灵芝子实体多糖对小鼠急性酒精肝损伤预防的代谢组分析

灵芝多糖是灵芝的主要药理活性成分之一。本研究通过检测血清指标分析灵芝子实体多糖（Ganoderma lingzhi fruitbody polysaccharides,GLFPS）对小鼠急性酒精性肝损伤的预防作用并结合代谢组学探究作用机制。结果显示,GLFPS显著抑制因酒精作用而升高的小鼠血清中ALT、AST、TG、TC和ADH水平。通过代谢组分析,在模型组与对照组中得到85个差异代谢物,其中三磷酸腺苷（adenosine triphosphate）、L-天门冬氨酸（L-aspartic acid）以及赖氨酸（L-lysine）等在相互作用网络中起重要作用,说明酒精能引起小鼠肝脏腺苷和氨基酸代谢的改变。GLFPS组与模型组有58个差异代谢物,主要包括脂质和有机氧化物,说明GLFPS可以通过调节小鼠肝脏中脂质与有机化合物代谢来预防急性酒精肝损伤。对差异代谢物进行KEGG富集分析发现主要涉及胆碱代谢、甘油磷脂代谢和ABC转运蛋白。GLFPS能够有效缓解这3个代谢通路中因酒精作用发生明显改变的代谢。综上可见,灵芝子实体多糖能够通过调节小鼠胆碱代谢、甘油磷脂代谢以及部分ABC转运蛋白有效预防酒精性肝损伤。     

多烯磷脂酰胆碱胶囊联合复方益肝灵胶囊治疗抗结核药物致肝损伤患者的临床疗效

目的:研究多烯磷脂酰胆碱胶囊联合复方益肝灵胶囊治疗抗结核药物致肝损伤患者的临床疗效。方法:选取2014年4月到2015年4月我院收治的抗结核药物致肝损伤患者150例,按照随机数字表法将患者分为研究组和对照组,每组75例,两组均继续行抗结核治疗,对照组给予常规保肝药物治疗,研究组给予多烯磷脂酰胆碱胶囊联合复方益肝灵胶囊保肝治疗,比较两组临床疗效,治疗前后谷丙转氨酶(ALT)、谷草转氨酶(AST)以及r-谷氨酰转移酶(r-GT)。结果:研究组有效率为89.3%显著高于对照组的73.3%,两组比较差异具有统计学意义(P0.05);两组治疗后AST、ALT以及r-GT显著低于治疗前,且治疗后研究组AST、ALT以及r-GT均显著低于对照组,比较差异均具有统计学意义(均P0.05)。结论:多烯磷脂酰胆碱胶囊联合复方益肝灵胶囊治疗抗结核药物致肝损伤具有较好临床疗效,能增强对肝脏的保护作用。     

樟芝发酵滤液干膏对酒精性肝病小鼠的保护作用

研究樟芝发酵滤液干膏（剂量为350,700和1 050mg/kg）对慢性酒精喂养加急性酒精灌胃的酒精性肝病小鼠模型的保肝作用。结果表明,樟芝发酵滤液干膏能显著降低小鼠血清谷丙转氨酶（ALT）和谷草转氨酶（AST）活力;降低小鼠血清游离脂肪酸（NEFA）、总胆固醇（TC）和甘油三酯（TG）的水平;H&E染色和油红O染色显示樟芝发酵滤液干膏可以改善肝组织脂质堆积。研究结果表明樟芝发酵滤液干膏对酒精性肝病有改善作用,可能是通过保护肝细胞、肝组织及整体肝脏降低了肝功酶的释放,减少肝脏脂质堆积来对酒精性肝病起到保护作用,可用于相关功能性食品及药品的开发。     

硒酸精氨酸对小鼠酒精性肝损伤的保护作用

目的探讨硒酸精氨酸对小鼠酒精性肝损伤的保护作用。方法用连续灌服酒精的方法建立小鼠酒精性肝损伤模型。将60只雄性小鼠随机分为四组：对照组,模型组,硒酸精氨酸处理组和二氧化硒处理组。连续灌胃8周后,测定小鼠血清中天冬氨酸氨基转移酶（AST）,丙氨酸转移酶（ALT）,肝匀浆中超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）、谷胱甘肽（GSH）的含量。对肝脏切片做HE染色和Masson染色,在光镜下观察肝脏病理学变化。结果硒酸精氨酸能显著降低酒精性肝损伤引起的AST的升高（P〈0．01）,有效保持了肝脏中GPx和SOD的活性（P〈0．01）。病理学观察结果与酶学变化相一致,硒酸精氨酸对肝脏的保护作用明显优于二氧化硒。结论硒酸精氨酸对小鼠酒精性肝损伤具有显著的保护作用,效果也优于二氧化硒。     

转录因子Nrf2在肝脏疾病中的作用

NF-E2相关因子2(nuclear erythroid 2-related factor 2,Nrf2)是一种能调节肝脏中大量解毒和抗氧化防御基因表达的重要转录因子.氧化应激与各种形式的肝损伤有密切的关系.Nrf2由亲电体压力或氧化应激激活,并通过结合抗氧化反应元件(antioxidant response element,ARE)诱导其靶基因,从而对细胞产生保护作用.因此,Nrf2通路在肝脏疾病中的作用已被深入研究.多种动物模型研究结果表明,Nrf2通路通过靶基因表达,在对抗病毒性肝炎、药物性肝损伤、酒精性肝病、非酒精性脂肪肝及肝癌方面表现出了不同的生物功能.根据Nrf2及其信号通路在对抗肝损伤中产生保护作用的相关文献,本文综述并讨论了其作为治疗肝损伤的药物作用靶点方面可能的应用前景.     

益生菌通过调整正常菌群缓解酒精性肝损伤的研究进展

许多临床试验表明慢性酒精性肝损伤会引起肠道菌群的失调,主要表现为双歧杆菌、乳杆菌数量减少,革兰氏阴性菌大量繁殖,破坏肠道屏障功能,增加肠道通透性,使细菌来源的内毒素大量释放出来,引起血液内毒素增加,并在肝脏中累积,超出肝脏的清除能力,导致肝损伤。本文主要综述益生菌通过调整正常菌群这一机制来缓解酒精性肝损伤的研究进展,进而深入了解酒精引起肠道菌群变化(酒精的摄入会导致肠道中拟杆菌、厚壁菌数量减少,革兰氏阴性变形菌、革兰氏阳性放线菌数量增加,同时肠道内细菌来源的内毒素水平增加)导致肝损伤的发病机制,以及益生菌如何通过调整肠道正常菌群改善酒精性肝损伤。     

肝脏免疫系统在酒精性肝损伤中的作用启示

酒精性肝病的致病因素是单一,但其发病机制复杂,目前尚不完全清楚。肝脏免疫系统被认为是独特的免疫系统,其作用越来越引起重视。肝内既有参与外周循环的淋巴细胞,也有长期定居于此的免疫细胞;加上肝脏解剖结构和血液循环的特殊性决定了肝脏独特的免疫微环境。研究肝脏免疫系统在酒精性肝病发病机制的作用,将有助于进一步阐明酒精性肝病发病机制,为酒精性肝病的预防和治疗提供新的靶点。     

NLRP3炎症小体在慢性肝病及肝损伤中的研究进展

NLRP3炎症小体广泛存在于肝实质和非实质细胞中，它可以感知和识别各种外源性和内源性危险信号，进而促进炎症介质的释放，触发免疫反应与细胞焦亡。近年来，随着对NLRP3炎症小体认识的逐步深入，其异常激活被认为与慢性肝病及肝损伤的发生、发展密切相关。因此，NLRP3炎症小体被认为是相关肝脏疾病治疗的一个重要分子靶点。本文主要讨论了NLRP3炎症小体的调控机制及其在酒精性肝病、非酒精性肝病、肝纤维化、药物性肝损伤中的相关研究进展，并总结了NLRP3炎症小体相关靶点抑制剂在慢性肝病及肝损伤中的应用，从而为NLRP3炎症小体在慢性肝病及肝损伤中的相关研究和新药开发提供理论依据和参考。     

磷脂酰胆碱特异性磷脂酶C的研究

随着人们对信号转导认识的逐步加深,各种磷脂酶在信号通路中的作用也日渐受到重视,并日趋明了。其中磷脂酶Ａ２（ＰＬＡ２）、磷脂酰胆碱特异性磷脂酶Ｄ（ＰＣ－ＰＬＤ）的基因已克隆,对磷脂酰肌醇特异性磷脂酶Ｃ（ＰＩ－ＰＬＣ）也有较深了解,而对磷脂酰胆碱特异性磷...     

肠道菌群在慢性肝脏疾病中作用的研究进展

随着肠-肝轴机制研究的不断深入,肠道菌群与多种慢性肝脏疾病如非酒精性脂肪性肝病、酒精性肝病、肝硬化等相关性研究日益增多。肠道菌群通过肠道菌群失调、物质能量代谢改变及免疫反应激活等机制在多种肝脏疾病发生发展中发挥重要作用。本文对肠道菌群与慢性肝脏疾病关系的研究进展进行综述。     

Recent Advances in Alcoholic Liver Disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease

A significant body of evidence indicates that endotoxemia and endotoxin-mediated hepatocellular damage play a crucial role in the pathogenesis of alcoholic liver disease. A close correlation between endotoxemia and the severity of alcohol-induced liver injury is supported by a number of clinical and experimental studies. Elevated intestinal permeability appears to be the major factor involved in the mechanism of alcoholic endotoxemia and the pathogenesis of alcoholic liver disease. Ethanol and its metabolic derivatives, acetaldehyde in particular, alter intracellular signal-transduction pathways leading to the disruption of epithelial tight junctions and an increase in paracellular permeability to macromolecules. Studies addressing the mechanisms of such epithelial disruption and the protective factors that prevent ethanol and acetaldehyde-mediated disruption of epithelial tight junctions are critically important in the investigations toward the search of preventive and therapeutic strategies for alcoholic liver disease.     

酒精性肝病合并HBV感染并发肝衰竭对NF-κB信号通路的影响

由于酗酒人数的增长,HBV感染合并酒精性肝病患者的数量在中国逐年增加,酒精性肝病与HBV感染会严重影响肝功能。目前中国已成为引起肝硬化的第二大病因。而乙型肝炎病毒感染合并酒精性肝病是最常见的,且会对肝脏造成严重的损伤。本实验的检测了NF-κB信号通路和IL-8、TNF-α和Cleaved caspase-3基因及蛋白的表达,结果表明,酒精性肝病合并HBV感染并发肝衰竭会激活NF-κB信号通路,并上调IL-8、TNF-α和Cleaved caspase-3基因和蛋白的表达,说明酒精性肝病合并HBV感染不仅对肝脏造成了极其严重的损伤,还造成肝脏组织或细胞炎症的发生和细胞凋亡及组织纤维化。通过以上的研究,本实验为揭示酒精性肝病合并HBV并发肝衰竭的分子机制,以及为后续研究酒精性肝病合并HBV并发肝衰竭的靶向治疗提供理论参考。     

解酒护肝饮解酒及对急慢酒精性肝损伤的保护作用

为了评价解酒护肝饮解酒效果及其对急、慢性酒精性肝损伤保护作用机制,本研究通过建立醉酒模型,确定致醉剂量;通过醉酒睡眠实验比较解酒护肝饮解酒特性;通过测定醉酒小鼠血乙醇含量的变化,研究解酒护肝饮对乙醇代谢的影响;通过建立急慢性酒精性肝损伤模型,测定AST、ALT、SOD活性,GSH、MDA水平,HE染色切片观察肝组织形态学的变化。研究发现小鼠最佳致醉剂量为11 m L/kg;与模型组比较,解酒护肝饮高(HD)、中剂量组(MD)均可延长醉酒时间、缩短醒酒时间(p<0.05),高、中剂量组可降低酒精灌胃后2 h、3 h时间点血乙醇含量(p<0.05);与模型组比较,急慢性酒精肝损伤模型各剂量组均能显著降低血清AST、ALT活性(p<0.05),急性酒精性肝损伤模型中,各剂量组肝组织SOD、GSH水平上升(p<0.05),MDA水平下降(p<0.05),而在慢性酒精性肝损伤模型肝组织中,低剂量组(LD)的SOD、GSH及MDA水平没有统计学差异;病理切片观察可见,急慢性酒精肝损伤模型高、中、低剂量组均能显著改善肝组织因乙醇而导致的肝损伤,并且高、中剂量组效果较好。本研究表明解酒护肝饮可显著延长醉酒时间,缩短醒酒时间,降低血乙醇的含量,对酒精诱导的肝损伤有较好的保护作用。     

Ferroptosis is involved in alcohol-induced cell death in vivo and in vitro

ABSTRACT

A critical pathogenic factor in the development of lethal liver failure is cell death induced by the accumulation of lipid reactive oxygen species. In this study, we discovered and illuminated a new mechanism that led to alcoholic liver disease via ferroptosis, an iron-dependent regulated cell death. Study in vitro showed that both necroptosis inhibitor and ferroptosis inhibitors performed significantly protective effect on alcohol-induced cell death, while apoptosis inhibitor and autophagy inhibitor had no such effect. Our data also indicated that alcohol caused the accumulation of lipid peroxides and the mRNA expression of prostaglandin-endoperoxide synthase 2, reduced the protein expression of the specific light-chain subunit of the cystine/glutamate antiporter and glutathione peroxidase 4. Importantly, ferrostatin-1 significantly ameliorated liver injury that was induced by overdosed alcohol both in vitro and in vivo. These findings highlight that targeting ferroptosis serves as a hepatoprotective strategy for alcoholic liver disease treatment.     

Salvianic acid A alleviates chronic alcoholic liver disease by inhibiting HMGB1 translocation via down‐regulating BRD4

Alcoholic liver disease (ALD) is the major cause of chronic liver disease and a global health concern. ALD pathogenesis is initiated with liver steatosis, and ALD can progress to steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Salvianic acid A (SAA) is a phenolic acid component of Danshen, a Chinese herbal medicine with possible hepatoprotective properties. The purpose of this study was to investigate the effect of SAA on chronic alcoholic liver injury and its molecular mechanism. We found that SAA significantly inhibited alcohol‐induced liver injury and ameliorated ethanol‐induced hepatic inflammation. These protective effects of SAA were likely carried out through its suppression of the BRD4/HMGB1 signalling pathway, because SAA treatment largely diminished alcohol‐induced BRD4 expression and HMGB1 nuclear translocation and release. Importantly, BRD4 knockdown prevented ethanol‐induced HMGB1 release and inflammatory cytokine production in AML‐12 cells. Similarly, alcohol‐induced pro‐inflammatory cytokines were blocked by HMGB1 siRNA. Collectively, our results reveal that activation of the BRD4/HMGB1 pathway is involved in ALD pathogenesis. Therefore, manipulation of the BRD4/HMGB1 pathway through strategies such as SAA treatment holds great therapeutic potential for chronic alcoholic liver disease therapy.     

Protective effects of sulforaphane and aerobic exercise on acute alcoholic hepatic injury in mice

ObjectiveThe paper intends to study the protective effects of sulforaphane (SF) on acute alcoholic hepatic injury in mice by intragastric administration of SF, aerobic exercise and the approach of SF integrated with aerobic exercise.Methodology60 NIH mice were randomly divided into 6 groups of equal number according to their body weight and were intragastrically administrated with 50% ethanol. The serum and liver indexes of each group of mice were detected, and the liver was stained with oil red O for pathological examination.ResultsCompared with the model group, the serum TG and the ratio of liver to body weight of the model mice that suffered from acute alcoholic hepatic injury could be significantly decreased in the group that practiced aerobic exercise, the group administered with SF, and the group treated with the approach of SF integrated with aerobic exercise (P < 0.05). The contents of TG and MDA in liver could be significantly decreased (P < 0.05) and SOD activity could be significantly increased (P < 0.05) both in the group administered with SF and the group treated with the approach of SF integrated with aerobic exercise. Serum VLDL (P < 0.05) could also be significantly reduced in the group treated with the approach of SF integrated with aerobic exercise.ConclusionBoth SF and aerobic exercise could alleviate alcohol-induced acute alcoholic hepatic injury in mice possibly thanks to the working mechanism related to antioxidant stress that reduced the harm posed by alcohol on hepatic cells. In addition, the protective effect of SF on acute alcoholic hepatic injury in mice was stronger than that of aerobic exercise, while the approach of SF integrated with aerobic exercise had the strongest protective effect on acute alcoholic hepatic injury in mice.     

Fractures on the chest radiograph in detection of alcoholic liver disease.

The presence of fractures seen on routine chest radiography was assessed in patients with liver disease to see whether it might provide a useful marker of alcoholism. Chest radiographs taken at the time of liver biopsy were examined in 149 patients--72 with alcoholic liver disease (32 (44%) cirrhotic) and 77 with various forms of non-alcoholic liver disease (15 (19 . 5%) cirrhotic)--and in 149 controls. Fractures (85 rib, two clavicular) were much more common in patients with alcoholic liver disease (20 subjects; 28%) than in patients with non-alcoholic liver disease (1; 1 . 3%) or controls 10; 6 . 7%). In alcoholic liver disease rib fractures were significantly more likely to be bilateral or multiple (more than two) or both (p less than 0 . 01). Of patients with alcoholic liver disease, those with fractures were significantly older than those without, but there was no difference in sex, social class, the proportion with cirrhosis, or the proportion known to be alcoholic at the time of the radiograph. In liver disease fractures on the chest radiograph diagnosed alcoholism with 95% specificity and 28% sensitivity. These often overlooked or ignored findings in the chest radiograph may have a wider role in the detection of alcoholism.     

Cytofluorimetric research on the glycogen content of the hepatocytes in patients with various forms of alcoholic liver lesions

By cytofluorometry employing the cytofluorometric PAS reaction, a study was made of the total glycogen and of its two fractions in liver parenchymal cells, both in the norm and in patients with chronic alcoholism (alcoholic steatosis, chronic alcoholic hepatitis, and mixed forms of alcoholic-viral hepatitis, viral hepatitis with steatosis and also viral hepatitis). The examination was performed on preparations-smears of isolated hepatocytes, obtained from the live puncture liver biopsies. The quantitative analysis has shown the increase in the total glycogen content in hepatocytes of patients with alcoholic hepatitis in comparison with the norm and with chronic viral hepatitis. The transition from a reverse stage--alcoholic steatosis--to alcoholic hepatitis was accompanied by a sharp increase in the total glycogen content and by an obvious change in the ratio of glycogen fractions, towards the hard soluble fraction in liver cells. The quantitative analysis of glycogen fractions in liver cells of patients with chronic alcoholic disease may be an appreciated marker of differential diagnostics of different stages and forms of alcoholic liver disease.