Previous studies have demonstrated that the dysregulation of microRNAs (miRs) is frequently associated with cancer progression. Deregulation of miR-106b-3p has been observed in various types of human cancer. However, the biological function of miR-106b-3p in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, the aim of this study was to investigate the role of miR-106b-3p in ESCC. In the current study, the results indicated that miR-106b-3p was upregulated in ESCC cell lines and tissues. An increase in miR-106b-3p using miR mimics significantly promoted the proliferation of ESCC cells in vitro. Furthermore, the results demonstrated that miR-106b-3p overexpression promoted migration, invasion and epithelial-mesenchymal transition (EMT) of ESCC cells. In addition, zinc and ring finger 3 (ZNRF3) was identified as a target of miR-106b-3p in ESCC cells, and the ZNRF3 expression level was inversely associated with miR-106b-3p. It was also demonstrated that miR-106b-3p has a role in EMT by regulating Wnt/β-catenin signaling pathway in ESCC. In conclusion, these data suggested that miR-106b-3p promotes cell proliferation and invasion, partially by downregulating ZNRF3 and inducing EMT via Wnt/β-catenin signaling in ESCC cells. Thus, miR-106b-3p and ZNRF3 may be novel molecular targets for the future treatment of ESCC.
A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.
Background and aim: Many reported studies have been conducted to investigate the association of angiotensin II type 1 receptor (AT1R) A1166C gene polymorphism with myocardial infarction (MI) susceptibility. However, the results from those reports are still conflicting. This meta-analysis was performed to study the relationship between AT1R A1166C gene polymorphism and MI risk. Method: The databases of PubMed, Embase, and Cochrane Library were searched as of 1 March 2012, and eligible investigations were recruited into this meta-analysis. Results: Eighteen investigations were identified for the analysis of association between AT1R A1166C gene polymorphism and MI risk, 11 in Caucasians, three in Asians, two in Africans, one in the population of Brazil and one in the population of Durban, South Africa . There was a marked association between AT1R C allele and MI susceptibility for overall populations (odds ratio (OR)=1.12, 95% confidence interval (CI): 1.01-1.25, p=0.03), and AT1R AA genotype was associated with a lower risk of MI in overall populations (OR=0.87, 95% CI: 0.78-0.98, p=0.02). However, AT1R A1166C gene polymorphism was not associated with MI risk in the sub-groups of Caucasians, Asians, Africans, Brazil and Durban populations. Conclusions: C allele is a risk factor for the MI susceptibility in overall populations, and AA genotype might be a protective factor against the MI risk in overall populations. However, more case-control association investigations on larger, stratified populations are required in the future.
ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.
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