The present study investigated the effect of extract of Poria cocos polysaccharides(PCP) on cytochrome P450 2 E1(CYP2 E1) and nuclear factor κB(NF-κB) inflammatory signaling pathways in alcoholic liver disease(ALD) mice and explored its protective effect and mechanism. Sixty male C57 BL/6 N mice of SPF grade were randomly divided into a control group, a model group, a positive drug group(bifendate, 200 mg·kg~(-1)), and high-(200 mg·kg~(-1)) and low-dose(50 mg·kg~(-1)) PCP groups. Gao-binge mo-del was induced and the mice in each group were treated correspondingly. Liver morphological and pathological changes were observed and organ index was calculated. Serum levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were detected. Malondialdehyde(MDA) and superoxide dismutase(SOD) in liver tissues were detected by assay kits. The levels of interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) were detected by ELISA. The activation of macrophages was observed by immunofluorescence staining and protein expression of CYP2 E1, Toll-like receptor 4(TLR4), NF-κB p65, and phosphorylated NF-κB p65(p-NF-κB p65) were analyzed by Western blot. The ALD model was properly induced. Compared with the model group, the PCP groups significantly improved the pathological injury of liver tissues. Immunofluorescence staining revealed that compared with the model group, the groups with drug intervention showed decreased macrophages in liver tissues. Additionally, the PCP groups showed reduced ALT, AST, MDA, IL-6, and TNF-α(P<0.05), and potentiated activity of SOD(P<0.01). PCP extract has the protective effect against alcoholic liver injury in mice, and the underlying mechanism may be related to the regulation of the expression of CYP2 E1 and inhibition of TLR4/NF-κB inflammatory signaling pathway to reduce oxidative stress and inflammatory injury, thereby inhibiting the development of ALD.
Animals ; Cytochrome P-450 CYP2E1/pharmacology* ; Liver ; Liver Diseases, Alcoholic/pathology* ; Male ; Mice ; NF-kappa B/metabolism* ; Plant Extracts/pharmacology* ; Polysaccharides/pharmacology* ; Wolfiporia

Antrodia camphorata, a well-known and highly valued edible medicinal mushroom with intriguing activities like liver protection, has been traditionally used for the treatment of alcoholic liver disease. A. camphorata shows highly medicinal and commercial values with the demand far exceeds the available supply. Thus, the petri-dish cultured A. camphorata (PDCA) is expected to develope as a substitute. In this paper, nineteen triterpenes were isolated from PDCA, and thirteen of them were the unique anthroic acids in A. camphorata, including the main content antcin K, which suggested that PDCA produced a large array of the same anthroic acids as the wild one. Furthermore, no obvious acute toxicity was found suggesting the edible safety of PDCA. In mice alcohol-induced liver injury model, triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) had been reduced by the PDCA powder as well as the main content antcin K, which indicated that the PDCA could protect alcoholic liver injury in mice model and antcin K could be the effective component responsible for the hepatoprotective activities of PDCA against alcoholic liver diseases.
Alanine Transaminase ; blood ; Aldehyde Dehydrogenase ; blood ; Animals ; Antrodia ; chemistry ; Aspartate Aminotransferases ; blood ; Biological Products ; chemistry ; pharmacology ; therapeutic use ; Chemical and Drug Induced Liver Injury ; etiology ; prevention & control ; Cholestenes ; chemistry ; pharmacology ; therapeutic use ; Cholesterol, VLDL ; blood ; Disease Models, Animal ; Ethanol ; toxicity ; Female ; Fruiting Bodies, Fungal ; chemistry ; Liver ; drug effects ; metabolism ; pathology ; Liver Diseases, Alcoholic ; prevention & control ; Male ; Malondialdehyde ; blood ; Mice ; Molecular Structure ; Triglycerides ; blood ; Triterpenes ; chemistry ; pharmacology ; therapeutic use

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. Only 20% of heavy alcohol consumers develop alcoholic liver cirrhosis. The intestinal microbiota (IM) has been recently identified as a key player in the severity of liver injury in ALD. Common features of ALD include a decrease of gut epithelial tight junction protein expression, mucin production, and antimicrobial peptide levels. This disruption of the gut barrier, which is a prerequisite for ALD, leads to the passage of bacterial products into the blood stream (endotoxemia). Moreover, metabolites produced by bacteria, such as short chain fatty acids, volatile organic compounds (VOS), and bile acids (BA), are involved in ALD pathology. Probiotic treatment, IM transplantation, or the consumption of dietary fiber, such as pectin, which all alter the ratio of bacterial species, have been shown to improve liver injury in animal models of ALD and to be associated with an improvement in gut barrier function. Although the connections between the microbiota and the host in ALD are well established, the underlying mechanisms are still an active area of research. Targeting the microbiome through the use of prebiotic, probiotic, and postbiotic modalities could be an attractive new approach to manage ALD.
Alcoholics* ; Bacteria ; Bile Acids and Salts ; Dietary Fiber ; Fatty Acids, Volatile ; Gastrointestinal Microbiome ; Humans ; Liver ; Liver Cirrhosis, Alcoholic ; Liver Diseases, Alcoholic* ; Microbiota* ; Models, Animal ; Mortality ; Mucins ; Pathology ; Prebiotics ; Probiotics ; Rivers ; Tight Junctions

Non-alcoholic fatty liver disease (NAFLD) is believed to be the most prevalent liver disease worldwide and a major cause of chronic liver injury. It is characterized by lipid accumulation in the absence of significant alcohol consumption and frequently progresses to steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Although many studies have been conducted to better understand NAFLD since it was first recognized, there are still many gaps in knowledge of etiology, prognosis, prevention and treatment. Methionine-choline deficient (MCD) diet, a well-established experimental model of NAFLD in rodents, rapidly and efficiently produces the clinical pathologies including macrovesicular steatosis and leads to disease progression. In this study, we measured the response to MCD diet in C57BL/6N mice obtained from three different sources; Korea NIFDS, USA, and Japan. We evaluated changes in body weight, food consumption, and relative weights of tissues such as liver, kidney, gonadal white adipose tissue, inguinal white adipose tissue, and brown adipose tissue. These basic parameters of mice with an MCD diet were not significantly different among the sources of mice tested. After 3 weeks on an MCD diet, histopathological analyses showed that the MCD diet induced clear fat vacuoles involving most area of the acinus in the liver of all mice. It was accompanied by increased serum activities of alanine aminotransferase and aspartate aminotransferase, and decreased levels of serum triglyceride and cholesterol. In conclusion, the response of C57BL6N mice originating from different sources to the MCD diet showed no significant differences as measured by physiological, biochemical, and histopathological parameters.
Adipose Tissue, Brown ; Adipose Tissue, White ; Alanine Transaminase ; Alcohol Drinking ; Animals ; Aspartate Aminotransferases ; Body Weight ; Carcinoma, Hepatocellular ; Cholesterol ; Diet ; Disease Progression ; Fatty Liver* ; Gonads ; Japan ; Kidney ; Korea ; Liver ; Liver Cirrhosis ; Liver Diseases ; Methionine* ; Mice* ; Models, Theoretical ; Non-alcoholic Fatty Liver Disease ; Pathology ; Prognosis ; Rodentia ; Triglycerides ; Vacuoles ; Weights and Measures

Studies examining the association of hemochromatosis (HFE) gene polymorphisms and susceptibility to alcoholic liver disease (ALD) yielded inconsistent results. Thus, we performed a metaanalysis to investigate whether the variations in HFE gene increase the risk of ALD. The studies published up to Feb. 2014 were identified by searching PubMed/MEDLINE, ISI Web of Science, EMBASE and China National Knowledge Infrastructure databases, which was complemented by screening the references of the retrieved studies. For all genotypes and alleles, the odds ratios (ORs) with 95% confidence intervals (CIs) according to the heterogeneity were pooled using fixed-effect model. Sixteen studies with 1933 cases and 9874 controls were included for this meta-analysis. C282Y/C282Y, C282Y/wild type, H63D/wild type and C282Y/H63D were found not to be associated with susceptibility to ALD, but increased risk of H63D/H63D (OR: 1.52, 95% CI: 1.05-2.22, P=0.029) was observed for ALD when compared to total control. Comparison of ALD patients with alcoholics without liver damage revealed a significant association of D allele, as well as a marginal association of H63D/wild type with ALD, while H63D/H63D was not significantly associated with ALD although increased value of OR was obtained. The presence of Y allele and other genotypes yielded insignificant findings when ALD patients were compared with alcoholics without liver damage. No evident publication bias or significant heterogeneity among studies was detected in this meta-analysis. In conclusion, our metaanalysis showed a marginal higher prevalence of H63D variant in ALD but did not support an increased risk of C282Y mutation.
Alleles ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Hemochromatosis Protein ; genetics ; Humans ; Liver Diseases, Alcoholic ; genetics ; pathology ; Mutation ; Polymorphism, Single Nucleotide

Nonalcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver, occurring when fat is accumulated in the liver without alcohol consumption. NAFLD is the most common liver disorder in advanced countries. NAFLD is a spectrum of pathology involving hepatic steatosis with/without inflammation and nonalcoholic steatohepatitis with accumulation of hepatocyte damage and hepatic fibrosis. Recent studies have revealed that NAFLD results in the progression of cryptogenic cirrhosis that leads to hepatocarcinoma and cardiovascular diseases such as heart failure. The main causes of NAFLD have not been revealed yet, metabolic syndromes including obesity and insulin resistance are widely accepted for the critical risk factors for the pathogenesis of NAFLD. Nuclear receptors (NRs) are transcriptional factors that sense environmental or hormonal signals and regulate expression of genes, involved in cellular growth, development, and metabolism. Several NRs have been reported to regulate genes involved in energy and xenobiotic metabolism and inflammation. Among various NRs, farnesoid X receptor (FXR) is abundantly expressed in the liver and a key regulator to control various metabolic processes in the liver. Recent studies have shown that NAFLD is associated with inappropriate function of FXR. The impact of FXR transcriptional activity in NAFLD is likely to be potential therapeutic strategy, but still requires to elucidate underlying potent therapeutic mechanisms of FXR for the treatment of NAFLD. This article will focus the physiological roles of FXR and establish the correlation between FXR transcriptional activity and the pathogenesis of NAFLD.
Alcohol Drinking ; Bile Acids and Salts ; Bile* ; Cardiovascular Diseases ; Fatty Liver ; Fibrosis ; Heart Failure ; Hepatocytes ; Inflammation ; Insulin Resistance ; Liver ; Metabolism ; Non-alcoholic Fatty Liver Disease* ; Obesity ; Pathology ; Receptors, Cytoplasmic and Nuclear ; Risk Factors

Along with the aging process, the spectrum of liver disease changes greatly. Nonalcoholic fatty liver disease (NAFLD) in elderly people lead to low liver function and is also the major cause of extrahepatic diseases, such as cardiovascular disease and malignant tumor. This review provides an overview of the morphological structure and function of the liver in aged people, and discusses the characteristics of weakness, malnutrition and limited movement in the elderly, as well as the current status of multiple diseases and multiple drug use. Finally, this article puts forward some appropriate regimens for the diagnosis and treatment of NAFLD in elderly people to provide a reference for clinical practice.
Aged ; Cardiovascular Diseases ; Humans ; Liver ; pathology ; Malnutrition ; Neoplasms ; Non-alcoholic Fatty Liver Disease ; diagnosis ; pathology ; therapy ; Risk Factors

To study the protective effect and the mechanism of asiatic acid (AA) from Potentilla chinensis on alcohol hepatic injury in rats. Male Wistar rats were randomly divided into six groups: the normal control group, the AA control group (8 mg · kg(-1) AA), the model group (5.0-9.0 g · kg(-1) alcohol) and high, medium and low-dose AA-treated groups (alcohol + 8, 4, 2 mg · kg(-1) AA). Each group was orally administered with the corresponding drugs once a day for 24 weeks. Approximately 1. 5 hours after the final administration, all rats were killed, and their blood samples and hepatic tissues were collected. The AST and ALT in rat serum and the contents of MPO, TNF-α, IL-1β, SOD, GSH-Px, GSH-Rd and MDA in hepatic tissues were detected. The expressions of NF-κB, TLR4, CD14, MyD88, TRIF and protein expression in hepatic tissues were measured by western blot. The pathological changes in liver tissues were observed by histological examination. The results showed that compared with the model group, the AA-treated groups showed significant decreases in serum ALT, AST and MDA and increases in the activities of SOD, GSH-Px, GSH-Rd and MPO. Moreover, AA markedly inhibited the expressions of TNF-α, IL-1β, TLR4, CD14, MyD88 and NF-κB. The histological examination showed alleviated hepatic issue ijury to varying degrees. In short, asiatic acid (AA) from P. chinensis could protect alcohol-induced hepatic injury in rats. Its mechanism may be related to the inhibition of NF-κB inactivation and the reduction of inflammatory response.
Animals ; Liver ; drug effects ; pathology ; Liver Diseases, Alcoholic ; prevention & control ; Male ; NF-kappa B ; physiology ; Pentacyclic Triterpenes ; pharmacology ; Potentilla ; chemistry ; Protective Agents ; pharmacology ; Rats ; Rats, Wistar ; Toll-Like Receptor 4 ; antagonists & inhibitors

OBJECTIVETo study the protective effect of Acai berries(Euterpe oleraceae) on chronic alcoholic hepatic injury in rats and their mechanism.

METHODWistar rats were fed for 1 week and randomly divided into blank group, model group, Dongbao Gantai group, Acai 1.6, 0.8, 0.4 g . kg-1 groups. The blank group was given distilled water, and the other groups were orally given 56% white spirit (Erguotou) for eight weeks at the dosages of 8 mL . kg-1 in the 1st week, which increased by 0.1 mL week by week till to 15 mL . kg-1, in order to establish the chronic hepatic injury model, and observe the effect of Acai berry freeze-dried powder on hepatocyte membrane permeability, liver lipid peroxidation, changes in inflammatory cytokines and pathological changes in hepatocytes.

RESULTAcai berries could significantly reduce serum ALT and AST(P<0.05), MDA(P<0.05), TG(P<0.05) and serum TNF-α and IL-6(P <0.05) and increase GSH and SOD(P <0.05). According to liver histopathological observation, livers in the model group were dominated by steatosis, some livers suffered spotty necrosis and inflammatory cell infiltration; The positive drug and Acai groups showed different changes in pathologic changes in rat livers.

CONCLUSIONAcai berries show s specific protective effect on alcoholic hepatic injury. Its mechanism may be correlated with the inhibition of such inflammatory factors as TNF-α and IL-6.

Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Chronic Disease ; Cytokines ; blood ; Euterpe ; chemistry ; Hepatocytes ; drug effects ; Interleukin-6 ; blood ; Lipid Peroxidation ; drug effects ; Liver ; drug effects ; Liver Diseases, Alcoholic ; metabolism ; pathology ; prevention & control ; Male ; Plant Extracts ; pharmacology ; Rats ; Rats, Wistar ; Triglycerides ; blood ; Tumor Necrosis Factor-alpha ; blood

OBJECTIVETo determine whether Toll-like receptor 4 (TLR4) is involved in development of gut leakiness in alcoholic steatohepatitis using an in vivo animal model and an in vitro cell culture system.

METHODSMice were fed an alcohol (ethanol group, EtOH) or isocaloric liquid diet (control group, Ctrl). Successful establishment of the alcoholic steatohepatitis model was assessed at week 6 by measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and evaluating the liver pathology using hematoxylin and eosin (HandE) staining of liver tissues. Gut permeability was assessed by measuring serum endotoxin and urine lactulose/mannitol (L/M) levels and evaluating HandE-stained colon tissues. Intestinal and colon tissue expression levels of TLR4 were assessed by immunohistochemistry. Cultured Caco-2 cells were exposed to 25 - 400 mmol/L EtOH and changes in TLR4 were assessed by enzyme-linked immunoassay and in permeability were assessed by intracellular uptake of FD4.

RESULTSThe mice in the EtOH group had significantly higher levels of serum ALT (46.5 +/- 6.9 U/L vs. Ctrl: 30.9 +/- 4.4 U/L, P less than 0.01), serum AST (53.3 +/- 7.9 U/L vs. Ctrl: 29.3 +/- 3.8 U/L, P less than 0.01), serum endotoxin (0.33 +/- 0.05 Eu/L vs. Ctrl: 0.27 +/- 0.04 Eu/L, P less than 0.01), and urine L/M (2.59 +/- 0.44% vs. Ctrl: 2.17 +/- 0.31%, P less than 0.05). The mice in the EtOH group also had significantly higher expression levels of TLR4 in intestinal tissues (13.1 +/- 2.0 ng/ml vs. Ctrl: 7.4 +/- 1.2 ng/L, P less than 0.01) and in colonic tissues (18.5 +/- 2.7 ng/ml vs. Ctrl: 9.1 +/- 1.6 ng/ml, P less than 0.01). The intestinal histopathology of the two groups was not different. Immunohistochemical staining of colonic tissues showed brown particles distributed in the endochylema and membrane of the EtOH group, which was almost completely absent in the Ctrl group. EtOH treatment of Caco-2 cells led to a dose-dependent increase in TLR4 expression and in cellular permeability.

CONCLUSIONChronic alcohol exposure induced TLR4 expression and cellular permeability in gut tissues. Activation of TLR4 may be involved in development of gut leakiness in alcoholic liver disease.

Animals ; Disease Models, Animal ; Gastrointestinal Tract ; metabolism ; Liver Diseases, Alcoholic ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred C57BL ; Toll-Like Receptor 4 ; metabolism