Shunai Liu

Background. Chronic hepatitis B cirrhosis is often accompanied by glucose metabolism disorder, and intestinal microbiota was closely related to both cirrhosis and diabetes. There are few studies on the role of intestinal microbiota in hepatitis B liver cirrhosis and diabetes mellitus (LCDM). The purpose of this study was to investigate the characteristics of intestinal microbiota in patients with LCDM and to evaluate the relationship between the severity of intestinal microbiota imbalance and clinical significance. Methods. A case-controlled study was conducted. People who met the inclusion and exclusion criteria of chronic HBV-related liver cirrhosis (LC), LCDM, and healthy controls (HC) were enrolled in, and their fecal and blood samples were collected. The V3-V4 region of 16s rDNA gene of fecal microbiota was sequenced; the bioinformatics analysis including α-diversity, β-diversity, and linear discriminant analysis (LDA) effect size (LEfSe) was performed; and the correlation between bacteria and clinical indexes was analyzed. Results. A total of 70 participants completed fecal and blood tests, including 20 HC, 20 LCDM, and 30 LC. The α diversity of intestinal microbiota in the LCDM decreased than that in the HC. The abundance of Proteobacteria, Streptococcus, Escherichia-Shigella, and Lactobacillus increased, while the abundance of Bacteroidota, Bacteroides, Prevotella, Faecalibacterium, and Lachnospira decreased in the LCDM compared with the HC. The abundance of Lactobacillus, Roseburia, and Veillonella and the degree of hepatitis B cirrhosis dysbiosis indicator (HBCDI) increased in the LCDM than in the LC. The abundance of Escherichia-Shigella, Veillonella, and Lactobacillus positively correlated with liver injury and fasting blood glucose (FBG) level. The abundance of Escherichia-Shigella, Veillonella, Streptococcus, and Lactobacillus increased more significantly when FBG and glycosylated hemoglobin level increased. Conclusion. Intestinal microbiota of patients with LCDM was significantly disordered, and the degree was more serious than that cirrhosis patients without diabetes.

To investigate whether IL‑21 levels predict treatment outcomes of salvage therapy among patients with suboptimal response (SOR) to nucleos(t)ide analogues (NAs), serum IL‑21 levels were measured in a prospective cohort of hepatitis B e antigen (HBeAg)‑positive patients with SOR to antiviral therapy. The patients switched therapy to entecavir (ETV) with or without adefovir (ADV) for 104 weeks. IL‑21 levels at treatment week 12 in patients who achieved HBeAg loss with undetectable levels of hepatitis B virus (HBV)‑DNA at week 104 were the primary endpoint and the results were compared with those of corresponding patients without such an endpoint. Furthermore, IL‑21 levels at treatment week 12 in patients who achieved an HBeAg‑level decline at week 104 were assessed as the secondary endpoint. Among 24 enrolled patients with SOR to ADV (n=21), telbivudine (n=2) or ETV (n=1), the median (10‑90th percentile) levels of HBeAg, HBV‑DNA and ALT at baseline were 2.7 (0.2‑3.1) log₁₀ S/CO, 5.2 (3.5‑7.5) log₁₀ IU/ml and 0.9 (0.5‑3.1) upper limit of normal, respectively. Comparison of the patients with and without HBeAg loss at week 104 indicated that their mean IL‑21 levels did not significantly differ at week 12 (63.0±14.4 vs. 55.9±10.5 pg/ml; P=0.26). In the secondary endpoint analyses of patients with and without HBeAg level decline, the elevated levels of IL‑21 at the first 12 weeks were significantly higher in the decline group (15.6±8.3 vs. 3.1±13.2 pg/ml; P=0.03). Following adjustment for confounding factors, the elevated levels of IL‑21 from baseline to week 12 independently predicted an HBeAg level decline at week 104 (odds ratio=1.137, R²=0.23; P=0.047). In conclusion, the serum IL‑21 levels at the first 12 weeks during the salvage therapy independently predicted HBeAg level decline at treatment week 104 in patients with SOR to NAs (ClinicalTrials.gov identifier: NCT01829685; date of registration, April 2013).

When alcohol-related liver disease occurs, the number and composition ratio of intestinal microorganisms will accordingly change. The alcohol-induced changes in the intestinal microbiota play a pivotal role in the process of developing the alcohol-related liver disease through the translocation of microbial products due to increased intestinal permeability. In recent years, therapeutic interventions with a concentration on regulating intestinal microbiota have been conducted for patients with alcohol-related liver disease. We aimed to provide a critical review and updates on the prevention and treatment of alcohol-related liver disease through regulating intestinal microbiota. A literature search was performed on the PubMed database for studies published in English about the therapeutic intervention with microbiota using animal models and patients with alcohol-related liver disease (1/2010–4/2020). The accumulating pieces of evidence suggest that the therapeutic use of probiotics, prebiotics, antibiotics, phages, or fecal microbial transplantation may have several influences on alcohol-related liver disease patients. Emergent data unveiled that these interventions can further regulate the composition of intestinal microbiota, minimize the negative impact of microbiota on the liver, and prevent disease progression from mild to severe alcoholic hepatitis, fibrosis, cirrhosis, or even liver cancer. The current review provides updates on the advances of therapeutic interventions with the effects of regulating intestinal microbiota on patients who have alcohol-related liver disease. In addition, the data gaps and research directions on further exploration of the role of intestinal microbiota for the management of the alcohol-related liver disease are also discussed.

Coronavirus disease 2019 (COVID‐19) has become a major global public health concern. The mortality rate for critically ill patients is up to 60%, and, thus, reducing the disease severity and case mortality is a top priority. Currently, cytokine storms are considered as the major cause of critical illness and death due to COVID‐19. After a systematical review of the literature, we propose that cross‐reactive antibodies associated with antibody‐dependent enhancement (ADE) may actually be the cause of cytokine storms. It would be more difficult to develop vaccines for highly pathogenic human coronaviruses (CoVs) if ADE characteristics are taken into consideration. Therefore, it is urgent to find an effective way to prevent the occurrence of severe illness as severe acute respiratory syndrome CoV‐2 specific drugs or vaccines are still in development. If the activation of memory B cells can be selectively inhibited in high‐risk patients at an early stage of COVID‐19 to reduce the production of cross‐reactive antibodies against the virus, we speculate that ADE can be circumvented and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such needs and it is recommended to conduct clinical trials for mTOR inhibitors in preventing the severity of COVID‐19.

COVID-19 has become a severe global public health concern. The critical illness has a mortality rate of 61.5%, and thus, reducing the severity and mortality is top priority. Currently, inflammatory storms are considered as the cause of critical illness and death due to COVID-19. However, After systematical review of the literature, we proposed that cross-reactive antibodies-associated antibody-dependent enhancement (ADE) may actually be the cause of cytokine storms. If the activation of memory B cells can be selectively inhibited in high-risk patients at an early stage of COVID-19 to reduce the production of cross-reactive antibodies of the virus, we speculate that the ADE can be avoided and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such conditions. We recommend that pharmaceutical companies conduct clinical trials urgently.

Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) modulates cellular apoptosis, which is involved in the occurrence and development of liver cancer. The mechanisms of apoptosis inhibition by NS5A in liver cancer cells remains unclear. Beclin 1, which functions upstream of autophagosome formation, is upregulated by NS5A. Autophagy, an evolutionarily conserved catabolic process, has a crucial role in tumor initiation and progression. Autophagy was blocked by inhibitors 3‑methyladenine and chloroquine, or via knockdown of Beclin 1. Flow cytometric analysis and western blotting were used to detect apoptosis. It was found that inhibition of autophagy attenuated the NS5A‑mediated apoptosis inhibition of HepG2 cells. Furthermore, it was confirmed that Beclin 1 expression by NS5A was involved in the negative regulation of starvation‑induced liver cancer apoptosis, which was accompanied by reduced p53 and apoptosis regulator Bax expression, as well as decreased caspase‑3/-7 activation. Therefore, inhibition of autophagy may be promising therapeutic strategy in the treatment of HCV‑associated liver cancer.

Hypertriglyceridemia leads to liver steatosis, cardiovascular disease, and type 2 diabetes. Although HCBP6 (hepatitis C virus core‐binding protein 6) was previously shown to be an HCV (hepatitis C virus) core‐binding protein, its biological function remains unclear. Here, we demonstrate that HCBP6 negatively regulates intracellular triglyceride (TG) levels in hepatocytes. We found that bidirectional manipulation of hepatocyte HCBP6 expression by knockdown or overexpression results in increased or decreased TG accumulation, respectively. In addition, HCBP6 mRNA and protein levels exhibited significant time‐ and dose‐dependent increases in a cellular model of lipid‐overload hepatic steatosis. Furthermore, TG levels are regulated by HCBP6‐sterol regulatory element binding protein 1c (SREBP1c)‐mediated fatty acid synthase (FASN) expression. We also demonstrate that HCBP6 mRNA and protein expression is inhibited by microRNA‐122 (miR‐122), and miR‐122 overexpression elicited more robust translational repression of luciferase activity driven by the full 3′‐UTR of HCBP6. Taken together, our results provide new evidence that miR‐122‐regulated HCBP6 functions as a sensor protein to maintain intrahepatocyte TG levels. J. Cell. Biochem. 116: 2375–2384, 2015.