐dependent manner. Key findings In‐vitro co‐supplementation of F. limonia methanolic extract or marmesin significantly minimized alteration in levels of AST and ALT and improved cell viability. Oral administration of F. limonia methanolic extract or marmesin significantly prevented CCl₄‐induced elevation in the plasma markers of hepatic damage and hepatic lipid peroxidation and a decrease in hepatic antioxidants. In‐vivo hepatoprotective potential of F. limonia methanolic extract and marmesin was evident from the minimal alterations in the histoarchitecture of liver. Conclusions This has been the first scientific report on the hepatoprotective potential of F. limonia root bark methanolic extract and marmesin.     

Aloe‐Emodin Quinone Pretreatment Reduces Acute Liver Injury Induced by Carbon Tetrachloride

Aloe contains several active compounds including aloin, a C‐glycoside that can be hydrolyzed in the gut to form aloe‐emodin anthrone which, in turn, is auto‐oxidized to the quinone aloe‐emodin. On the basis of the claimed hepatoprotective activity of some antraquinones, we studied aloe‐emodin in a rat model of carbon tetrachloride (CCl₄) intoxication, since this xenobiotic induces acute liver damage by lipid peroxidation subsequent to free radical production. Twelve rats were treated with CCl₄ (3 mg/kg) intraperitoneally and six were protected with two intraperitoneally injections of aloe‐emodin (50 mg/kg; CCl₄+aloe‐emodin); six other rats were only aloe‐emodin injected (aloe‐emodin) and six were untreated (control). Histological examination of the livers showed less marked lesions in the CCl₄+aloe‐emodin rats than in those treated with CCl₄ alone, and this was confirmed by the serum levels of L‐aspartate‐2‐oxoglutate‐aminotransferase (394±38.6 UI/l in CCl₄, 280±24.47 UI/l in CCl₄+aloe‐emodin rats; P<0.05). We also quantified changes in hepatic albumin and tumour necrosis factor‐α mRNAs. Albumin mRNA expression was significantly lower only in the liver of CCl₄ rats (P<0.05 versus control) and was only slightly reduced in the CCl₄+aloe‐emodin rats. In contrast tumour necrosis factor‐α mRNA was significantly higher (P<0.05) in the CCl₄ than the control rats and almost equal in the CCl₄+aloe‐emodin, aloe‐emodin and control groups. In conclusion, aloe‐emodin appears to have some protective effect not only against hepatocyte death but also on the inflammatory response subsequent to lipid peroxidation.     

CCl4致大鼠慢性肝损伤模型参数优化及代谢组学评价

目的 研究CCl₄致大鼠慢性肝损伤模型的最佳造模剂量和时间,并进行代谢组学评价。方法 SPF级雄性SD大鼠随机分为6组,即对照组和10%、20%、30%、40%、50% CCl₄组。CCl₄组sc给予不同浓度的CCl₄大豆油溶液,注射体积为2 mL/kg,每周2次,连续8周,对照组给予等体积溶剂油。大鼠于造模0、2、4、6、8周末置代谢笼12 h收集尿液,取出后采用眼球后静脉丛穿刺法取静脉血0.3 mL,常规分离血清;4、6周末各处死3只大鼠,取肝脏;8周末造模后处死大鼠,分离各脏器,称质量计算脏器系数。观察动物体质量、肝脏外观和病理切片、全自动生化仪检测血清丙氨酸转氨酶（ALT）和天门冬氨酸转氨酶（AST）。对10% CCl₄组尿液进行氢核磁共振（¹H-NMR）代谢组学测定,运用SPSS、MatLab7.5、SIMCA-P软件对数据进行分析。结果 对照组大鼠体质量保持增长;随着CCl₄剂量增高,各模型组大鼠体质量增长速度渐趋缓慢。造模8周后,与对照组比较,10% CCl₄组肝脏系数显著升高（P<0.01）,其他组肝脏系数无显著性变化;20%~50% CCl₄组的脾脏、肾脏系数,20%、40%、50% CCl₄组的肺脏系数均显著升高（P<0.05、0.01）。造模4周后,10% CCl₄组大鼠肝脏出现了慢性炎症表现,而20%~50% CCl₄组大鼠肝脏损伤明显,出现明显坏死现象;6周后,造模组大鼠肝脏均出现肝硬化病变。造模组大鼠血清ALT和AST与对照组比较均显著升高（P<0.05、0.01）,且均出现了先升高后降低趋势。代谢组学研究结果显示,造模4周起大鼠尿液与0周可以显著分离。共寻找到差异代谢物15个,6条重要的代谢通路,涉及能量代谢、脂质代谢、氨基酸和核苷酸代谢等途径。结论 慢性肝损伤模型造模剂量以10% CCl₄、2 mL/kg为宜,造模时间以4~6周为宜,代谢组学研究可以动态追踪造模过程。     

Liver fibrosis in mice induced by carbon tetrachloride and its reversion by luteolin

Hepatic fibrosis is effusive wound healing process in which excessive connective tissue builds up in the liver. Because specific treatments to stop progressive fibrosis of the liver are not available, we have investigated the effects of luteolin on carbon tetrachloride (CCl₄)-induced hepatic fibrosis. Male Balb/C mice were treated with CCl₄ (0.4 ml/kg) intraperitoneally (i.p.), twice a week for 6 weeks. Luteolin was administered i.p. once daily for next 2 weeks, in doses of 10, 25, and 50 mg/kg of body weight. The CCl₄ control group has been observed for spontaneous reversion of fibrosis. CCl₄-intoxication increased serum aminotransferase and alkaline phosphatase levels and disturbed hepatic antioxidative status. Most of these parameters were spontaneously normalized in the CCl₄ control group, although the progression of liver fibrosis was observed histologically. Luteolin treatment has increased hepatic matrix metalloproteinase-9 levels and metallothionein (MT) I/II expression, eliminated fibrinous deposits and restored architecture of the liver in a dose-dependent manner. Concomitantly, the expression of glial fibrillary acidic protein and α-smooth muscle actin indicated deactivation of hepatic stellate cells. Our results suggest the therapeutic effects of luteolin on CCl₄-induced liver fibrosis by promoting extracellular matrix degradation in the fibrotic liver tissue and the strong enhancement of hepatic regenerative capability, with MTs as a critical mediator of liver regeneration.     

灵芝孢子油对大鼠肝纤维化的干预作用

目的 探讨灵芝孢子油对大鼠肝纤维化的影响。方法 选择40% CCl₄皮下注射诱导SD大鼠肝纤维化形成,造模同时用低、中、高剂量（0.33,0.67,2.00 g·kg^-1）灵芝孢子油灌胃干预（每组10只）,观察血浆谷草转氨酶（AST）、谷丙转氨酶（ALT）、丙二醛（MDA）、透明质酸（HA）和肝组织MDA、羟脯氨酸（HyP）等的变化,肝组织HE和Masson染色观察病理变化。结果 灵芝孢子油能显著降低CCl₄所致的肝纤维化大鼠血浆AST、ALT、MDA、HA水平（P<0.05）,降低肝组织HyP、MDA含量（P<0.05）,肝脏病理显示纤维化程度明显减轻（P<0.05）。结论 灵芝孢子油对CCl₄诱导的大鼠肝纤维化具有保护作用。     

Deferoxamine alleviates liver fibrosis induced by CCl4 in rats

Several chronic liver diseases can lead to the occurrence of hepatic fibrosis through the accumulation of iron, which causes induction of oxidative stress and consequently activation of fibrogenesis. The present study was designed to investigate the potential antifibrotic and anti‐oxidant effects of deferoxamine (DFO), a well‐known iron chelator in an experimental rat model of liver injury using carbon tetrachloride (CCl₄). First, the potential effective dose of DFO was screened against CCl₄‐induced acute hepatotoxicity. Then, rats were co‐treated with DFO (300 mg/kg, i.p.) for 6 weeks starting from the third week of CCl₄ induction of chronic hepatotoxicity. Liver function was assessed in addition to histopathological examination. Furthermore, oxidative stress and fibrosis markers were assessed. It was found that treatment of animals with DFO significantly counteracted the changes in liver function; histopathological lesions and hepatic iron deposition that were induced by CCl₄. DFO also significantly counteracted the CCl₄‐induced lipid peroxidation increase and reduction in antioxidant activities of superoxide dismutase and glutathione peroxidase enzymes. In addition, DFO ameliorated significantly liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cells (HSCs) activation marker; alpha smooth muscle actin and transforming growth factor‐beta (TGF‐β). Together, these findings indicate that DFO possesses a potent antifibrotic effect due to its antioxidant properties that counteracted oxidative stress and lipid peroxidation and restored antioxidant enzymes activities as well as reducing HSCs activation and fibrogenesis.     

Evaluation of the effect of losartan and methotrexate combined therapy in adjuvant-induced arthritis in rats

There is increasing body of evidence documenting the involvement of angiotensin II in inflammatory diseases. Moreover the up-regulation of angiotensin II AT₁ receptors in the synovium of rheumatoid arthritis patients has been previously described.This study aimed at investigating the anti-inflammatory effect of losartan, the selective angiotensin II AT₁ receptor blocker, and comparing the efficacy of methotrexate alone and in combination with losartan in adjuvant arthritis in rats. Twelve days post adjuvant injection, Sprague-Dawley rats were treated with methotrexate (1 mg/kg/week), losartan (20 mg/kg/day) and their combination for 15 days. Severity of arthritis was assessed by hind paw swelling, arthrogram scores. Serum was analyzed for measurement of albumin, C-reactive protein (CRP), nitrite/nitrate concentrations, interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), aspartate transaminase (AST) and alanine transaminase (ALT). Histopathological examination was done for hind paws and livers. Methotrexate and losartan monotherapies significantly reduced all parameters of inflammation and arthritis with better results in the methotrexate group except for the transaminases where losartan caused more significant reduction in their serum levels. The combined therapy showed better results than methotrexate and losartan alone. Hind paws showed better improvement of inflammatory cell infiltration and bone resorption in the combined therapy group. Disturbances in liver architecture and fibrosis caused by adjuvant arthritis were reverted to normal status in the combined therapy group in contrast to losartan and methotrexate monotherapies. In conclusion, methotrexate and losartan combined therapy provided more effective anti-inflammatory and hepatoprotective effects than either drug alone.     

Hydroxysafflor yellow A suppresses liver fibrosis induced by carbon tetrachloride with high-fat diet by regulating PPAR-γ/p38 MAPK signaling

Context: One approach to protect against liver fibrosis is the use of herb-derived natural compounds, such as hydroxysafflor yellow A (HSYA). The antifibrosis effect of HYSA against liver fibrosis has been investigated; however, its mechanisms have not yet been entirely revealed.

Objectives: To study the protective effects of HSYA on liver fibrosis induced by carbon tetrachloride (CCl₄) and a high-fat diet (HFD), and to determine the mechanism of action of HSYA.

Materials and methods: CCl₄ and HFD were used to mimic liver fibrosis in rats, and serum biochemical indicators were determined. The antifibrosis effects of HSYA were evaluated and its mechanisms were investigated by histopathological analysis, immunohistochemical staining, enzyme-linked immunosorbent assays, real-time-PCR, and western blotting.

Results: HSYA reduced CCl₄- and HFD-mediated liver fibrosis and ameliorated serum biochemical indicator, downregulated the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) (0.31?±?0.03 protein, 0.59?±?0.02 mRNA) and transformin growth factor-β1 (TGF-β1) (0.81?±?0.02 protein, 0.58?±?0.04 mRNA), and upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) (1.57?±?0.13 protein, 2.48?±?0.19 mRNA) and matrix metallopeptidases-2 (MMP-2) (2.31?±?0.16 protein, 2.79?±?0.22 mRNA) (p?Discussion and conclusion: These data demonstrate a novel role for HSYA in inhibiting CCl₄- and HFD-mediated liver fibrosis, and reveal that PPAR-γ and p38 MAPK signaling play pivotal roles in the prevention of liver fibrosis induced by CCl₄ and HFD.     

Hepatoprotective effects of Portulaca oleracea extract against CCl4-induced damage in rats

Abstract

Context: Purslane (Portulaca oleracea L., Portulacaceae) has been traditionally used in folk medicine to afford protection against liver injury, although its actual efficacy remains uncertain.

Objective: To evaluate purslane as a hepatoprotective agent, we investigated the protective effect of its ethanol extract against carbon tetrachloride (CCl₄)-induced hepatic toxicity in rats.

Materials and methods: A total of 108 male Wistar rats were randomly divided into 12 groups. The first group was maintained as normal control, whereas CCl₄ (0.5?ml/kg bw, 50% CCl₄ in olive oil, i.p.), purslane extract (0.005, 0.01, 0.05, 0.1, and 0.15?g/kg bw, intragastrically), and purslane extract (five doses as above) along with CCl₄ were administered to the Groups II, III–VII, and VIII–XII, respectively. The rats were sacrificed on the 30th day, and blood was withdrawn by cardiac puncture. Liver damage was assessed by measuring hepatic marker enzymes (ALT, AST, ALP, GGT, and SOD) and histopathological observation.

Results: Treatment with CCl₄ resulted in increased serum activities of marker enzymes with a concomitant decrease in SOD. Histological alterations were also observed in the liver tissue upon CCl₄ treatment. Administration of purslane extract (0.01, 0.05, 0.1, and 0.15?g/kg b.w.) significantly showed a marked tendency towards normalization of all measured biochemical parameters in CCl₄-treated rats. Histopathological changes also paralleled the detected alteration in markers of liver function.

Discussion and conclusion: These results demonstrate that purslane exerts protective effects against CCl₄-induced damage in rat liver and supports a potential therapeutic use of purslane as an alternative for patients with liver diseases.     

Alleviation of CCl4-induced cirrhosis in rats by tetramethylpyrazine is associated with downregulation of leptin and TGF-β1 pathway

This study was conducted to investigate the effect of tetramethylpyrazine (TMP) on CCl₄-induced fibrosis in rats and the possible roles of leptin, TGF-β1, Smad3, and Smad7 in this process. Liver fibrosis in rats was induced by the subcutaneous injection of 60% CCl₄ (0.3?mL /100?g body weight, biweekly ) for 12 weeks. Rats in TMP prevention and treatment groups were given TMP (10?mg /100?g body weight, daily) by gavage from days 1 and 31 after the start of CCl₄ injection, respectively. The mRNA expression of leptin, OB-Rb, TGF-β1, and TGF-βRII in the liver were detected by RT-PCR, whereas Smad3 and Smad7 protein were determined by Western blot. The results showed that hepatic cirrhosis was obviously alleviated in both TMP prevention and treatment groups. The mRNA expression of leptin, OB-Rb, TGF-β1 and -βRII, and Smad3 protein were higher in the cirrhotic models. In TMP prevention and treatment groups, these markers of expression were higher, compared with that of the normal control, but were lower when compared with that of the cirrhotic model group. Smad7 protein expression was lower in the cirrhotic model group than in the normal control. Smad7 expression in TMP prevention and treatment groups was higher, compared with that in the cirrhotic model group. Liver collagen in the TMP prevention group was the lowest among all CCl₄ injection groups. In conclusion, TMP can prevent and alleviate the development of liver fibrosis in rats. The possible mechanism could involve the downregulation of leptin, Ob-Rb, TGF-β1, TGF-βRII, and Samd3, and upregulation of Smad7.     

Carotenoid lutein protects rats from paracetamol‐, carbon tetrachloride‐ and ethanol‐induced hepatic damage

Objectives Carotenoids are a class of natural fat‐soluble pigments that are found in many fruits and vegetables. Consumption of a diet rich in carotenoids has been epidemiologically correlated with a lower risk for several diseases. In the present study the carotenoid lutein (3,3′‐dihydroxy‐β,ε‐carotene) was evaluated for its hepatoprotective activity in rats. Methods Paracetamol, 20% ethanol and carbon tetrachloride were used to induce liver toxicity. Key findings Levels of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase and alkaline phosphatases, which were increased in the serum, were found to be significantly reduced by the treatment of lutein in a dose‐dependent manner, indicating that lutein may reduce the hepatotoxicity induced by these agents_. Serum bilirubin was also significantly lower in lutein‐treated groups compared with control. Increased lipid peroxidation, conjugated diene and hydroperoxides in the liver tissue produced by the administration of paracetamol were found to be reduced in the lutein‐treated groups. Levels of antioxidant enzymes, like superoxide dismutase, catalase, glutathione peroxidase and glutathione, were found to be increased in lutein‐treated groups compared with control group during alcohol‐ and CCl₄‐induced liver toxicity. Hydroxyproline, which is an indicator of fibrosis in liver tissue, was high in the ethanol‐treated control group. Hydroxyproline levels were decreased by simultaneous lutein administration. Conclusions Histopathological evidence confirmed the protection offered by lutein from the tissue damage caused by hepatotoxins. The hepatoprotective action may be due to lutein's ability to scavenge reactive oxygen radicals.     

Effects of Eriobotrya japonica seed extract on oxidative stress in rats with non‐alcoholic steatohepatitis

Objectives Non‐alcoholic steatohepatitis is associated with the deposition of lipid droplets in the liver, and is characterised histologically by the infiltration of inflammatory cells, hepatocellular degeneration and liver fibrosis. Oxidative stress may play an important role in the onset and deterioration of non‐alcoholic steatohepatitis. We previously reported that an Eriobotrya japonica seed extract, extracted in 70% ethanol, exhibited antioxidant actions in vitro and in vivo. In this study, we examined the effect of this extract in a rat model of non‐alcoholic steatohepatitis. Methods The seed extract was given in the drinking water to fats being fed a methionine‐choline‐deficient diet for 15 weeks. Key findings Increases in alanine aminotransferase and aspartate aminotransferase levels were significantly inhibited in rats fed the seed extract compared with the group on the diet alone. Formation of fatty droplets in the liver was also inhibited. Antioxidant enzyme activity in liver tissue was higher than in the diet‐only group and lipid peroxidation was reduced compared with rats that also received the extract. Expression of 8‐hydroxy‐2′‐deoxyguanosine and 4‐hydroxy‐2‐nonenal was lower in the rats given the seed extract than in the diet‐only group. In the former, liver tissue levels of transforming growth factor‐β and collagen were also decreased. Conclusions Thus, the E. japonica seed extract inhibited fatty liver, inflammation and fibrosis, suggesting its usefulness in the treatment of non‐alcoholic steatohepatitis.     

毛菊苣提取物对四氯化碳诱导大鼠肝纤维化的防治作用

目的 观察毛菊苣提取物抗慢性肝纤维化的作用。方法 将Wistar大鼠随机分为毛菊苣提取物低、中、高剂量（50、100、150 mg/kg）组,秋水仙碱（colchicine,0.5 mg/kg）组,模型组和正常组,ig给药。给药同时各组sc四氯化碳（CCl₄）造模,每周2次。于60 d后,检测大鼠血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总蛋白（TP）、白蛋白（ALB）、肝组织丙二醛（MDA）、谷胱甘肽过氧化物酶（GSH-Px）、羟脯氨酸（Hyp）及肝组织病理变化。结果 与模型组比较,毛菊苣提取物低、中、高剂量组均能明显降低肝纤维化大鼠血清中ALT、AST的含量及肝组织中MDA和Hyp的含量（P＜0.01）,明显提高血清TP、ALB水平（P＜0.05、0.01）及肝组织GSH-Px活性（P＜0.01）;肝脏组织学检查表明,毛菊苣提取物可明显改善肝组织病理损伤程度,其作用呈一定的量效关系。结论 毛菊苣提取物对实验性慢性肝损伤具有保护肝细胞,减少肝损伤,抗肝纤维化作用。     

Tracking anti‐fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: An insight

The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl₄ for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti‐inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α‐smooth muscle actin, transforming growth factor (TGF)‐β1 antibodies and platelet‐derived growth factor receptor β (PDGFRβ) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl₄‐induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF‐β1 levels and tissue expression of its antibody, as well expression of PDGFRβ. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)‐1 and IL‐6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF‐β1 levels and decreasing expression of PDGFRβ.