保肝降酶的天然药物研究进展

天然药物治疗肝损伤的功效及其低毒性已得到广泛的认可。由于大多肝损伤均有氧化应激的参与,天然药物的保肝作用通常与其抗氧化特性或激发体内抗氧化防御系统的能力有关。然而,越来越多的证据表明,除了抗氧化,天然药物还具有许多其他保肝机制。文章综述了近年来保肝降酶的天然药物的研究进展,将国内外已报道的天然药物分黄酮类、生物碱类、皂苷类、多糖类、木脂素类、萜类及其他类并分别列举其治疗机制及效果,为天然药物保肝降酶相关性的研究提供文献依据和研究思路,并对未来保肝降酶的新药研发方向进行展望。     

保肝降酶的天然药物研究进展

天然药物治疗肝损伤的功效及其低毒性已得到广泛的认可。由于大多肝损伤均有氧化应激的参与,天然药物的保肝作用通常与其抗氧化特性或激发体内抗氧化防御系统的能力有关。然而,越来越多的证据表明,除了抗氧化,天然药物还具有许多其他保肝机制。文章综述了近年来保肝降酶的天然药物的研究进展,将国内外已报道的天然药物分黄酮类、生物碱类、皂苷类、多糖类、木脂素类、萜类及其他类并分别列举其治疗机制及效果,为天然药物保肝降酶相关性的研究提供文献依据和研究思路,并对未来保肝降酶的新药研发方向进行展望。     

体外肝细胞损伤模型分子机制探讨

肝损伤是临床常见的危害人类健康的疾病,是各种原因引起肝脏疾病的共同的表现,也是各型肝病共同的病理基础。建立稳定可靠体外肝细胞损伤模型,对于肝损伤病理机制研究及有效防治肝损伤药物筛选提供了前提。针对肝细胞损伤分子机制不同,目前已成功建立基于免疫损伤、氧化损伤、脂肪损伤等体外肝细胞损伤模型,用于临床药物筛选及疗效作用机制研究,本文对目前常见体外肝细胞损伤模型及其发生的分子生物学机制进行探讨。     

磷脂酰胆碱对酒精性肝病保护作用的研究进展

酒精性肝病已逐渐成为第二大肝脏疾病,威胁着人类的健康。乙醇引发肝损伤的机制主要包括其代谢产物乙醛对肝细胞造成的毒性作用、自由基损伤及对肝脏线粒体产生的毒性作用等。已证实,磷脂酰胆碱对酒精肝损伤具有明显的保护作用。简要介绍了酒精肝病机制及磷脂酰胆碱对酒精性肝损伤的保护作用研究进展,以期为治疗酒精性肝病提供帮助。     

铁代谢紊乱和其它致病因素介导的肝氧化损伤及抗氧化保护策略研究进展

铁是人体所必需的微量元素,独特的化学活性使其成为血红蛋白和多种酶类的重要组成部分,同时,铁也可以催化产生各种自由基分子。作为铁的主要储存器官,肝脏在维持机体铁稳态中起着中心枢纽作用。当肝脏发生铁调节紊乱或者受到各种肝脏致病因素(丙型肝炎病毒、乙型肝炎病毒和酒精)侵袭时,都会造成自由基分子的过量生成。若机体的抗氧化防御系统不能将这些自由基及时清除,将会导致氧化应激损伤介导的肝损伤。目前的研究表明,针对肝脏疾病患者进行去铁及抗氧化治疗是一种有效的治疗模式。因此,研究肝脏铁代谢及各种肝脏疾病致病因素引起的氧化应激具有重要的理论和临床意义。     

百里香精油对硫代乙酰胺诱导的小鼠急性肝损伤的保护作用

为探究百里精油抗氧化能力及其潜在的保肝作用,通过测定百里香精油对DPPH自由基、ABTS自由基的清除能力,确定百里香精油的体外抗氧化能力。同时建立硫代乙酰胺(TAA)急性小鼠肝损伤模型,通过测定小鼠的肝脏指数,血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP)活性和肝脏中苯二醛(MDA)、谷胱甘肽(GSH)含量和超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、过氧化氢酶(CAT)的活性来评价百里香精油的保肝效果。结果表明,百里香精油具有良好的体外抗氧化活性及对硫代乙酰胺诱导的肝损伤小鼠的保护效果,其中高剂量精油对小鼠肝损伤的保护效果显著(P0.01)。本文旨在为百里香精油作为天然植物源保肝药物的研究与开发奠定理论基础。     

microRNA在对乙酰氨基酚所致肝损伤中抗损伤作用研究进展

药物引起的急性肝损伤(drug-induced liver injury,DILI)是导致肝衰竭的重要原因,其中以对乙酰氨基酚(acetaminophen,APAP)最常见。microRNA为一类非编码小RNA,在肝脏中具有重要的生物学功能,其对APAP所致肝损伤过程中代谢损伤、炎症发展以及肝再生等病理过程具有显著调控作用,对APAP所致肝损伤(acetaminophen-induced liver injury,AILI)发生发展产生重要影响。APAP所致的肝损伤能引起不同种类microRNA含量的变化,其中多种microRNA表达含量的变化能抑制炎症的发展,减轻肝损伤程度,对肝组织起保护作用。这属于机体应对损伤刺激时所表现的自我保护性机制。本文对在AILI中具有抗损伤作用的microRNA相关研究进行综述,并总结microRNA作用靶点与调控机制。     

巨噬细胞在β肾上腺素受体过度激活致肝脏纤维化过程中的研究进展

机体作为一个复杂的微环境,各个脏器之间是否正常运作具有紧密的关联。已知心力衰竭可以引起肝功能障碍,那么肝脏疾病是否对心功能也有影响并不明确。肝脏纤维化是目前慢性肝脏疾病发展为肝硬化必经之阶段,而β肾上腺素受体(β-adrenergic receptor,β-AR)的功能改变与纤维化密切相关,且巨噬细胞在脏器纤维化的发生发展中有着不可替代的作用。已知β肾上腺素受体激动剂可以通过作用于机体免疫细胞上的β肾上腺素受体发挥作用,进而引起相应脏器的免疫功能紊乱,并最终诱导纤维化的发生。本文对肝功能障碍和心功能损伤的关系,β肾上腺素受体过度激活在肝损伤和心功能障碍中的影响,以及巨噬细胞在其中发挥的作用加以综述。     

大鼠酒精性肝损伤模型及蛋白表达指纹图谱的建立

目的:建立大鼠酒精性肝损伤模型,以蛋白质芯片技术为实验手段对损伤过程中的大鼠血清及肝脏蛋白质变化进行观察,以期获得损伤过程中的蛋白标志物,建立损伤过程蛋白表达指纹图谱;观察有机硒对大鼠肝脏损伤的防护作用。方法:用食用酒精辅以橄榄油对大鼠进行肝损伤,动态检测大鼠肝重比、血清生化指标,并进行肝组织病理切片观察;应用表面加强激光电离解吸飞行时间质谱技术对大鼠肝损伤过程进行跟踪检测,获得蛋白标志物,同时证实有机硒对肝损伤具有一定的防护作用。结果:肝重比、生化指标及病理切片均表明损伤模型已基本建立,同时验证了有机硒的肝损伤保护作用。在12周的损伤过程中,发现大鼠血清中有4个具有统计学意义的蛋白标志物,其相对分子质量(Mr)分别为7010、8307、11624和14041;在肝组织中发现了2个有统计意义的蛋白标志物,其Mr分别为5931.2和7104.6。结论:建立了大鼠酒精性肝损伤模型,获得了血清及肝脏蛋白标志物,为后期进行临床实验提供了可行的研究方法;同时为有机硒应用于临床进行肝损伤防护奠定了良好的实验基础。     

丹参在肝脏疾病防治中的应用及作用机制研究进展

丹参为唇形科多年生草本丹参Salvia miltiorrhiza Beg.的干燥根及根茎。临床与药理学研究发现丹参对胆汁淤积性肝损害、免疫性肝损害、肝纤维化、肝癌、药物性肝损伤等多种肝病具有防治作用。本文对丹参在肝脏疾病防治中的应用及作用机制进行了全面综述,以期为丹参相关保肝药物的开发及临床合理用药提供理论指导。     

Rare earth cerium oxide nanoparticles attenuated liver fibrosis in bile duct ligation mice model

Liver fibrosis is one of the major liver complications which eventually progresses to liver cirrhosis and liver failure. Cerium oxide nanoparticles, also known as nanoceria (NC) are nanoparticles with potential antioxidant and anti-inflammatory activities. Herein, we evaluated the hepatoprotective and anti-fibrotic effects of nanoceria (NC) against bile duct ligation (BDL) induced liver injury. NC were administered i.p. for 12 days (0.5 and 2 mg/kg) to C57BL/6J mice. The biochemical markers of liver injury, oxidative and nitrosative stress markers, inflammatory cytokines were evaluated. Fibrosis assessment and mechanistic studies were conducted to assess the hepatoprotective effects of NC. Administration of NC proved to significantly ameliorate liver injury as evident by reduction in SGOT, SGPT, ALP and bilirubin levels in the treated animals. NC treatment significantly reduced the hydroxyproline levels and expression of fibrotic markers. In summary, our findings establish the hepatoprotective and anti-fibrotic effects of NC against BDL induced liver injury and liver fibrosis. These protective effects were majorly ascribed to their potential ROS inhibition and antioxidant activities through catalase, superoxide dismutase (SOD)-mimetic properties and auto-regenerating capabilities.     

灵芝总三萜对鹅膏毒肽中毒小鼠所致肝损伤的保护作用研究

鹅膏肽类毒素是蘑菇中毒导致死亡的最主要因素,用于鹅膏中毒治疗的解毒药物已有大量报道,水飞蓟宾（silibinin,SIL）被认为是目前最有效的解毒药物。灵芝作为我国传统的中药真菌,具有良好的保肝护肝作用。本文开展灵芝主要活性成分灵芝总三萜（Ganoderma total triterpenoids,GTT）和对照药物水飞蓟宾对α-鹅膏毒肽（α-amanitin,α-AMA）中毒小鼠所致肝损伤的保护作用及其抗氧化机理研究,结果表明α-鹅膏毒肽中毒小鼠经灵芝总三萜和水飞蓟宾治疗后小鼠血清中的ALT和AST活性显著降低,小鼠死亡率降低40%-50%,病理组织切片观察表明能明显减轻肝组织损伤的程度,说明灵芝总三萜与水飞蓟宾一样,对α-鹅膏毒肽中毒小鼠的肝具有很好的保护作用。灵芝总三萜给药组和水飞蓟宾给药组能显著增加肝组织中SOD和CAT的活性,显著降低肝脏中MDA含量,表明灵芝总三萜和水飞蓟宾具有抗氧化和自由基清除剂作用,能减轻α-鹅膏毒肽所引起的脂质过氧化伤害作用。     

Upregulation of heat shock protein 32 with hemin alleviates acute heat-induced hepatic injury in mice

Heat shock protein 32 (HSP32) is a stress response protein that can be induced by heat stress in the liver, and its induction can act as an important cellular defence mechanism against heat-induced liver injury. To investigate the functional role of HSP32 in protecting liver tissue against heat stress in mice and the mechanism by which it achieves this protective effect, HSP32 expression and carbon monoxide (CO) contents in a model of mice subjected to acute, transient heat exposure were examined. Furthermore, functional and histological parameters of liver damage and the possible involvement of oxidative stress to induce oxidative deterioration of liver functions and caspase-3 expression were also investigated in this study. We found that heat treatment of mice produced severe hepatic injury, whereas upregulation of HSP32 with hemin pretreatment prevented mice from liver damage. In contrast, addition of Sn-protoporphyrin (SnPP) to inhibit HSP32 expression completely reversed its hepatoprotective effect. It is concluded that upregulation of HSP32 by hemin could alleviate acute heat-induced hepatocellular damage in mice, and its by-product CO seems to play a more important role in hepatoprotective mechanism.     

Evaluation of hepatoprotective activity of legumes.

Mung bean, adzuki bean, black bean and rice bean are foods and folk medicines of Taiwan. We evaluated the effects of various water extract concentrations (100, 500 and 1000 mg/kg body wt.) and silymarin (25 mg/kg body wt. on acetaminophen-induced liver injury by measuring serum glutamate-oxalate-transaminase (sGOT) and serum glutamate-pyruvate-transaminase (sGPT) activities in rats. The results showed that the sGOT and the sGPT activities, increased by APAP, were decreased significantly (P < 0.05) through treatment with inceasing amounts up to 1000 mg/kg body wt. of the exracts. In particular, the mung bean aqueous extract showed the best hepatoprotective effect on APAP-induced hepatotoxicity. The pathological changes of liver injury caused by APAP improved by the treatment with all of the legume extracts, which were compared to silymarin as a standardized drug. In addition to these results, the extract of mung bean acted as a potential hepatoprotective agent in dietary supply.     

Effect of ghrelin on chronic liver injury and fibrogenesis in male rats: Possible role of nitric oxide

Recent studies have revealed that ghrelin may be an antioxidant and anti-inflammatory agent in many organs, however its role in chronic liver injury (CLI) remains unclear. The role of nitric oxide (NO) in CLI is controversial as evidence suggests that NO is either a primary mediator of liver cell injury or exhibits a protective effect against injurious stimuli. Recent evidence demonstrated that the therapeutic potential for ghrelin was through eNOS activation and increase in NO production. However, its role on NO production in the liver has not been previously investigated. The aim of this study was to investigate the role of ghrelin in treatment of CLI, and whether this action is mediated through NO. Forty male rats were divided into four groups: Group I: Control; Group II: chronic liver injury (CLI); Group III: CLI + Ghrelin; and Group IV: CLI + Ghrelin + l-NAME. Liver enzymes and tumor necrosis factor alpha (TNF-α), were measured to assess hepatocellular injury. Liver tissue collagen content, malondialdehyde (MDA), gene expression of Bax, Bcl-2, and eNOS were assessed to determine the mechanism of ghrelin action. Results showed that ghrelin decreased serum liver enzymes and TNF-α levels. Ghrelin also reduced liver tissue collagen, MDA, and Bax gene expression, and increased Bcl-2 and eNOS gene expression. The effects on TNF-α, collagen, MDA, Bax, and eNOS were partially reversed in Group IV, suggesting that ghrelin's action could be through modulation of NO levels. Therefore, ghrelin's hepatoprotective effect is partially mediated by NO release.     

Oral Hepatoprotective Ability Evaluation of Purple Sweet Potato Anthocyanins on Acute and Chronic Chemical Liver Injuries

In recent years, chemical liver injury cases increased significantly in Asian countries, and the imbalance in redox system was believed to be the main cause. Purple sweet potato anthocyanins (PSPA) have been shown to exert antioxidant activity and oxidative-stress-associated functional protein modulation through various signaling pathways, so it is considered to have the potential of liver injury preventive activity. In order to evaluate the hepatoprotective potency of PSPA according to its free radical scavenging and antioxidant effects, three acute chemical liver injury models were set up with ethanol, acetaminophen and carbon tetrachloride. PSPA at moderate and high doses obviously attenuated the tested serum biomarker levels and liver index in our experiments. Besides, one chronic liver injury model set up with carbon tetrachloride was also applied, in which PSPA was orally administrated after the liver damage had been formed. Both the serum biomarker levels and histopathological analysis showed that PSPA was able to attenuated chronic liver injury. Our experimental results demonstrated the potential of PSPA as an oral hepatoprotective agent against chemical liver injury from food plant.     

Evodiamine and rutaecarpine from Tetradium ruticarpum in the treatment of liver diseases

BackgroundLiver is the pivotal organ responsible for plasma protein production, biliary secretion, xenobiotic elimination, glucose and lipid homeostasis. Dysregulation of these functions usually leads to liver diseases and further related complications. The incidence of liver diseases is increasing worldwide, with high morbidity and mortality when at advanced stages, and has become significant public health concern and substential economic burden. Thus, novel therapeutic strategies for managing liver diseases progression are urgently required. T. ruticarpum is one of the most famous and frequently used herbal medicine and has been prescribed in traditional Chinese medicine (TCM) formulas for the treatment of various ailments, including liver diseases. A considerable amount of bioactive ingredients have been isolated and identified from the roots of T. ruticarpum, including alkaloids, saponins, phenols, volatile oils and other compounds. Among these compounds, evodiamine (EVO) and rutaecarpine (RUT) are believed to be the most bioactive compounds.PurposeTo summarize recent findings regarding to the metabolism, pharmacological/toxicological effects of EVO and RUT and to highlight the potential therapeutic effects of them against liver diseases.MethodsOnline academic databases (including PubMed, Google Scholar, Web of Science and CNKI) were searched using search terms of “T. ruticarpum”, “Wu Zhu Yu”, “evodiamine”, “rutaecarpine”, “liver” and combinations to include published studies of EVO and RUT primarily from 2004–2019. Several critical previous studies beyond this period were also included.ResultsEvodiamine (EVO) and rutaecarpine (RUT) are believed to be the most bioactive alkaloids in T. ruticarpum, having anti-inflammation, anti-fibrosis, anti-lipotoxicity, anti-cancer activities, and thus having potential to improve liver disorders. In the current review, we comprehensively summarized recent progresses in the studies of EVO- and RUT-mediated promising hepatoprotective effects and also provide novel insights regarding the potential use of EVO and RUT as therapeutic options for the treatment of liver diseases.ConclusionWith further in-depth pharmacology and pharmacokinetic studies, we believe that natural products in T. ruticarpum and their derivatives will become promising medicines with improved clinical efficacy for the treatment of liver diseases in the immediate future.     

Hepatoprotective effect of pyrroloquinoline quinone against alcoholic liver injury through activating Nrf2-mediated antioxidant and inhibiting TLR4-mediated inflammation responses

The present study was aimed at investigating the hepatoprotective effect of pyrroloquinoline quinone (PQQ) against acute alcoholic liver injury in mice. Acute alcoholic liver injury model was established in mice, and they were administrated with PQQ to investigate its hepatoprotective effect. Our results shows that PQQ can significantly ameliorate acute alcoholic liver injury by decreasing the hepatic marker enzymes, including serum alanine transaminase (ALT) and aspartate transaminase (AST), and increasing the levels of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in the liver. And PQQ can also significantly reduce the content of hepatic triglyceride (TG) and malondialdehyde (MDA). Moreover, PQQ attenuated alcohol-induced oxidative damage by activating NF-E2-related factor 2 (Nrf2)-mediated signaling pathway, and inhibiting Toll-like receptor 4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) signaling pathway. Our findings have elucidated the liver protection mechanism of PQQ, which would encourage the further exploitation of PQQ as a hepatoprotective functional food.