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

BACKGROUNDStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases with high mortality rates. This study was designed to analyze the pathogenic factors, clinical manifestations, complications, treatment, and prognosis of SJS/TEN and to explore the differences between surviving and deceased patients.

METHODSSJS/TEN patients admitted to Beijing Friendship Hospital from January 2006 to December 2015 were included in the study. Patients' data were retrospectively analyzed. Comparative studies were performed on the survival group and the deceased group, and Fisher's exact probability test was used for statistical analysis.

RESULTSAmong the 88 patients included, 40 (45.5%) were male with a mean age of 45 ± 18 years. Forty-eight (54.5%) had SJS, 34 (38.6%) had SJS/TEN, and 6 (6.8%) had TEN. Fifty-three (60.2%) cases were caused by medications, mainly antibiotics (n = 24) followed by traditional Chinese medicines (n = 7). Forty-two cases (47.7%) developed visceral damage. Eighty-two patients improved or recovered and were discharged from hospital, and six patients died. Comparative studies on the survival group and the deceased group showed that the presence of malignant tumor ( χ2 = 27.969,P < 0.001), connective tissue diseases ( χ2 = 9.187, P= 0.002), previous abnormal liver/kidney functions ( χ2 = 6.006, P= 0.014), heart rate >100 times/min ( χ2 = 6.347, P= 0.012), detached skin area >20% ( χ2 = 5.594, P= 0.018), concurrent mucosal involvement at the mouth, eyes, and external genitals ( χ2 = 4.945, P= 0.026), subsequent accompanying liver/kidney damage ( χ2 = 11.839, P= 0.001, and χ2 = 36.302,P < 0.001, respectively), and SCORTEN score >2 ( χ2 = 37.148,P < 0.001) increased the risk of death.

CONCLUSIONSSJS/TEN is mainly caused by medications, and nearly half of patients develop visceral damage. Multiple factors increase the mortality risk.

Adult ; Anti-Bacterial Agents ; therapeutic use ; Connective Tissue Diseases ; metabolism ; pathology ; Eye ; pathology ; Female ; Genitalia ; pathology ; Humans ; Kidney ; metabolism ; pathology ; Liver ; metabolism ; pathology ; Male ; Middle Aged ; Mouth ; pathology ; Retrospective Studies ; Skin ; metabolism ; pathology ; Stevens-Johnson Syndrome ; drug therapy ; metabolism ; pathology

Cytosolic retinoic acid-inducible gene I (RIG-I) is an important innate immune RNA sensor and can induce antiviral cytokines, e.g., interferon-β (IFN-β). Innate immune response to hepatitis B virus (HBV) plays a pivotal role in viral clearance and persistence. However, knowledge of the role that RIG-I plays in HBV infection is limited. The woodchuck is a valuable model for studying HBV infection. To characterize the molecular basis of woodchuck RIG-I (wRIG-I), we analyzed the complete coding sequences (CDSs) of wRIG-I, containing 2778 base pairs that encode 925 amino acids. The deduced wRIG-I protein was 106.847 kD with a theoretical isoelectric point (pI) of 6.07, and contained three important functional structures [caspase activation and recruitment domains (CARDs), DExD/H-box helicases, and a repressor domain (RD)]. In woodchuck fibroblastoma cell line (WH12/6), wRIG-I-targeted small interfering RNA (siRNA) down-regulated RIG-I and its downstrean effector-IFN-β transcripts under RIG-I' ligand, 5'-ppp double stranded RNA (dsRNA) stimulation. We also measured mRNA levels of wRIG-I in different tissues from healthy woodchucks and in the livers from woodchuck hepatitis virus (WHV)-infected woodchucks. The basal expression levels of wRIG-I were abundant in the kidney and liver. Importantly, wRIG-I was significantly up-regulated in acutely infected woodchuck livers, suggesting that RIG-I might be involved in WHV infection. These results may characterize RIG-I in the woodchuck model, providing a strong basis for further study on RIG-I-mediated innate immunity in HBV infection.
Animals ; Cell Line, Tumor ; Cloning, Molecular ; DEAD Box Protein 58 ; antagonists & inhibitors ; genetics ; immunology ; Fibroblasts ; immunology ; pathology ; Gene Expression ; Hepatitis B ; genetics ; immunology ; pathology ; veterinary ; Hepatitis B Virus, Woodchuck ; Immunity, Innate ; Interferon-beta ; genetics ; immunology ; Isoelectric Point ; Kidney ; immunology ; pathology ; virology ; Liver ; immunology ; pathology ; virology ; Marmota ; genetics ; immunology ; virology ; Open Reading Frames ; Protein Domains ; RNA, Double-Stranded ; RNA, Small Interfering ; genetics ; metabolism ; Rodent Diseases ; genetics ; immunology ; pathology ; virology

BACKGROUND/AIMS: Chronic liver disease leads to liver fibrosis, and although the liver does have a certain regenerative capacity, this disease is associated with dysfunction of the liver vessels. C-reactive protein (CRP) is produced in the liver and circulated from there for metabolism. CRP was recently shown to inhibit angiogenesis by inducing endothelial cell dysfunction. The objective of this study was to determine the effect of CRP levels on angiogenesis in a rat model of liver dysfunction induced by bile duct ligation (BDL). METHODS: The diameter of the hepatic vein was analyzed in rat liver tissues using hematoxylin and eosin (H&E) staining. The expression levels of angiogenic factors, albumin, and CRP were analyzed by real-time PCR and Western blotting. A tube formation assay was performed to confirm the effect of CRP on angiogenesis in human umbilical vein endothelial cells (HUVECs) treated with lithocholic acid (LCA) and siRNA-CRP. RESULTS: The diameter of the hepatic portal vein increased significantly with the progression of cirrhosis. The expression levels of angiogenic factors were increased in the cirrhotic liver. In contrast, the expression levels of albumin and CRP were significantly lower in the liver tissue obtained from the BDL rat model than in the normal liver. The CRP level was correlated with the expression of albumin in hepatocytes treated with LCA and siRNA-CRP. Tube formation was significantly decreased in HUVECs when they were treated with LCA or a combination of LCA and siRNA-CRP. CONCLUSION: CRP seems to be involved in the abnormal formation of vessels in hepatic disease, and so it could be a useful diagnostic marker for hepatic disease.
Angiogenic Proteins/genetics/metabolism ; Animals ; Bile Ducts/surgery ; C-Reactive Protein/*analysis/genetics/metabolism ; Cells, Cultured ; Disease Models, Animal ; Hepatic Veins/abnormalities ; Hepatocytes/cytology/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Lithocholic Acid/pharmacology ; Liver/metabolism/pathology ; Liver Cirrhosis/etiology ; Liver Diseases/metabolism/*pathology ; Male ; Microscopy, Fluorescence ; Mitochondria/drug effects/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Serum Albumin/genetics/metabolism

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

OBJECTIVETo explore the effect of repeated hypoxic preconditioning (RHP) on renal ischemia-reperfusion-induced hepatic dysfunction in rats and the underlying mechanism.

METHODSA total of 120 normal SD rats were randomly divided into 4 groups (n=40), namely RHP surgical group, RHP sham-operated (RHPS) group, nonhypoxic surgical group (IRI group), and nonhypoxic sham-operated group (S group). The rats in the hypoxic groups were exposed to hypoxia in a hypoxic chamber for 5 days prior to establishment of renal ischemia-reperfusion model by resection of the right kidney and clamping the left renal hilum. Serum alanine aminotransferase (ALT), IL-17 A, TNF-a, liver superoxide dismutase (SOD) and nitric oxide (NO) were detected at 2, 8 and 24h after reperfusion, and Western blotting was used to determine the expression of p-PI3K and p-AKT;HE staining was used to observe the structural changes in the liver.

RESULTSCompared with IRI group, RHP group showed significantly milder hepatic damage, lower ALT levels and higher NO levels at 2, 8, and 24 after reperfusion (P<0.05); TNF-a levels were lowered at 24 h (P<0.05) and SOD increased at 8 h after the reperfusion (P<0.05). Compared with S group, IRI group and RHP group showed significantly higher IL-17A levels (P<0.05) but without significant difference between the latter two groups (P>0.05). The expressions of p-PI3K and P-Al

CONCLUSIONRepeated hypoxic preconditioning can attenuate hepatic injury induced by renal ischemia-reperfusion injury in rats.

Alanine Transaminase ; blood ; Animals ; Hypoxia ; Interleukin-17 ; blood ; Ischemic Preconditioning ; Kidney ; pathology ; Kidney Diseases ; physiopathology ; Liver ; physiopathology ; Nitric Oxide ; blood ; Phosphatidylinositol 3-Kinases ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; Superoxide Dismutase ; blood ; Tumor Necrosis Factor-alpha ; blood

BACKGROUNDPreeclampsia is a multifactorial disease during pregnancy. Dysregulated lipid metabolism may be related to some preeclampsia. We investigated the relationship between triglycerides (TGs) and liver injury in different preeclampsia-like mouse models and their potential common pathways.

METHODSPreeclampsia-like models (Nw-nitro-L-arginine-methyl ester [L-NAME], lipopolysaccharide [LPS], apolipoprotein C-III [Apo] transgnic mice + L-NAME, β2 glycoprotein I [βGPI]) were used in four experimental groups: L-NAME (LN), LPS, Apo-LN and βGPI, respectively, and controls received saline (LN-C, LPS-C, Apo-C, βGPI-C). The first three models were established in preimplantation (PI), early-, mid- and late-gestation (EG, MG and LG). βGPI and controls were injected before implantation. Mean arterial pressure (MAP), 24-hour urine protein, placental and fetal weight, serum TGs, total cholesterol (TC) and pathologic liver and trophocyte changes were assessed.

RESULTSMAP and proteinuria were significantly increased in the experimental groups. Placenta and fetal weight in PI, EP and MP subgroups were significantly lower than LP. Serum TGs significantly increased in most groups but controls. TC was not different between experimental and control groups. Spotty hepatic cell necrosis was observed in PI, EG, MG in LN, Apo-LN and βGPI, but no morphologic changes were observed in the LPS group. Similar trophoblastic mitochondrial damage was observed in every experimental group.

CONCLUSIONSEarlier preeclampsia onset causes a higher MAP and urine protein level, and more severe placental and fetal damage. Preeclampsia-like models generated by varied means lead to different changes in lipid metabolism and associated with liver injury. Trophoblastic mitochondrial damage may be the common terminal pathway in different preeclampsia-like models.

Animals ; Cholesterol ; blood ; Disease Models, Animal ; Female ; Fetal Weight ; physiology ; Liver ; injuries ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondrial Diseases ; blood ; pathology ; Placenta ; metabolism ; Pre-Eclampsia ; blood ; pathology ; Pregnancy ; Triglycerides ; blood ; Trophoblasts ; pathology

OBJECTIVETo study the expression of arginase-1 (Arg-1), glypican-3 (GPC3), hepatocyte paraffin antigen 1 (HepPar-1) and alpha-fetoprotein (AFP) in hepatocellular carcinoma (HCC), benign liver lesions (BLL) and metastatic carcinoma (MC), and their applications in diagnosis and differential diagnosis.

METHODSImmunohistochemical study (EnVision method) for Arg-1, GPC3, HepPar-1 and AFP was carried out in three groups of liver lesions, including 85 cases of HCC, 35 cases of BLL and 19 cases of MC. The relationship between expression of Arg-1, GPC3, HepPar-1 and AFP and clinicopathologic features in HCC was also analyzed.

RESULTSThe positive expression rate of Arg-1 was 90.6% (79/85) in HCC and 100% (35/35) in BLL. Arg-1 expression was observed in 1 of the 19 cases of MC studied. The positive expression rate of GPC3 was 82.4% (70/85) in HCC, 5.3% (1/19) in MC and 0 (0/35) in BLL. The positive expression rate of AFP was 47.1% (40/85) in HCC and 0 in BLL or MC. The positive expression rate of HepPar-1 was 72.9% (62/85) in HCC, 100% (35/35) in BLL and 2/19 in MC. Arg-1 has a higher sensitivity in highlighting hepatocellular lesions than AFP and HepPar-1 (P=0.000 versus P=0.002). The specificity of GPC3 expression in HCC was 98.1%.

CONCLUSIONSArg-1 is a sensitive hepatocellular marker in delineation of liver lesions.GPC3 is a relatively specific marker in diagnosis of HCC.

Adenocarcinoma ; metabolism ; secondary ; Adult ; Aged ; Antibodies, Monoclonal ; metabolism ; Antibodies, Neoplasm ; metabolism ; Antigens, Neoplasm ; immunology ; Arginase ; metabolism ; Biomarkers, Tumor ; metabolism ; Breast Neoplasms ; metabolism ; pathology ; Carcinoma, Hepatocellular ; diagnosis ; metabolism ; pathology ; Diagnosis, Differential ; Female ; Glypicans ; metabolism ; Humans ; Liver Diseases ; diagnosis ; metabolism ; Liver Neoplasms ; diagnosis ; metabolism ; pathology ; Male ; Middle Aged ; Rectal Neoplasms ; metabolism ; pathology ; Survival Rate ; alpha-Fetoproteins ; metabolism

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