MicroRNA-29a-3p Prevents Drug-Induced Acute Liver Failure through Inflammation-Related Pyroptosis Inhibition.

OBJECTIVE: Little is known about the role of microRNA-29a-3p (miR-29a-3p) in inflammation-related pyroptosis, especially in drug-induced acute liver failure (DIALF). This study aimed to identify the relationship between miR-29a-3p and inflammation-related pyroptosis in DIALF and confirm its underlying mechanisms. METHODS: Thioacetamide (TAA)- and acetaminophen (APAP)-induced ALF mouse models were established, and human samples were collected. The expression levels of miR-29a-3p and inflammation and pyroptosis markers were measured by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, or immunochemical staining in miR-29a-3p knock-in transgenic mouse (MIR29A(KI/KI)) DIALF models. In addition, RNA sequencing was conducted to explore the mechanisms. RESULTS: MiR-29a-3p levels were decreased in TAA- and APAP-induced DIALF models. MiR-29a-3p prevented DIALF caused by TAA and APAP. RNA sequencing and further experiments showed that the protective effect of miR-29a-3p on DIALF was mainly achieved through inhibition of inflammation-related pyroptosis, and the inhibition was dependent on activation of the PI3K/AKT pathway. In addition, miR-29a-3p levels were reduced, and pyroptosis was activated in both peripheral blood mononuclear cells and liver tissues of DIALF patients. CONCLUSION: The study supports the idea that miR-29a-3p inhibits pyroptosis by activating the PI3K/AKT pathway to prevent DIALF. MiR-29a-3p may be a promising therapeutic target for DIALF.

Prevalence of Cirrhosis/Advanced Fibrosis Among HBsAg-Negative and HBcAb-Positive US Adults: A Nationwide Population-Based Study.

INTRODUCTION: Evaluation of cirrhosis appears to be easily overlooked in the clinic for the HBsAg-negative (hepatitis B surface antigen-negative) and HBcAb-positive (hepatitis B core antibody-positive) population. Herein, we determine the prevalence of cirrhosis/advanced fibrosis among HBsAg-negative/HBcAb-positive US adults. METHODS: Data came from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. A total of 3115 HBsAg-negative/HBcAb-positive US adults were enrolled in this study. We assessed cirrhosis by using the Fibrosis-4 (FIB-4) and aspartate aminotransferase to platelet ratio index (APRI) score. RESULTS: Out of 50,201 NHANES adults, 45,087 were tested for HBcAb/HBsAg, of whom 3115 met the inclusion criteria (HBsAg-negative/HBcAb-positive with available data for FIB-4/APRI). The weighted proportion of HBsAg-negative/HBcAb-positive among US adults was 4.46% (95% CI 4.17-4.75%), affecting 9.87 million US adults. According to the results of the FIB-4, the weighted prevalence of cirrhosis/advanced fibrosis among HBsAg-negative/HBcAb-positive US adults was 3.76% (95% CI 2.80-4.72%), which corresponds to 371,112 (95% CI 276,360-465,864) HBsAg-negative/HBcAb-positive American adults who had already developed cirrhosis. Among those, cirrhosis/advanced fibrosis in the HBsAb-negative (hepatitis B surface antibody) group (6.28%, 95% CI 4.10-8.45%) was significantly higher than in the HBsAb-positive group (3.08%, 95% CI 2.07-4.08%). Results were similar when APRI was used. CONCLUSION: According to the FIB-4, 3.76% of HBsAg-negative and HBcAb-positive US adults had cirrhosis/advanced fibrosis, much higher than in the general population of the USA. Our data highlight the importance of cirrhosis screening in the HBsAg-negative/HBcAb-positive population to prevent advanced liver disease, especially in those who are HBsAb-negative.

MicroRNA-29b-3p prevents Schistosoma japonicum-induced liver fibrosis by targeting COL1A1 and COL3A1.

Schistosomiasis is one of the world's major public health problems in terms of morbidity and mortality, causing granulomatous inflammation and cumulative fibrosis. This study explored in vivo and vitro effects of miR-29b-3p in granulomatous liver fibrosis by targeting COL1A1 and COL3A1 in Schistosoma japonicum infection. Thirty male Balb/c mice were assigned to normal control and model (percutaneous infection of cercariae of S. japonicum) groups. NIH-3T3 mouse embryonic fibroblasts were designated into blank, NC, miR-29b-3p mimic, TGF-ß1, TGF-ß1 + NC, and TGF-ß1 + miR-29b-3p mimic groups. HE and Masson staining were employed to observe the pathological changes and collagenous fibrosis. The expression of α-SMA, COL1A1, COL3A1, TIMP-1 was determined by immunohistochemistry. The RT-qPCR, Western blotting and immunofluorescence staining were conducted to determine expression of miR-29b-3p, COL1A1, and COL3A1. CCK-8 assay and flow cytometry were performed to evaluate viability and apoptosis. The relative expression of miR-29b-3p decreased in the model group. The model group showed marked fibrosis in liver tissues. The expression of α-SMA, COL1A1, COL3A1, TIMP-1 was higher in the model group than that in the normal control group. Dual luciferase reporter gene assay revealed that miR-29b-3p directly targeted COL1A1 and COL3A1. Compared with the blank, NC, TGF-ß1 and TGF-ß1 + NC groups, the miR-29b-3p mimic group exhibited up-regulated expression of miR-29b-3p and MMP-9 but down-regulated expression of TIMP-1, HSP47, α-SMA, COL1A1, and COL3A1; while lower cell viability but higher apoptosis rate showed. It indicated that miR-29b-3p prevents S. japonicum-induced liver fibrosis by inhibiting COL1A1 and COL3A1.