Identification of critical residues in the regulatory protein HBx for Smc5/6 interaction and hepatitis B virus production.

The host structural maintenance of chromosomes 5/6 complex (Smc5/6) is a restriction factor of hepatitis B virus (HBV) that inhibits the transcription of viral ccDNA. HBV antagonizes this restriction by expressing the regulatory X protein (HBx) which targets Smc5/6 for degradation via DNA damage-binding protein 1 (DDB1) E3 ubiquitin ligase. However, the molecular insights into how Smc5/6 interacts with HBx remain elusive. In this study, we systematically investigated the interaction between Smc5/6 and HBx. Smc5/6 interacts with HBx through multiple sites in the absence of DDB1 in the pull-down assay. HBx C-terminal is sufficient for the interaction. Most importantly, residue Phe132, which is strictly conserved in all HBV subtypes, is critical for interaction with Smc5/6 both in vitro and in vivo. Mutation of this site (F132A) results in defect in Smc5/6 interaction, extrachromosomal reporter transcription, and HBV production both in cells and in mouse model. Collectively, our data identifies a key residue on HBx for Smc5/6 interaction and viral production. These results provide valuable information for both basic research and therapeutic drugs targeting HBx.

LncRNA-MALAT1 as a novel biomarker of cadmium toxicity regulates cell proliferation and apoptosis.

Cadmium (Cd) and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not well understood. This study aimed to investigate whether lncRNA-MALAT1 could serve as a novel biomarker of Cd toxicity in cells, animals and Cd-exposed workers, and regulate cell proliferation, apoptosis, migration and invasion. MALAT1 expression increased gradually in CdCl2 transformed 16HBE cells. The cell apoptosis, migration and invasion were significantly inhibited, and the mRNA and protein expression of FOXC2, STAT, BAX, EGFR, and TGF-ß1 reduced, but BCL-2 increased (P < 0.05) after silencing MALAT1 by siRNA in CdCl2 treated 16HBE cells of 15th and 35th passages. Cadmium increased MALAT1 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood MALAT1 expression and urinary/blood Cd concentrations, and there were significant correlations of MALAT1 expression with the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd exposed workers. This study suggests that the expression of MALAT1 is upregulated and regulates the cell cycle progression, proliferation, apoptosis, migration and invasion in Cd toxicity. MALAT1 may serve as a novel valuable biomarker of cadmium exposure and cadmium toxicity.

Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis.

New treatments, such as sipuleucel-T and androgen receptor- (AR-) directed therapies (enzalutamide (Enz) and abiraterone acetate (AA)), have emerged and been approved for the management of castration-resistant prostate cancer (CRPC). There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group) and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group). Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p > 0.05). However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA) level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p > 0.05).

MicroRNAs-mRNAs Expression Profile and Their Potential Role in Malignant Transformation of Human Bronchial Epithelial Cells Induced by Cadmium.

BACKGROUND: Our study was designed to elucidate whether there were miRNA and mRNA aberrantly expression profiles and potential role in malignant transformation of 16HBE induced by Cd. METHODS: mRNA and miRNA expression profiles were determined in 35th Cd-induced 16HBE and untreated 16HBE by microarray. A series of bioinformatics analyses such as predicting targets, GO, KEGG were performed to find DEGs, coexpressing networks between miRNAs and mRNAs and its functions. RESULTS: 498 DEGs were found. 8 Cd-responsive novel miRNAs predicted previously were identified, and 5 of them were downregulated. 214 target genes were predicted for the Cd-responsive miRNAs, many of which appeared to regulate gene networks. Target gene CCM2 was showed reciprocal effect by miRNAs. According to the combination analysis, hsa-miR-27b-3p regulated most of the mRNAs, especially upregulated expression genes. The differentially expressed miRNAs are involved in the biological processes and channels, and these GO and KEGG enrichment analyses result were significantly enriched in the Cd-responsive. DISCUSSION: These results provided a tight link for the miRNA-mRNA integrated network and implied the role of novel miRNAs in malignant transformation of 16HBE induced by Cadmium. It is better to understand the novel molecular mechanism of cadmium-induced tumorigenesis.

Combined therapy of diabetic peripheral neuropathy with breviscapine and mecobalamin: a systematic review and a meta-analysis of Chinese studies.

OBJECTIVE: A meta-analysis on combined therapy of diabetic peripheral neuropathy (DPN) with breviscapine and mecobalamin was performed to evaluate the efficacy of this therapy. METHODS: Six English databases (Medline, Cochrane Library, PubMed, EMBASE, Web of Science, and CINAHL) and four Chinese databases (China National Knowledge Infrastructure, VIP Journals Database, CBM, and Wanfang database) were searched for studies on the clinical trials in which DPN was treated with breviscapine and mecobalamin, and RevMan 5.1 package was employed for analyzing pooled trials and publication bias. RESULTS: A total of 17 articles including 1398 DPN patients were identified. Homogeneity was observed among different studies (P = 0.74). The efficacy of combined therapy with breviscapine and mecobalamin was significantly better than that in control group [P < 0.0001 (OR = 5.01, 95% CI: 3.70-6.78)]. CONCLUSION: Available findings suggest that the therapeutic efficacy of breviscapine combining mecobalamin is superior to mecobalamin alone, and this strategy is required to be popularized in clinical practice.