Da Cheng,Cichun Wu,Ying Li,Yao Liu,Juan Mo,Lei Fu,Shifang Peng
Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF) is a clinical syndrome of severe liver damage. HBV infection is affected by N6-methyladenosine (m 6 A) RNA modification. Here, we investigated whether methyltransferase-like 3 (METTL3)-mediated m 6 A methylation can affect ACLF. Human hepatic cells (THLE-2) were treated with lipopolysaccharide (LPS) to induce cell damage. Proliferation, apoptosis and m 6 A modification were measured by MTT assay , flow cytometry and Dot blot assay. Our results showed that HBV infection significantly enhanced the levels of m 6 A modification and elevated the expression of METTL3 and mature-miR-146a-5p in THLE-2 cells, which was repressed by cycloleucine (m 6 A inhibitor). METTL3 overexpression enhanced m 6 A modification and promoted mature-miR-146a-5p expression. METTL3 overexpression promoted HBV replication and apoptosis, enhanced the levels of pro-inflammatory cytokines, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and repressed cell proliferation in THLE-2 cells, which attributed to repress miR-146a-5p maturation. Moreover, a severe liver failure mouse model was established by HBV infection to verify the impact of METTL3 knockdown on liver damage in vivo . HBV-infection led to a severe liver damage and increase of apoptosis in hepatic tissues of mice, which was abolished by METTL3 knockdown. METTL3 knockdown reduced METTL3 expression and impeded miR-146a-5p maturation in HBV-infected mice. In conclusion, this work demonstrates that METTL3 inhibition ameliorates liver damage in mouse with HBV-associated ACLF, which contributes to repress miR-146a-5p maturation. Thus, this article suggests a novel therapeutic avenue to prevent and treat HBV-associated ACLF.
Ma Yan,Xu Minhua,Liu Hancong,Yu Tiantian,Guo Ping,Liu Wenbin,Jin Xiaobao
Gordonia sp. are members of the actinomycete family, their contribution to the environment improvement and environmental protection by their biological degradation ability, but there are few studies on the antimicrobial activity of their secondary metabolites. Our team isolated and purified an actinomycete WA 4-31 from the intestinal tract of Periplaneta americana, firstly identified the strain WA 4-31 by the morphological characteristics and the phylogenetic analyses, and found it was completely homologous to the strain of Gordonia terrae from the Indian desert. Meanwhile, actinomycin D (1), actinomycin X2 (2), mojavensin A (3) and cyclic (leucine-leucne) dipeptide (4) were obtained from the EtOAc extract from the broth of WA 4-31. Compounds 1–4 showed anti-fungus activities against Candida albicans, Aspergillus niger, A. fumigatus and Trichophyton rubrum, also anti-MRSA and inhibited Escherichia coli in different degree. Interestingly, we found when 3 was mixed with 4 with ratio of 1:1, the activity of the mixture on anti-Candida albicans was better than the single. Besides, compounds 1–3 had varying degrees of antiproliferative activities on CNE-2 and HepG-2 cell lines. These indicated that Gordonia rare actinomycete from the intestinal tract of Periplaneta americana possessed a potential as a source of active secondary metabolites.
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