ML 221

Resveratrol attenuates ICAM-1 expression and monocyte adhesiveness to TNF-alpha-treated endothelial cells: evidence for an anti-inflammatory cascade mediated by the miR-221/222/AMPK/p38/NF-kappaB pathway.[Pubmed:28338009]

Sci Rep. 2017 Mar 24;7:44689.

Resveratrol, an edible polyphenolic phytoalexin, improves endothelial dysfunction and attenuates inflammation. However, the mechanisms have not been thoroughly elucidated. Therefore, we investigated the molecular basis of the effects of resveratrol on TNF-alpha-induced ICAM-1 expression in HUVECs. The resveratrol treatment significantly attenuated the TNF-alpha-induced ICAM-1 expression. The inhibition of p38 phosphorylation mediated the reduction in ICAM-1 expression caused by resveratrol. Resveratrol also decreased TNF-alpha-induced IkappaB phosphorylation and the phosphorylation, acetylation, and translocation of NF-kappaB p65. Moreover, resveratrol induced the AMPK phosphorylation and the SIRT1 expression in TNF-alpha-treated HUVECs. Furthermore, TNF-alpha significantly suppressed miR-221/-222 expression, which was reversed by resveratrol. miR-221/-222 overexpression decreased p38/NF-kappaB and ICAM-1 expression, which resulted in reduced monocyte adhesion to TNF-alpha-treated ECs. In a mouse model of acute TNF-alpha-induced inflammation, resveratrol effectively attenuated ICAM-1 expression in the aortic ECs of TNF-alpha-treated wild-type mice. These beneficial effects of resveratrol were lost in miR-221/222 knockout mice. Our data showed that resveratrol counteracted the TNF-alpha-mediated reduction in miR-221/222 expression and decreased the TNF-alpha-induced activation of p38 MAPK and NF-kappaB, thereby suppressing ICAM-1 expression and monocyte adhesion. Collectively, our results show that resveratrol attenuates endothelial inflammation by reducing ICAM-1 expression and that the protective effect was mediated partly through the miR-221/222/AMPK/p38/NF-kappaB pathway.

Overexpression of miRNA-221 promotes cell proliferation by targeting the apoptotic protease activating factor-1 and indicates a poor prognosis in ovarian cancer.[Pubmed:28350128]

Int J Oncol. 2017 Mar 7.

MicroRNAs are a class of small non-coding, endogenous RNAs involved in cancer development and progression. MicroRNA-221 (mir-221) has been reported to have both an oncogenic and tumor-suppressive role in human tumors, but the role of miR-221 in ovarian cancer is poorly understood. In the present study, the expression levels of miR-221 and the apoptosis protease activating factor 1 (APAF1) protein in 63 samples of ovarian cancer tissues and the cell lines, IOSE25, A2780, OVCAR3, SKOV3 and 3AO were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Cell proliferation was measured using cell counting kit-8 (CCK-8); cell migration and invasion were detected using a transwell assay; cell apoptosis was evaluated by flow cytometry and hoechst staining, and a luciferase assay was performed to verify a putative target site of miR-221 in the 3'-UTR of APAF1 mRNA. Expression of miR-221 was upregulated in ovarian cancer tissues. Patients with increased miR-221 expression levels had a reduced disease-free survival (P=0.0014) and overall survival (P=0.0058) compared with those with low miR-221 expression. Transfection of SKOV3 and A2780 cell lines with miR-221 inhibitor induced APAF1 protein expression, suppressed cell proliferation and migration and promoted tumor cell apoptosis. In conclusion, the APAF1 gene was confirmed as a direct target of miR-221 and overexpression of APAF1 suppressed ovarian cancer cell proliferation and induced cell apoptosis in vitro. These findings indicate that miR-221-APAF1 should be studied further as a potential new diagnostic or prognostic biomarker for ovarian cancer.

miRNA-101-1 and miRNA-221 expressions and their polymorphisms as biomarkers for early diagnosis of hepatocellular carcinoma.[Pubmed:28366737]

Infect Genet Evol. 2017 Jul;51:173-181.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor with an increasing incidence. Hepatitis C virus (HCV) is one of the major risk factors that lead to HCC development. MicroRNAs are conserved non-coding RNAs which regulate gene expression at the posttranscriptional level. They have been recently identified as important regulators that affect carcinogenesis. Of these miRNAs, are miR-221 and miR-101-1, which their aberrant expressions have been reported to play an important role in HCC. PATIENTS AND METHODS: In this study, we investigated the association between miR-221 and miR-101-1 polymorphisms and their expressions and the early prediction of HCC in HCV infected patients. Quantitative real-time PCR (qPCR) was done to estimate the expression levels of miRNA-221 and miRNA-101-1 in serum. To detect the genotyping of miR-221 and miR-101-1 related SNPs, DNA was extracted. Then, genotyping was performed using real-time PCR. RESULTS: We found that rs7536540 polymorphism in miR-101-1 is significantly associated with development of HCC. In addition, our results showed no significant association between rs17084733 polymorphism in miR-221 and HCC occurrence. We confirmed the upregulation of miR-221 and the downregulation of miR-101-1 in HCC. As regards HCV patients, miR-221and miR-101-1 were found to be upregulated. CONCLUSION: Both miR-221 and miR-101-1 expression levels may be useful as noninvasive diagnostic biomarkers for early prediction of HCC among HCV patients.

Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor.[Pubmed:23010269]

Bioorg Med Chem Lett. 2012 Nov 1;22(21):6656-60.

The recently discovered apelin/APJ system has emerged as a critical mediator of cardiovascular homeostasis and is associated with the pathogenesis of cardiovascular disease. A role for apelin/APJ in energy metabolism and gastrointestinal function has also recently emerged. We disclose the discovery and characterization of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221), a potent APJ functional antagonist in cell-based assays that is >37-fold selective over the closely related angiotensin II type 1 (AT1) receptor. ML221 was derived from an HTS of the ~330,600 compound MLSMR collection. This antagonist showed no significant binding activity against 29 other GPCRs, except to the kappa-opioid and benzodiazepinone receptors (<50/<70%I at 10 muM). The synthetic methodology, development of structure-activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented.

ML221 is a potent apelin (APJ) functional antagonist, inhibiting apelin-13-mediated activation of APJ, with IC50s of 0.70 μM in the cAMP assay, and 1.75 μM in the β-arrestin assay, and EC80 of 10 nM in both assays.

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