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Although concomitant nonalcoholic steatohepatitis (NASH) is common in chronic hepatitis B (CHB), the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear. We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment.In the post-hoc analysis of a multicenter trial, naïve CHB patients receiving 72-week entecavir treatment were enrolled. We evaluated the biochemical, viral and histopathological responses of these patients. The histopathological features of NASH were also evaluated, using paired liver biopsies at baseline and week 72.A total of 1000 CHB patients were finally enrolled for analysis, with 18.2% of whom fulfilling the criteria of NASH. A total of 727 patients completed entecavir antiviral treatment and received the second biopsy. Serum HBeAg loss, HBeAg seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH (P0.05). Among patients with NASH, the hepatic steatosis, ballooning, lobular inflammation scores and fibrosis stages all improved during follow-up (all P0.001), 46% (63/136) achieved NASH resolution. Patients with baseline body mass index (BMI) ≥ 23 kg/mLower BMI and weight reduction but not virologic factors determine NASH resolution in CHB. The value of weight management in CHB patients during antiviral treatment deserves further evaluation.

The dysregulation of cholesterol metabolism is a high-risk factor for non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and atherosclerosis (AS). Cholesterol transport maintains whole-body cholesterol homeostasis. Low-density apolipoprotein receptor (LDLR) mediates cholesterol uptake in cells and plays an important role in the primary route of circulatory cholesterol clearance in liver cells. Caveolins 1 is an integral membrane protein and shuttle between the cytoplasm and cell membrane. Caveolins 1 not only plays a role in promoting cholesterol absorption in cells but also in the transport of cellular cholesterol efflux by interacting with the ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI). These proteins, which are associated with reverse cholesterol transport (RCT), are potential therapeutic targets for NAFLD and AS. Many studies have indicated that natural products have lipid-lowering effects. Moreover, natural molecules, derived from natural products, have the potential to be developed into novel drugs. However, the mechanisms underlying the regulation of cholesterol transport by natural molecules have not yet been adequately investigated. In this review, we briefly describe the process of cholesterol transport and summarize the mechanisms by which molecules regulate cholesterol transport. This article provides an overview of recent studies and focuses on the potential therapeutic effects of natural molecules; however, further high-quality studies are needed to firmly establish the clinical efficacies of natural molecules.

Chronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese patients with CHB and an Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial.After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis.A total of 1,000 patients were recruited; the median age was 42.0 years; 69.9% were male and 58.3% were HBeAg positive. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV monotherapy (p = 0.008 [p = 0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than ETV monotherapy (p = 0.018). There were no differences in the other 2 secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis, including the treatment allocation as a parameter, also demonstrated that ETV+BRC treatment was associated with a reduced incidence of HCC. The ITT and PP analyses showed consistent results.ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in patients with CHB and advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention.Patients with chronic hepatitis B virus infection are at an increased risk of developing liver cancer (specifically hepatocellular carcinoma [HCC]). While there are effective antiviral treatments that can suppress the virus in chronically infected patients, the risk of HCC remains. Herein, we show that adding a traditional Chinese medicine called Biejia-Ruangan compound to an antiviral reduced the risk of HCC in patients with chronic hepatitis B.

Background Long-term nucleos(t)ide analogue (NA) treatment can reverse liver fibrosis in chronic hepatitis B (CHB), but its effect on fibrosis regression remains limited. Biejia-Ruangan (BR) has been approved in China as an antifibrotic traditional Chinese medicine drug in patients with chronic liver diseases. A multicenter randomized controlled trial aims to evaluate the effect of BR on fibrosis regression in CHB patients treated with NAs. Methods CHB patients with histologically confirmed advanced fibrosis or cirrhosis were randomly assigned to receive entecavir (ETV) (0.5 mg per day) plus BR (2 g 3 times a day) or placebo for 72 weeks. Liver fibrosis regression was defined as a reduction of ≥ 1 point by the Ishak fibrosis stage (IFS). Results Overall, 500 patients were enrolled in each group as the intention-to-treat population. The rate of fibrosis regression after 72 weeks of treatment was significantly higher in the ETV + BR group (40% vs 31.8%; P = .0069). Among 388 patients with cirrhosis (ie, IFS ≥ 5) at baseline, the rate of cirrhosis reversal (ie, IFS ≤ 4) was significantly higher in the ETV + BR group (41.5% vs 30.7%; P = .0103). Conclusions Addition of BR to the current standard treatment with NAs in CHB patients with advanced fibrosis or cirrhosis can improve liver fibrosis regression. Clinical Trials Registration NCT01965418.

Objective To analyze the differentially expressed genes (DEGs) in patients with poor response to ursodeoxycholic acid (UDCA) therapy and to provide theoretical basis for the treatment of primary biliary cholangitis (PBC). Methods The GEO database was searched to obtain UDCA response related gene chip dataset. The DEGs were screened and the protein-protein interaction (PPI) network was constructed. The enrichment analysis of the biological function and signaling pathway of DEGs were carried out with the use of DAVID database. The CIBERSORT deconvolution algorithm was used to analyze the infiltration of 22 kinds of immune cells. Finally, Coremine database was used to predict traditional Chinese medicine (TCM) by analyzing the DEGs that were not only related to UDCA response, but also related to the immune cell infiltration. Results By analyzing the gene chips from UDCA responders and UDCA poor-responders, 99 DEGs were obtained. Biological function and signaling pathway enrichment analysis showed that the up-regulated DEGs were mainly enriched in immune response, virus infection, and PI3K/AKT signaling pathway and the down-regulated DEGs were mainly enriched in immune response, inflammatory reaction, complement cascade reaction, virus infection and systemic lupus erythematosus. The analysis of immune cell infiltration showed that naive B cells, resting memory CD4

Background Ganxianfang (GXF) formula as a traditional Chinese medicine (TCM) is used for liver fibrosis in clinical practice while its mechanism is unclear. The aim of this study is to explore the molecular mechanism of GXF against CCl4-induced liver fibrosis rats. Methods Detected the main compounds of GXF by UPLC-MS/MS. Evaluated the efficacy of GXF (1.58, 3.15, 4.73 g/kg/day) and Fuzheng Huayu (FZHY, positive control, 0.47 g/kg/day) through serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels and histopathological changes. Explored the underlying mechanisms by integrating our total liver RNA sequencing (RNA-seq) data with recent liver single-cell sequencing (scRNA-seq) studies. Verified potential pharmacodynamic substances of GXF by hepatic stellate cell (HSC)-T6 line. Results Main compounds were identified in GXF by UPLC-MS/MS, including baicalin, wogonoside and matrine etc. With GXF-high dose treatment, the elevation of ALT and AST induced by CCl4 were significantly reduced, and the protective effect of GXF-high dose treatment was better than FZHY. Liver histopathological changes were alleviated by GXF-high dose treatment, the ISHAK scoring showed the incidence of liver cirrhosis (F5/F6) decreased from 76.5 to 55.6%. The results of liver hydroxyproline content were consistent with the histopathological changes. RNA-seq analysis revealed the differential genes (DEGs) were mainly enriched in ECM-receptor interaction and chemokine signaling pathway. GXF effectively inhibited collagen deposition and significantly downregulated CCL2 to inhibit the recruitment of macrophages in liver tissue. Integrating scRNA-seq data revealed that GXF effectively inhibited the expansion of scar-associated Trem2+CD9+ macrophages subpopulation and PDGFRα+PDGFRβ+ scar-producing myofibroblasts in the damaged liver, and remodeled the fibrotic niche via regulation of ligand-receptor interactions including TGFβ/EGFR, PDGFB/PDGFRα, and TNFSF12/TNFRSF12a signaling. In vitro experiments demonstrated that baicalin, matrine and hesperidin in GXF inhibited the activation of hepatic stellate cells. Conclusions This study clarified the potential anti-fibrotic effects and molecular mechanism of GXF in CCl4-induced liver fibrosis rats, which deserves further promotion and application.

Background: A year ago, a new type of coronavirus emerged. Once treated for severe and critical COVID-19 infections, patients are discharged from the hospital for further treatment and rehabilitation. The aim of this study was to evaluate the efficacy and safety of a newly developed comprehensive rehabilitation program based on traditional Chinese medicine (TCM) in the rehabilitation of patients with severe and critical COVID-19.Methods: We recruited a total of 72 patients who had suffered from severe and critical COVID-19 infections and were undergoing rehabilitation in Chongqing, China. A comprehensive rehabilitation program was formulated according to the TCM syndromes of these patients. Specific treatments included oral TCM, Baduanjin, Moxibustion, Acupoint application, and foot baths. Prior to the initiation of treatment, and four weeks after the initiation of treatment, we carried out a range of assessments, including the TCM Syndrome curative effect score, the modified Medical Research Council (mMRC) dyspnea score, the St. George's Respiratory Questionnaire, the Short Form (SF)-36 Quality of Life Scale, and the 6-minute walking test. We also carried out CT scans, serology tests. Statistical analysis was also conducted to evaluate the efficacy and safety of TCM on severe and critical COVID-19 patients.Results: Analysis showed that there were significant differences (P < 0.05) when compared before and after four weeks of TCM treatment, in terms of the TCM syndrome curative effect score, mMRC dyspnea score, St. George's Respiratory Questionnaire score, SF-36 Quality of Life Scale score, and the 6-minute walking test. We also identified significant differences (P < 0.05) between these two timepoints, with regards to the neutrophil ratio, lymphoid cell ratio, lymphocytes, platelets, red blood cells, and hemoglobin. There were no significant differences when compared between the two timepoints with regards to white blood cells and neutrophils (P > 0.05). The efficacy of chest CT scans was 83.9%. Logistic regression showed that the CT scans of patients who did not take the TCM decoction did not improve significantly. The higher a patient’s score on the 6-minute walking test, the higher the probability of no significant improvement on the CT scan.Conclusions: A comprehensive rehabilitation program based on TCM improved a number of clinical parameters in patients suffering from severe and critical COVID-19 infections, including quality of life, clinical symptoms, exercise endurance, and respiratory function. TCM also enhanced lymphocytes, lymphocyte ratio, platelet, red blood cell (RBC) count, and hemoglobin content. TCM also appeared to contribute to the absorption of lung lesions.

Background: In recent years, more and more studies revealed that liver fibrosis progression could happen at early stage in chronic hepatitis B (CHB) patients. However, there is no anti-fibrotic agent available at present in modern medicine.He-He-Shu-YangParticles (HHSYP) and Anluohuaxian Pills (AHP)are two commonly used Traditional Chinese Medicine (TCM) agents for liver fibrosis, but there is no data of them for early liver fibrosis(F1 or F2) in multicenter, randomized controlled trial. Therefore, the aim of this study is to evaluate efficacy and safety ofHHSYP plus AHP for early liver fibrosis in CHB patients. Methods/design: For the 72-week randomized controlled study, 480 CHB patients with early liver fibrosis are randomly assigned at a 2:1 ratio to two groups: the intervention group and the placebo group. The intervention group was treated with HHSYP plus AHP. The placebo group was treated with placebo of HHSYP and AHP. The primary end point is the histological change after 72-week treatment.Discussion: Although previous studies have confirmed the anti-fibrosis efficacy of HHSYP and AHP in CHB patients, the efficacy and safety of their combination treatment for early liver fibrosis is still not clear.Therefore, this will be the first multicenter randomized trial to prove the efficacy and safety of combination TCM treatment of HHSYP and AHP for early liver fibrosis, which will use histological changes as the primary end point. This will provide reliable data for the TCM combination treatment of early liver fibrosis and might give a new direction for further international studies on liver fibrosis.Ethics and dissemination: This study protocol was approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (BF2018-175-01) and all other participating centers (Project number2018ZX10725506-003).The study findings will be published in peer-reviewed journals and presented at the national and international conferences. Trial registration: Chinese Clinical Trial Registration: ChiCTR1900025897, Registered:13 September 2019, http://www.chictr.org.cn/edit.aspx?pid=40222&htm=4

Due to economic development and lifestyle changes, the incidence of non‑alcoholic fatty liver disease (NAFLD) has gradually increased in recent years. However, the pathogenesis of NAFLD is not yet fully understood. To identify candidate genes that contribute to the development and progression of NAFLD, two microarray datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified and functional enrichment analyses were performed. A protein‑protein interaction network was constructed and modules were extracted using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. The enriched functions and pathways of the DEGs included 'cellular macromolecule biosynthetic process', 'cellular response to chemical stimulus', 'extracellular matrix organization', 'metabolic pathways', 'insulin resistance' and 'forkhead box protein O1 signaling pathway'. The DEGs, including type‑1 angiotensin II receptor, formin‑binding protein 1‑like, RNA‑binding protein with serine‑rich domain 1, Ras‑related C3 botulinum toxin substrate 1 and polyubiquitin‑C, were identified using multiple bioinformatics methods and validated in vitro with reverse transcription‑quantitative polymerase chain reaction analysis. In conclusion, five hub genes were identified in the present study, and they may aid in understanding of the molecular mechanisms underlying the development and progression of NAFLD.

Background: HBeAg-positive chronic infection is a unique phase of chronic hepatitis B virus (HBV) infection. Current guidelines advise against starting antiviral treatment for HBeAg-positive chronic hepatitis B virus (HBV) infection patients, some data suggest treating such patients may reduce the risk of hepatocellular carcinoma. We aimed to explore whether these patients can have evident histological liver injury (EHLI), and develop a non-invasive model for identifying EHLI in such patients. Method: We assessed whether HBeAg-positive chronic HBV infection patients can have EHLI defined by Ishak fibrosis stage ≥3 and/or histologic activity index ≥ 9 in a prospective multicenter study. Logistic and Lasso regression was used to select the optimal predictors. We used Akaike information criterion, discrimination improvement, net reclassification improvement to develop and validate models predicting EHLI risk in training cohort and two external validation cohorts. Findings: Of these 336 patients met the inclusion criteria, 181(54%) were HBeAg-positive chronic HBV infection, of whom 60 patients (33%) had EHLI, the proportion of significant fibrosis was higher than that of significant inflammation (33% vs. 8%, P

Background: Non-invasive evaluation for liver fibrosis is of great clinical interest and value, but current models fail to accurately stage and differentiate each stage of liver fibrosis, especially in patients with chronic hepatitis B (CHB), and never taking off to be used clinically. Methods: This multicenter, prospective study used unbiased penalized logistic regression, assessed 30 variables referencing to histologic fibrosis stage in a large training cohort (n=800), and established simpler novel non-invasive program score (SNNPS). An independent validation cohort (n=400) was used to validate the SNNPS. Finally, a mobile program was then developed for one-step detailed calculation of certain hepatic fibrosis staging. Findings: Five variables-liver stiffness measurement (LSM), platelet counts, age, serum hyaluronic acid and spleen diameter, were identified as independent predictors for fibrosis stage and developing SNNPS that has AUCs of 0.893, 0.897, and 0.909 for significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Using sub-models of SNNPS, S1 score ≤ 2.875 was 86% specific and 82% sensitive for mild fibrosis, S2 score ≤ 4.06 was 85% specific and 86% sensitive for significant fibrosis, and S3 score ≤ 4.402 or > 4.402 was 93% specific and 91% sensitive for advanced fibrosis or cirrhosis. In validation set, AUCs for significant fibrosis, advanced fibrosis, and cirrhosis were 0.904, 0.912, and 0.897, respectively. The SNNPS with highest LR and lowest LR- was significantly more specific and sensitive than AAR, APRI, LSM alone and Hepascore, and can be calculated via a mobile program in one-step. Interpretation: Using sophisticated mathematic modelling and a large multicenter study data developed and validated SNNPS that is superior to previously reported models, and can be easily calculated via mobile program to accurately diagnose various hepatic fibrosis stages in CHB patients in a wider range. Trial Registration Number: ClinicalTrials.gov. Identifier: NCT65418 Funding Information: National Major Science and Technology Special Project of China (2013ZX10005002). Competing Interest Declaration: The authors declare that there is no conflict of interest in this study Ethical Approval Statement: The study meets the requirements of Declaration of Helsinki, and protocol was approved by the ethics committee of each participating institution, and a written informed consent was obtained from all patients.