Adverse Effect of Nonalcoholic Fatty Liver Disease on the Therapeutic Response in Patients with Chronic Hepatitis B.

Background and Aims: The impact of nonalcoholic fatty liver disease (NAFLD) on the treatment outcome of chronic hepatitis B (CHB) is undefined and deserves an in-depth investigation. Methods: Histologically-proven CHB receiving first-line antiviral regimens as initial therapy was enrolled and grouped by the concurrence of NAFLD, and followed up at six monthly intervals. Therapeutic response related data were recorded and compared at multiple time points. Kaplan-Meier and Cox regression analyses were utilized to estimate the impact of NAFLD on complete virological response (CVR). Results: We enrolled 267 patients (CHB: 164; CHB with NAFLD: 103) with comparable follow-up durations. They were also comparable in baseline HBV DNA levels and HBeAg positivity. Patients with concomitant NAFLD showed less significant decline in HBV DNA, qHBsAg, pgRNA, and liver enzyme levels over time; moreover, their cumulative incidences of CVR were significantly lower and that of low-level viremia (LLV) were significantly higher at 6, 12, 18, 24 months. First CVR of CHB was delayed with the presence NAFLD (11.0 vs. 7.0 months, p<0.001) and further prolonged with higher grade of liver steatosis (Grade 2-3 vs. 1: 13.0 vs. 9.0 months). On multivariate analysis, HBeAg positivity (HR: 0.650, p=0.036), grade of steatosis (G2 [HR: 0.447, p=0.004]; G3 [HR: 0.085, p=0.002]) and HBV DNA (log10 IU/mL) (HR: 0.687, p<0.001) were significantly associated with delayed CVR, whereas grade of necroinflammation (HR: 1. 758, p<0.001) accelerated the CVR. Conclusions: In CHB patients receiving initial antiviral therapy, NAFLD was associated with higher levels of HBV DNA, pgRNA, and liver enzymes, and higher incidence of LLV and delayed CVR.

Co-administration of obeticholic acid and simvastatin protects against high-fat diet-induced non-alcoholic steatohepatitis in mice.

Non-alcoholic steatohepatitis (NASH) has no approved therapy. The farnesoid X nuclear receptor (FXR) agonist obeticholic acid (OCA) has shown promise as a drug for NASH, but can adversely affect plasma lipid profiles. Therefore, the present study aimed to investigate the effects and underlying mechanisms of OCA in combination with simvastatin (SIM) in a high-fat diet (HFD)-induced model of NASH. C57BL/6J mice were fed with a HFD for 16 weeks to establish the NASH model. The mice were randomly divided into the following five groups: HFD, HFD + OCA, HFD + SIM, HFD + OCA + SIM and control. After 16 weeks, the mice were sacrificed under anesthesia. The ratios of liver weight to body weight (Lw/Bw) and of abdominal adipose tissue weight to body weight were calculated. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglycerides and low-density lipoprotein were measured. Liver sections were stained with hematoxylin and eosin. The protein levels of FXR, small heterodimeric partner (SHP) and cytochrome P450 family 7 subfamily A member 1 (CYP7A1) in the liver were detected by western blotting, while the mRNA levels of FXR, SHP, CYP7A1, bile salt export pump, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), sterol regulatory element binding protein-1 (SREBP1) and fatty acid synthase (FASN) were examined by reverse transcription-quantitative polymerase chain reaction. The administration of OCA with or without SIM reduced the liver inflammation score compared with those of the HFD and HFD + SIM groups, with no significant difference between the HFD + OCA and HFD + OCA + SIM groups. The steatosis score followed similar trends to the inflammation score. In HFD-fed mice, OCA combined with SIM prevented body weight gain compared with that in HFD and HFD + OCA groups, and reduced the Lw/Bw ratio compared with that in the HFD and HFD + SIM groups. In addition to preventing HFD-induced increases of ALT and AST, the combination of OCA and SIM reduced the mRNA levels of IL-6, TNF-α, SREBP1 and FASN. On the basis of these results, it may be concluded that the strategy of combining OCA with SIM represents an effective pharmacotherapy for NASH.

Hepatic Macrophage activation and the LPS pathway in patients with different degrees of severity and histopathological patterns of drug induced liver injury.

BACKGROUND: Inflammatory activation of hepatic macrophages plays a primary role in drug-induced liver injury (DILI). However, the exact mechanism underlying DILI remains unclear. METHODS: A total of 328 DILI patients and 80 healthy individuals were prospectively enrolled in this study. The DILI patients were categorized into subgroups based on either disease severity or histopathological patterns. Plasma soluble CD163 (sCD163) and hepatic CD163 were examined to determine hepatic macrophage activation, and CD8, CD20, and MUM-1 were assessed to determine cellular immunity using immunohistochemistry. The lipopolysaccharide (LPS) pathway proteins [e.g. LPS, soluble CD14 (sCD14), and LPS-binding protein (LBP)] were measured using enzyme-linked immunosorbent assay. RESULTS: Plasma sCD163 levels were nine-fold higher in DILI patients than in healthy controls at the baseline, but significantly decreased at the 4-week follow-up visit after treatment. The numbers of hepatic macrophages, B cells, and plasma cells were significantly higher in the liver tissues from DILI patients than those from healthy controls. Furthermore, the baseline levels of LPS pathway proteins in the DILI patients were significantly higher than those in the controls. Notably, these proteins significantly decreased at the 4-week follow-up visit but remained significantly higher than the levels for the controls. CONCLUSIONS: Hepatic inflammation in DILI involves the activation of hepatic macrophages and cellular immunity, in which the LPS pathway likely plays a role, at least in part. As such, this study has improved our understanding of the pathological mechanisms for DILI and may facilitate the development of better treatments for patients with DILI.

CD14+ monocytes and CD163+ macrophages correlate with the severity of liver fibrosis in patients with chronic hepatitis C.

Hepatic fibrosis is a crucial pathological process involved in the development of chronic hepatitis C (CHC) and may progress to liver cirrhosis and hepatocellular carcinoma. Activated peripheral blood monocytes and intrahepatic macrophages further promote hepatic fibrogenesis by releasing proinflammatory and profibrogenic cytokines. The present study aimed to investigate the role of peripheral CD14+ monocytes and intrahepatic CD163+ macrophages in hepatitis C virus (HCV)-associated liver fibrosis and clarify whether serum soluble CD163 (sCD163) may serve as a fibrosis marker in patients with CHC. A total of 87 patients with CHC and 20 healthy controls were recruited. Serum sCD163 levels were measured by ELISA. Frequencies of peripheral CD14+ monocytes and inflammatory cytokines expressed by CD14+ monocytes were analyzed by flow cytometry. The degree of fibrosis in human liver biopsies was graded using the Metavir scoring system and patients were stratified into two groups based on those results (F<2 vs. F≥2). Hepatic expression of CD163 was examined by immunohistochemical staining. The diagnostic values of sCD163, aspartate aminotransferase to platelet ratio index (APRI), fibrosis 4 score (FIB-4) and the aspartate aminotransferase to alanine aminotransferase ratio (AAR) in significant fibrosis (F≥2) were evaluated and compared using receiver operating characteristic (ROC) curves. The results indicated that the serum sCD163 levels and the frequency of CD14+ monocytes were significantly higher in the patients than that in the controls and positively correlated with liver fibrosis. The level of serum sCD163 was consistent with hepatic CD163 expression in the liver sections from patients. The frequencies of interleukin (IL)-8- and tumor necrosis factor-α-expressing monocytes were increased and that of IL-10-expressing monocytes was decreased in the patients. The area under the ROC curve (AUROC) for sCD163, APRI, FIB-4 and AAR was 0.876, 0.785, 0.825 and 0.488, respectively, and the AUROC for sCD163 was significantly higher than those for APRI and AAR. In conclusion, sCD163 may serve as a novel marker for assessing the degree of liver fibrosis in HCV-infected patients.

Multicenter prospective study to validate a new transient elastography device for staging liver fibrosis in patients with chronic hepatitis B.

OBJECTIVES: To validate the operational and diagnostic performances of a new device for transient elastography (TE), FibroTouch, for liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: In this prospective multicenter study, adult patients with CHB and valid liver pathological results were recruited to validate the operational and diagnostic performance of a TE device by FibroTouch for staging liver fibrosis. RESULTS: In total, 517 patients with histologically proven CHB were enrolled. All had achieved at least 10 successful liver stiffness measurements (LSM), resulting in a success rate of 99.1% and reliable evaluations of 95.2%. Altogether 412 patients were included to analyze the diagnostic performance of FibroTouch. The area under the receiver operating characteristic curve for the LSM was 0.846 (95% confidence interval [CI] 0.808-0.880) for fibrosis stage ≥ F1, 0.850 (95% CI 0.811-0.883) for ≥ F2, 0.908 (95% CI 0.876-0.934) for ≥ F3 and 0.874 (95% CI 0.836-0.903) for F4. The diagnostic accuracy of LSM was superior to that of gamma-glutamyl transpeptidase-to-platelet ratio (GPR), aminotransferase-to-platelet ratio index (APRI), or fibrosis index based on 4 factors (FIB-4) index in staging fibrosis F2-F4 (P = 0.007 to < 0.0001). Optimal LSM cut-off values for diagnosing fibrosis stage ≥ F1, ≥ F2, ≥ F3, and F4 were 5.5 kPa, 7.85 kPa, 10.0 kPa, and 12.7 kPa, respectively. CONCLUSION: FibroTouch has a high success rate and good reliability in staging liver fibrosis in patients with CHB.

Yiqi Huoxue Recipe Improves Liver Regeneration in Rats after Partial Hepatectomy via JNK Pathway.

The liver is the only visceral organ that exhibits a remarkable capability of regenerating in response to partial hepatectomy (PH) or chemical injury. Improving liver regeneration (LR) ability is the basis for the favourable treatment outcome of patients after PH, which can serve as a potential indicator for postoperative survival. The present study aimed to investigate the protective effects of Yiqi Huoxue recipe (YQHX) on LR after PH in rats and further elucidate its underlying mechanism. A two-thirds PH rat model was used in this study. Wistar rats were randomly divided into four groups: sham-operated, PH, YQHX + PH, and Fuzheng Huayu decoction (FZHY) + PH groups. All rats were sacrificed under anesthesia at 24 and 72 h after surgery. The rates of LR were calculated, and the expression levels of cyclin D1 and c-jun were determined by immunohistochemical staining. The protein levels of p-JNK1/2, JNK1/2, p-c-jun, c-jun, Bax, and Bcl-2 were detected by Western blotting, while the mRNA levels of JNK1, JNK2, c-jun, Bax, and Bcl-2 were examined by real-time polymerase chain reaction (RT-PCR). At the corresponding time points, YQHX and FZHY administration dramatically induced the protein levels of p-JNK1/2 compared to the PH group (p < 0.05), while FZHY + PH group showed prominently increase in p-JNK1/2 protein levels compared to the YQHX + PH group (p < 0.05). A similar trend was observed for the expression levels of p-c-jun. Compared to the PH group, YQHX and FZHY markedly reduced the mRNA and protein expression levels of Bax at 24 h after PH, while those in the FZHY + PH group decreased more obviously (p < 0.05). Besides, in comparison with the PH group, YQHX and FZHY administration predominantly upregulated the mRNA and protein expression levels of Bcl-2 at 24 and 72 h after PH (p < 0.05). In conclusion, YQHX improves LR in rats after PH by inhibiting hepatocyte apoptosis via the JNK signaling pathway.

Serum N-glycan markers for diagnosing liver fibrosis induced by hepatitis B virus.

BACKGROUND: Hepatitis B virus (HBV) infection is the primary cause of hepatitis with chronic HBV infection, which may develop into liver fibrosis, cirrhosis and hepatocellular carcinoma. Detection of early-stage fibrosis related to HBV infection is of great clinical significance to block the progression of liver lesion. Direct liver biopsy is regarded as the gold standard to detect and assess fibrosis; however, this method is invasive and prone to clinical sampling error. In order to address these issues, we attempted to find more convenient and effective serum markers for detecting HBV-induced early-stage liver fibrosis. AIM: To investigate serum N-glycan profiling related to HBV-induced liver fibrosis and verify multiparameter diagnostic models related to serum N-glycan changes. METHODS: N-glycan profiles from the sera of 432 HBV-infected patients with liver fibrosis were analyzed. Significant changed N-glycan levels (peaks) (P < 0.05) in different fibrosis stages were selected in the modeling group, and multiparameter diagnostic models were established based on changed N-glycan levels by logistic regression analysis. The receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic efficacy of N-glycans models. These models were then compared with the aspartate aminotransferase to platelet ratio index (APRI) , fibrosis index based on the four factors (FIB-4), glutamyltranspeptidase platelet albumin index (S index), GlycoCirrho-test, and GlycoFibro-test. Furthermore, we combined multiparameter diagnostic models with alanine aminotransferase (ALT) and platelet (PLT) tests and compared their diagnostic power. In addition, the diagnostic accuracy of N-glycan models was also verified in the validation group of patients. RESULTS: Multiparameter diagnostic models constructed based on N-glycan peak 1, 3, 4 and 8 could distinguish between different stages of liver fibrosis. The area under ROC curves (AUROCs) of Model A and Model B were 0.890 and 0.752, respectively differentiating fibrosis F0-F1 from F2-F4, and F0-F2 from F3-F4, and surpassing other serum panels. However, AUROC (0.747) in Model C used for the diagnosis of F4 from F0-F3 was lower than AUROC (0.795) in FIB-4. In combination with ALT and PLT, the multiparameter models showed better diagnostic power (AUROC = 0.912, 0.829, 0.885, respectively) when compared with other models. In the validation group, the AUROCs of the three combined models (0.929, 0.858, and 0.867, respectively) were still satisfactory. We also applied the combined models to distinguish adjacent fibrosis stages of 432 patients (F0-F1/F2/F3/F4), and the AUROCs were 0.917, 0.720 and 0.785. CONCLUSION: Multiparameter models based on serum N-glycans are effective supplementary markers to distinguish between adjacent fibrosis stages of patients caused by HBV, especially in combination with ALT and PLT.

Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies.

Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.

Emperipolesis mediated by CD8+ T cells correlates with biliary epithelia cell injury in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by chronic destruction of the bile ducts. A major unanswered question regarding the pathogenesis of PBC is the precise mechanisms of small bile duct injury. Emperipolesis is one of cell-in-cell structures that is a potential histological hallmark associated with chronic hepatitis B. This study aimed to clarify the pathogenesis and characteristics of emperipolesis in PBC liver injury. Sixty-six PBC patients, diagnosed by liver biopsy combined with laboratory test, were divided into early-stage PBC (stages I and II, n = 39) and late-stage PBC (stages III and IV, n = 27). Emperipolesis was measured in liver sections stained with haematoxylin-eosin. The expressions of CK19, CD3, CD4, CD8, CD20, Ki67 and apoptosis of BECs were evaluated by immunohistochemistry or immunofluorescence double labelling. Emperipolesis was observed in 62.1% of patients with PBC, and BECs were predominantly host cells. The number of infiltrating CD3+ and CD8+ T cells correlated with the advancement of emperipolesis (R2  = 0.318, P < .001; R2  = 0.060, P < .05). The cell numbers of TUNEL-positive BECs and double staining for CK19 and Ki67 showed a significant positive correlation with emperipolesis degree (R2  = 0.236, P < .001; R2  = 0.267, P < .001). We conclude that emperipolesis mediated by CD8+ T cells appears to be relevant to apoptosis of BEC and thus may aggravate the further injury of interlobular bile ducts.

CSH guidelines for the diagnosis and treatment of drug-induced liver injury.

Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.

LncRNA-ATB/microRNA-200a/ß-catenin regulatory axis involved in the progression of HCV-related hepatic fibrosis.

OBJECTIVE(S): Long noncoding RNAs (lncRNAs)-activated by transforming growth factor beta (lncRNA-ATB) is known to be involved in the invasion of hepatocellular carcinoma by regulating target genes of miR-200a. However, the role and molecular mechanisms of lncRNA-ATB/miR-200a in HCV-related liver fibrosis remains unclear. In this study, we examined the expression of lncRNA-ATB/miR-200a, and their target gene ß-Catenin in liver tissues of HCV patients and hepatic stellate cells (HSCs) to elucidate the possible role of lncRNA-ATB/miR-200a axis in HSC activation and development of liver fibrosis. MATERIALS AND METHODS: Liver tissues were obtained by biopsy or surgery from eighteen HCV patients with severe liver fibrosis and six healthy subjects (control). Conditioned media (CM) from cultured HepG2-CORE cells (HepG2 cells stably expressing HCV core protein) were used to treat LX-2 cells. The binding sites between lncRNA-ATB/miR-200a and ß-catenin were predicted and then verified by a dual luciferase reporter assay. The effect of lncRNA-ATB/miR-200a/ß-catenin on HSC activation was assessed by examining the expression of alpha-smooth muscle actin (α-SMA) and collagen type 1 alpha 1 (Col1A1) in HSCs. Further, the regulatory role of lncRNA-ATB on HSC activation and miR-200a/ß-catenin expression was assessed by using siRNA-mediated knockdown of lncRNA-ATB. RESULTS: LncRNA-ATB was up-regulated in fibrotic liver tissues and activated LX-2 cells treated with CM from HepG2-CORE cells. Dual luciferase reporter assays confirmed that lncRNA-ATB contained common binding sites for miR-200a and ß-catenin. Decreased expression of miR-200a and increased expression of ß-catenin were observed in liver tissues of patients with HCV-related hepatic fibrosis and activated HSCs. Knockdown of lncRNA-ATB could down-regulate ß-catenin expression by up-regulating the endogenous miR-200a and suppress the activation of LX-2 cells. CONCLUSION: LncRNA-ATB/miR-200a/ß-catenin regulatory axis likely contributed to the development of liver fibrosis in HCV patients. Knockdown of lncRNA-ATB might be a novel therapeutic target for HCV-related liver fibrosis.

Tim-3 suppression combined with TLR3 activation enhances antiviral immune response in patients with chronic HCV infection.

OBJECTIVE: To investigate the regulation mechanism of T cell immunoglobulin and mucin domain-3 (Tim-3) combined with toll-like receptor 3 (TLR3) or TLR4 on antiviral immune and inflammatory response in patients with chronic hepatitis C virus (HCV) infection. METHODS: Patients with chronic HCV infection and healthy control subjects were recruited. Patients received interferon (IFN)-α based therapy. Plasma galectin-9 (Gal-9) was quantitated. Peripheral blood mononuclear cells (PBMCs) were cultured with TLR3 or TLR4 agonists, alone or in combination with Tim-3 antagonist. Levels of IFN-α, TNF-α, and 2'-5' oligoadenylate synthetase (2'-5'OAS), myxovirus resistance protein A (MxA) and suppressor of cytokine 1 (SOCS1) RNA in PBMC cultures were evaluated. RESULTS: Plasma Gal-9 levels were increased in patients (n = 52) compared with controls (n = 20) and significantly declined at treatment week 12 and 24 weeks post-treatment. IFN-α, 2'-5'OAS, MxA, TNF-α and SOCS1 were upregulated by TLR3 and TLR4 agonists. TNF-α and SOCS1 levels were suppressed by the addition of Tim-3 antagonist. CONCLUSIONS: Tim-3 blockade in combination with TLR activation induces the expression of antiviral molecules without a significant increase in TNF-α or SOCS1.

A Patient With Primary Biliary Cirrhosis Accompanied by Wilson's Disease.

INTRODUCTION: Both primary biliary cirrhosis (PBC) and Wilson's disease (WD) can cause copper retention in the liver, which is an important factor for liver cellular damage. Copper chelation may preserve liver cell function. It is challenging to distinguish WD from copper accumulation in patients with PBC. There have been few case reports of PBC co-occurrence with WD. CASE PRESENTATION: Here we report a case of PBC with WD in a 55-year-old Chinese male. In addition to the typical pathological characteristics of PBC and a large number of copper depositions in the liver, the patient showed WD ATP7B gene mutations. CONCLUSIONS: Co-occurrence of PBC with WD is rare, which can cause diffusely intrahepatic copper deposition. Early liver biopsy and genetic testing are necessary for the diagnosis. The combination of ursodeoxycholic acid with zinc and sodium dimercaptopropane sulfonate is effective.

Gamma-glutamyl transpeptidase to platelet ratio index is a good noninvasive biomarker for predicting liver fibrosis in Chinese chronic hepatitis B patients.

Objective To evaluate whether gamma-glutamyl transpeptidase to platelet ratio index (GPRI) can diagnose the extent of liver fibrosis in Chinese patients with chronic hepatitis B (CHB) infection. Methods This prospective observational study used liver biopsy results as the gold standard to evaluate the ability of GPRI to predict hepatic fibrosis compared with two other markers, the aspartate aminotransferase (AST) to platelet ratio index (APRI) and fibrosis-4 score (FIB-4). The clinical and demographic factors that affected GPRI, independent of liver fibrosis, were assessed using multivariate linear regression analyses. Results This study enrolled 312 patients with CHB. GPRI had a significantly positive correlation with liver fibrosis stage and the correlation coefficient was higher than that for APRI and FIB-4. The areas under the receiver operating curves for GPRI for significant fibrosis, bridging fibrosis, and cirrhosis were 0.728, 0.836, and 0.842, respectively. Of the three indices, GPRI had the highest diagnostic accuracy for bridging fibrosis and cirrhosis. Age, elevated AST and elevated total bilirubin levels were independent determinants of increased GPRI. Conclusion GPRI was a more reliable laboratory marker than APRI and FIB-4 for predicting the stage of liver fibrosis in Chinese patients with CHB.

Individualized treatment strategies and predictors of virological response for chronic hepatitis C: a multicenter prospective study from China.

Combination therapy comprising pegylated interferon-alpha (PegIFNα) and ribavirin (RBV) has been the standard of care for the chronic hepatitis C patients for more than a decade. Recently, direct antiviral agents show better efficacy, tolerance, and shorter treatment duration. However, the prohibitive costs of the regimens limit their use in developing countries where most of the HCV infection exists. Optimizing the treatment and understanding the host- and virus-factors associated with viral clearance were necessary for individualizing therapy to maximize sustained virologic response. To explore individualized antiviral strategies with PegIFNα-2a/IFNα-2b plus ribavirin for CHC patients, and to clarify predictive factors for virological response. A cohort of 314 patients were included in this open-label, prospective clinical trial, which received individualized doses of PegIFNα-2a or IFNα-2b combined with RBV according to body weight, disease status and complications, with the duration of 44 weeks after HCV RNA undetectable. All the IL-28B (rs8099917), IL-17A (rs8193036), IL-17B (rs2275913) and PD-1.1 SNPs were genotyped using the TaqMan system. The sustained virological response (SVR) in PegIFNα-2a group was significantly higher than that in IFNα-2b (85.8% vs 75.0%, P = 0.034), especially in HCV genotype 1 (84.0% vs 64.3%, P = 0.022). However, no significant differences were found in rapid virological response (RVR), complete early virological response (cEVR) and SVR between PegIFNα-2a and IFNα-2b according to different doses, respectively. The genotype frequency of IL-28B TT in patients with cEVR, SVR was higher than that in non-responsed patients (93.8% vs 78.1%, χ(2) = 7.827, P = 0.005; 95.9% vs 80.4%, χ(2) = 9.394, P = 0.002). No significant correlation between the genotype distribution of IL-17A, IL-17B and PD-1.1 with virological response. Individualized regimens of PegIFNα-2a/RBV and IFNα-2b/RBV could achieve satisfied virological response in Chinese HCV patients. The IL-28B (rs8099917) TT genotype is a clinical usefully marker for cEVR and SVR.

Dichlorvos induced autoimmune hepatitis: a case report and review of literature.

INTRODUCTION: Drug-induced liver injury is a frequent cause of hepatic dysfunction. Several drugs have been identified to cause autoimmune hepatitis (AIH). Environmental chemicals are capable of triggering a certain degree of liver injury. However, toxin induced AIH is rare. CASE PRESENTATION: We reported a woman with chronic (long-term) exposures to dichlorvos, which resulted in liver injury and cirrhosis. She was diagnosed after a second liver biopsy, which was correlated with laboratory findings. At the same time, she experienced hepatic cortical blindness during her first admission. CONCLUSIONS: Chronic (long-term) exposures to dichlorvos can lead to AIH. A detailed inquiry of medical history and liver biopsy are necessary for the diagnosis of toxin-induced AIH. Corticosteroid therapy is associated with favorable evolution.

Modulation of IKKß/NF-κB and TGF-ß1/Smad via Fuzheng Huayu recipe involves in prevention of nutritional steatohepatitis and fibrosis in mice.

OBJECTIVES: Fuzheng Huayu recipe (FZHY) exerts significant protective effects against liver fibrosis by strengthening the body's resistance and removing blood stasis. However, the molecular mechanisms through which FZHY affects liver fibrosis are still unclear. In this study, we examined the expression levels of factors involved in the inhibitor κB kinase-ß (IKK-ß)/nuclear factor-κB (NF-κB) and transforming growth factor beta 1 (TGF-ß1)/Smad signaling pathways to elucidate whether FZHY could attenuate nutritional steatohepatitis and fibrosis in mice. MATERIALS AND METHODS: C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrotic steatohepatitis. FZHY and/or heme oxygenase-1 (HO-1) chemical inducer (hemin) were administered to mice. The effects of FZHY alone and in combination with hemin were assessed by comparing the severity of hepatic injury, activation of hepatic stellate cells (HSCs), and the expression of oxidative stress, inflammation and fibrogenesis related genes. RESULTS: Administration of FZHY, hemin and FZHY plus hemin significantly ameliorated liver injury. Additionally, our analysis indicated that administration of these agents significantly attenuated oxidative stress, downregulated the expression of pro-inflammatory and pro-fibrotic genes, including IKK-ß, NF-κB, monocyte chemoattractant protein-1 (MCP-1), α-smooth muscle actin (α-SMA), TGF-ß1, Smad3 and Smad4, and upregulated the expression of the antifibrogenic gene Smad7 (P< 0.001). CONCLUSION: FZHY-containing therapies prevented nutritional steatohepatitis and fibrosis through modulating the expression of factors associated with the IKKß/NF-κB and TGF-ß1/Smad signaling pathways and oxidative stress related genes.

Nimesulide inhibits the growth of human esophageal carcinoma cells by inactivating the JAK2/STAT3 pathway.

Although selective COX-2 inhibitors have cancer-preventive effects and induce apoptosis, the mechanisms underlying these effects are not fully understood. This study investigated the effects of nimesulide, a selective COX-2 inhibitor, on apoptosis and on the JAK/STAT signaling pathway in Eca-109 human esophageal squamous carcinoma cells. The effects and mechanisms of nimesulide on Eca-109 cell growth were studied in culture and in nude mice with Eca-109 xenografts. Cells were cultured with or without nimesulide and/or the JAK2 inhibitor AG490. Cell proliferation was evaluated using the MTT assay, and apoptosis was investigated. COX-2 mRNA expression was measured using reverse transcription polymerase chain reaction, and protein expression was detected by Western blot analysis, immunohistochemistry, and flow cytometry. Nimesulide significantly inhibited Eca-109 cell viability in vitro in a dose- and time-dependent manner (P<0.05). Nimesulide also induced apoptosis, which was accompanied by a significant decrease in the expression of COX-2 and survivin and an increase in caspase-3 expression. Nimesulide downregulated the phosphorylation levels of JAK2 and STAT3, and JAK2 inhibition by AG490 significantly augmented both nimesulide-induced apoptosis and the downregulation of COX-2 and survivin (P<0.05). In vivo, nimesulide inhibited the growth of Eca-109 tumors and the expression of p-JAK2 and p-STAT3. Thus, nimesulide downregulates COX-2 and survivin expression and upregulates caspase-3 expression in Eca-109 cells, by inactivating the JAK2/STAT3 pathway. These effects may mediate nimesulide-induced apoptosis and growth inhibition in Eca-109 cells in vitro and in vivo.

Peroxisome proliferator-activated receptor α, a potential therapeutic target for alcoholic liver disease.

Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.

Regulatory phenotype, PD-1 and TLR3 expression in T cells and monocytes from HCV patients undergoing antiviral therapy: a randomized clinical trial.

BACKGROUND & AIMS: The cellular immunity has a profound impact on the status of hepatitis C virus (HCV) infection. However, the response of cellular immunity on the virological response in patients with antiviral treatment remains largely unclear. We aimed to clarify the response of peripheral T cells and monocytes in chronic hepatitis C patients with antiviral treatment. METHODS: Patients with chronic hepatitis C were treated either with interferon alpha-2b plus ribavirin (n = 37) or with pegylated interferon alpha-2a plus ribavirin (n = 33) for up to 24 weeks. Frequencies of peripheral regulatory T-cells (Tregs), programmed death-1 (PD-1) expressing CD4+ T-cells or CD8+ T-cells and toll-like receptor (TLR) 3 expressing CD14+ monocytes were evaluated by flow cytometry in patients at baseline, 12 and 24 weeks following treatment and in 20 healthy controls. RESULTS: Frequencies of Tregs, PD-1 and TLR3 expressing cells were higher in patients than those in control subjects (P<0.05). Patients with complete early virological response (cEVR) showed lower Tregs, PD-1 expressing CD4+ or CD8+ T-cells than those without cEVR at 12 weeks (P<0.05). Patients with low TLR3 expressing CD14+ monocytes at baseline had a high rate of cEVR (P<0.05). CONCLUSIONS: Low peripheral TLR3 expressing CD14+ monocytes at baseline could serve as a predictor for cEVR of antiviral therapy in chronic HCV-infected patients. The cEVR rates were significantly increased in the patients with reduced circulating Tregs, PD-1 expressing CD4+ or CD8+ T-cells. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR10001090.