Query: hepatic fibrosis

title: The associations of hub gene polymorphisms in PI3K/AKT/mTOR pathway and Schistosomiasis Japonica infection and hepatic fibrosis.
abstract: Increasing evidence shows that the PI3K/AKT/mTOR pathway can be activated by a variety of stimulus in immune cells. Schistosomiasis Japonica is a serious threat to human health in some lakes of China.  We analyzed the potential associations between the hub gene (PTEN, mTOR, AKT1 and AKT2) polymorphisms of PI3K/AKT/mTOR pathway and S. japonica risk, including infection risk, as well as immunological hepatic fibrosis risk. An immune database named Database of Immune Cell Expression, Expression quantitative trait loci and Epigenomics (DICE) was used to analyze the expression profiles of the hub genes in 15 types of immune cells.  Of them, two SNPs rs2295080 (mTOR) and rs7254617 (AKT2) were found associated with the risk of infection and fibrosis. We also performed a multivariant Cox regression analysis and found that HBV infection may increase hepatic fibrosis in chronic schistosomiasis patients, instead of genetic polymorphisms on PI3K/AKT/mTOR pathway or any other factors. We also found the expressions of mTOR (RICTOR) and AKT2 in T cells were higher than those in monocyte cells. And, the expressions of PTEN, mTOR (RICTOR) and AKT1 reduced both in activated CD4 T cells and activated CD8 T cells.  We concluded that rs2295080 may be an important marker in the diagnosis of susceptibility to schistosomiasis infection. But HBV infection not rs2295080 could promote immunological liver damage with fibrosis in patients with chronic schistosomiasis infection.

title: Prevalence of significant hepatic fibrosis using magnetic resonance elastography in a health check up clinic population
abstract: Significant hepatic fibrosis is associated with higher mortality. However, data on the estimated prevalence of liver fibrosis in the general population are scarce.

title: Ginsenoside Rg3 promotes regression from hepatic fibrosis through reducing inflammation mediated autophagy signaling pathway
abstract: Inflammation and autophagy occur during hepatic fibrosis development caused by various pathogens, and effectively curbing of autophage may delay the occurrence of hepatic fibrosis. The current study aimed to unravel the inhibitory effects of Ginsenoside Rg3 (G Rg3) on inflammation mediated hepatic autophagy to curb hepatic fibrosis caused by thioacetamide (TAA) induced subacute and chronic hepatic injury. TAA is mainly metabolized in the liver to cause liver dysfunction. After intraperitoneal injection of TAA for 4 or 10 weeks (TAA chronic mouse models) severe inflammatory infiltration and fibrosis occurred in the liver. Treatment with G Rg3 alleviated hepatic pathological changes and reversed hepatic fibrosis in the TAA chronic models with decreased deposition of collagen fibers, reduced expression of HSCs activation marker (a SMA) and reduced secretion of profibrogenic factors (TGF b1) G Rg3 decreased expressions of autophagy related proteins in mice of TAA chronic models. Notably, G Rg3 inhibited the survival of activated rat hepatic stellate cells (HSC T6) but had no cytotoxicity on human hepatocytes (L02 cell lines) G Rg3 dose dependently inhibited autophagy in vitro with less expression of p62 and fewer LC3a transformation into LC3b in inflammatory inducer lipopolysaccharide (LPS) induced rat HSC T6 cells. Furthermore, G Rg3 enhanced the phosphorylation of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (Akt) in vivo and in vitro. Besides, mTOR inhibitor Rapamycin and PI3K inhibitors LY294002 were employed in LPS treated HSC T6 cell cultures to verify that Rg3 partially reversed the increase in autophagy in hepatic fibrosis in vitro. Taken together, G Rg3 exerted anti fibrosis effect through the inhibition of autophagy in TAA treated mice and LPS stimulated HSC T6 cells. These data collectively unravel that G Rg3 may serve a promising anti hepatic fibrosis drug.

title: Congenital Hepatic Fibrosis in Children and Adults: Clinical Manifestations, Management, and Outcome Case Series and Literature Review
abstract: Congenital hepatic fibrosis is a hereditary fibropolycystic disease caused by ductal plate malformation. It is characterized by portal hypertension, but the manifestations, management, and outcome vary in children and adults. To raise awareness of medical staff, we have comprehensively compared the clinical features of congenital hepatic fibrosis between children and adults.  We retrospectively enrolled all patients diagnosed with congenital hepatic fibrosis at the Huashan Hospital from August 2015 to August 2017 and analyzed their familial, clinical, laboratory, imaging, treatment, and follow up data in detail. In addition, we reviewed cases with congenital hepatic fibrosis reported in the past 20 years in China and analyzed them according to the patients' age.  A total of eight patients were diagnosed with congenital hepatic fibrosis in the study, including four children and four adults. The onset age of the children, who suffered from severe complications of portal hypertension and needed liver transplantation, ranged from 1 to 15 years old. The disorder developed in adults aged 26 to 60 years old. Three adults complained of recurrent abnormal liver function at the onset of illness, and they mainly received conservative treatments. The literature review included 30 children and 33 adults. In comparison, hepatomegaly was more common in children than in adults (57% vs. 21% p 0.004) Malformation of kidneys and bile duct abnormalities were common, and multisystem involvement included eyes, other digestive organs, and genital and central nervous systems.  Serious complications of portal hypertension developed in children requiring liver transplantation, while adults often had mild to moderate liver injuries upon onset. Adults with CHF varied a lot in clinical manifestations. Multiorgan involvement and unusual course are helpful to make a diagnosis. Timely histological assessment by liver biopsy and multidisciplinary cooperation are crucial for definitive diagnosis and early intervention.

title: Combined therapy with ligustrazine and paeonol mitigates hepatic fibrosis through destroying mitochondrial integrity of stellate cell.
abstract: This study investigates the inhibitory effect and potential mechanism of ligustrazine combined with paeonol on hepatic fibrosis, as to provide a new therapeutic strategy for clinical hepatic fibrosis. The degree of liver injury collagen deposition and inflammation was assessed by hematoxylin and eosin staining, Masson, Sirius red staining and biochemically serum analysis. ATP and ROS levels in each group were detected by chemical fluorescence method. The apoptotic rate was measured by Tunel assay.  Tacker fluorescence staining and mitochondrial DNA copy number were measured to observe the effect of ligustrazine or/and paeonol on mitochondrial function of hepatic stellate cell (HSC) The expression of relevant proteins and genes were evaluated by using immunofluorescence RT PCR and western blot. Ligustrazine or/and paeonol significantly improve the pathological changes in liver tissue induced by CCl4, however, they reduced the levels of liver and fibrosis markers in tissue and serum. ROS, NOX1 and NOX2 were significantly increased and GSH was decreased in HSC, with the intervention of Ligustrazine or/and paeonol. We further found that Ligustrazine or/and paeonol can effectively inhibit liver inflammation in vivo. The expression of TNF a, IL 6 and IL 8 was upregulated in HSC. Moreover, Ligustrazine or/and paeonol promotes apoptosis and inhibit proliferation of HSC. Additionally, the inhibiting effects of the drug on collagen deposition was due to the interference with the expression of signaling pathway related proteins and genes such as, MMPS, TGF b, PDGF and BMP 2 in HSC. Mitochondrial activity of HSC was inhibited by Ligustrazine or/and paeonol. The inhibitory effects of ligustrazine or/and Paeonol on mitochondrial function is partially balanced by mitochondrial protective agent SS 31. Ligustrazine combined with paeonol exerts significant anti hepatic fibrosis effect in vivo and in vitro. This may due to the disruption of HSC mitochondrial function, thereby induced promoting oxidative stress, apoptosis, inflammation and inhibiting the formation and deposition of extracellular matrix.

title: Sequential Combination of FIB 4 Followed by M2BPGi Enhanced Diagnostic Performance for Advanced Hepatic Fibrosis in an Average Risk Population
abstract: The fibrosis 4 (FIB 4) index is the most widely used estimated formula to screen for advanced hepatic fibrosis; however, it has a considerable intermediate zone. Here, we propose an algorithm to reduce the intermediate zone and improve the diagnostic performance of screening for advanced liver fibrosis by incorporating Mac 2 binding protein glycan isomer (M2BPGi) into a FIB 4 based screening strategy in an average risk group. Four hundred eighty eight healthy and chronic liver disease subjects were analyzed using a 1:1 propensity score matched for age and sex. Advanced liver fibrosis =F3) was defined by magnetic resonance elastography (MRE, =3.6 kPa) Classification tree analysis was employed to improve diagnostic performance using a combination of the FIB 4 index and M2BPGi. The median serum M2BPGi levels of healthy subjects, patients without advanced fibrosis, and those with the condition were 0.48, 0.94, and 2.93, respectively. The area under the receiver operating characteristic (AUROC) curve of M2BPGi (0.918) for advanced fibrosis was the highest compared to those of the FIB 4 index (0.887) APRI (0.873) and AST/ALT ratio (0.794) When M2BPGi was incorporated following the FIB 4 index, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 87.1% 82.5% 54.0% and 96.4% respectively. Moreover, 74.3% (133/179) of cases in the intermediate zone of the FIB 4 index avoided unnecessary referrals. Two step pathway (FIB 4 followed by M2BPGi) could reduce unnecessary referrals and/or liver biopsies in an average risk population.

title: ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model.
abstract: Hepatic inflammasome activation is considered a major contributor to liver fibrosis in NASH. Apoptosis signal regulating kinase 1 (ASK1) is an apical mitogen activated protein kinase that activates hepatic JNK and p38 to promote apoptosis, inflammation, and fibrosis. The aim of the current study was to investigate whether pharmacologic inhibition of ASK1 could attenuate hepatic fibrosis driven by inflammasome activation using gain of function NOD like receptor protein 3 (Nlrp3) mutant mice. Tamoxifen inducible Nlrp3 knock in (Nlrp3A350V/+CreT KI) mice and WT mice were administered either control chow diet or diet containing the selective ASK1 inhibitor GS 444217 for 6 weeks. Livers of Nlrp3 KI mice had increased inflammation, cell death, and fibrosis and increased phosphorylation of ASK1, p38, and c Jun. GS 444217 reduced ASK1 pathway activation, liver cell death, and liver fibrosis. ASK1 inhibition resulted in a significant downregulation of genes involved in collagen production and extracellular matrix deposition, as well as in a reduced hepatic TNF a expression. ASK1 inhibition also directly reduced LPS induced gene expression of Collagen 1A1 (Col1a1) in hepatic stellate cells isolated from Nlrp3 KI mice. In conclusion, ASK1 inhibition reduced liver cell death and fibrosis downstream of inflammatory signaling induced by NLRP3. These data provide mechanistic insight into the antifibrotic mechanisms of ASK1 inhibition.

title: Western diet induces severe nonalcoholic steatohepatitis, ductular reaction, and hepatic fibrosis in liver CGI 58 knockout mice
abstract: Humans and rodents with Comparative Gene Identification 58 (CGI 58) mutations manifest nonalcoholic fatty liver disease (NAFLD) Here we show that liver CGI 58 knockout (LivKO) mice fed a Western diet rapidly develop advanced NAFLD, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. After 14 weeks of diet challenge, starting at 6 weeks of age, LivKO mice showed increased inflammatory cell infiltration and proinflammatory gene expression in the liver, which was associated with elevated plasma levels of aminotransferases. Hepatic ductular reactions, pericellular fibrosis, and bridging fibrosis were observed only in the LivKO mice. Consistently, the KO mice had a significant increase in hepatic mRNAs for fibrogenic genes. In addition, LivKO mice displayed massive accumulation of lipid droplets (LDs) in hepatocytes. LDs were also observed in the cholangiocytes of the LivKO mice, but not the floxed controls. Four of the five LD coat proteins, including perilipins 2, 3, 4, and 5, were increased in the CGI 58 KO liver. CRISPR/Cas9 mediated knockout of CGI 58 in Huh7 human hepatoma cells induced LD deposition and perilipin expression, suggesting a cell autonomous effect. Our findings establish the Western diet fed LivKO mice as an animal model of NASH and hepatic fibrosis. These animals may facilitate preclinical screening of therapeutic agents that counter against NAFLD progression.

title: Fugan Wan alleviates hepatic fibrosis by inhibiting ACE/Ang II/AT 1R signaling pathway and enhancing ACE2/Ang 1 7/Mas signaling pathway in hepatic fibrosis rat models.
abstract: Hepatic fibrosis is a repair and healing reaction for chronic injuries of liver. This study aimed to investigate protective effects of Fugan Wan (FGW) on hepatic fibrosis and clarify associated mechanisms. Hepatic fibrosis model was established by administrating dimethyl nitrosamine (DMN) to rats. Rats were divided into control, DMN and FGW groups. Haematoxylin and eosin (HE) staining was conducted to evaluate inflammatory response in hepatic fibrosis tissues. Sirius red staining was used to assess collagen disposition. Quantitative real time PCR (qRT PCR) was employed to detect antiotensin converting enzyme homologue 2 (ACE2) Mas, transforming growth factor b1 (TGF b1) mRNA. Western blot was used to examine collagen I, smooth muscle actin a (a SMA) angiotensin type 1 receptor (AT 1R) extra cellular regulated protein kinase (ERK) phosphorylated ERK (p ERK) c Jun and phosphorylated c Jun (p c Jun) expression. The results indicated that FGW significantly reduced inflammatory response of hepatic fibrosis tissues. FGW significantly decreased collagen deposition compared to that of DMN group (P 0.01) FGW significantly down regulated a SMA expression compared to that of DMN group (P 0.01) FGW significantly decreased AT 1R levels compared to that of DMN group (P 0.01) Comparing with DMN group, ACE2 and Mas mRNA levels were significantly increased in FGW group (P 0.01) FGW significantly down regulated p c Jun and p ERK1/2 compared to DMN group (P 0.01) GFW significantly inhibited compared to DMN group (P 0.01) In conclusion, FGW alleviated hepatic fibrosis by inhibiting ACE/Ang II/AT 1R signaling and enhancing ACE2/Ang 1 7/Mas signaling pathway in hepatic fibrosis rat models.

title: Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4 dependent ROS.
abstract: Angiotensin II (Ang II) has been reported to aggravate hepatic fibrosis by inducing NADPH oxidase (NOX) dependent oxidative stress. Alamandine protects against fibrosis by counteracting Ang II via the MrgD receptor, though the effects of alamandine on hepatic fibrosis remain unknown. Autophagy activated by reactive oxygen species (ROS) is a novel mechanism of hepatic fibrosis. However, whether autophagy is involved in the regulation of Ang II induced hepatic fibrosis still requires investigation. We explored the effect of alamandine on hepatic fibrosis via regulation of autophagy by redox balance modulation. In vivo, alamandine reduced ccl4 induced hepatic fibrosis, H2O2 content, protein levels of NOX4 and autophagy impairment. In vitro, Ang II treatment elevated NOX4 protein expression and ROS production along with upregulation of the ACE/Ang II/AT1R axis. These changes resulted in the accumulation of impaired autophagosomes in hepatic stellate cells (HSCs) Treatment withtheNOX4 inhibitor VAS2870, ROS scavenger N acetylcysteine, and NOX4 small interfering RNA (siRNA) inhibited Ang II induced autophagy and collagen synthesis. Alamandine shifted the balance of RAS toward the ACE2/alamandine/MrgD axis, and inhibited both Ang II induced ROS and autophagy activation, leading to attenuation of HSCs migration or collagen synthesis. In summary, alamandine attenuated liver fibrosis by regulating autophagy induced by NOX4 dependent ROS.