MicroRNA-941 regulates the proliferation of breast cancer cells by altering histone H3 Ser 10 phosphorylation

Abstract Breast cancer including triple negative breast cancer (TNBC) represents an important clinical challenge, as these tumours often develop resistance to conventional chemotherapeutics. MicroRNAs play a crucial role in cell-cycle regulation, differentiation, apoptosis, and migration. Herein, we performed Affymetrix Gene Chip miRNA 4.0 microarray and observed differential regulation of miRNAs (75 upregulated and 199 downregulated) in metastatic MDA-MB-231 cells as compared to immortalized human non-tumorigenic breast epithelial (MCF-10A) cells. MicroRNA-941 was significantly upregulated in MDA-MB-231 cells (almost nine-fold increase) in comparison to MCF-10A cells. Transfection of MiRNA-941 inhibitor significantly decreased the proliferation and migration of MDA-MB-231 cells by altering the expressions of p21, Cyclin D1, PP2B-B1, E-cadherin and MMP-13. Interestingly, we provide first evidence that inhibiting miR-941 prevents cell proliferation and phosphorylation of histone H3 at Ser10 residue. Xenograft model of breast cancer was developed by subcutaneous injection of MDA-MB-231 cells into the mammary fat pad of female athymic nude mice (Crl:NU-Foxn1nu). The tumours were allowed to grow to around 60 mm3, thereafter which we divided the animals into seven groups (n = 5). Notably, intratumoral injection of miR-941 inhibitor significantly abolished the tumour growth in MDA-MB-231 xenograft model. 5-Fluorouracil (10 mg/kg, i.p.) was used as positive control in our study. To the best of our knowledge, we report for the first time that targeting miR-941 improves the sensitivity of MDA-MB-231 cells to 5-fluorouracil. This can be of profound clinical significance, as it provides novel therapeutic approach for treating variety of cancers (overexpressing miRNA-941) in general and breast cancers in particular

General parameters, kidney function tests, glycemia, lipids, systemic RAS, morphometry at the end of the study after 20 weeks of high salt diet feeding.

<p>General parameters, kidney function tests, glycemia, lipids, systemic RAS, morphometry at the end of the study after 20 weeks of high salt diet feeding.</p

Histopathology of kidney, heart and aorta.

<p>A) Representative photomicrographs (1000X, 400X) of H&E- and picrosirius red staining of kidney, heart and aorta. B) Quantification of glomerular size, capsular space, glomerular count, renal fibrosis. C) Quantification of number of heart nuclei per high power focus, cardiac fibrosis, number of nuclei in aorta per unit area and vascular fibrosis in tunica media. N = 3; **P<0.01, ***P<0.001 vs. Control; ^SSSP<0.001, vs. HSD; ^UP<0.05, ^UUP<0.01, ^UUUP<0.001 vs. UNX.</p

General parameters, plasma kidney function tests, glycemic and lipid profile post-uninephrectomy during normal pellet diet feeding.

<p>General parameters, plasma kidney function tests, glycemic and lipid profile post-uninephrectomy during normal pellet diet feeding.</p

Basal haemodynamic parameters.

<p>A) SBP, B) HR, C) LVSP, D) LVEDP, E) +dP/dt, F)–dP/dt. SBP, systolic blood pressure; HR, heart rate; LVSP, left ventricular systolic pressure; LVEDP, left ventricular end- diastolic pressure; +dP/dt, maximum rate of LVP rise during isovolumetric contraction; -dP/dt, maximum rate of LVP decay during isovolumetric relaxation. Ctrl, normal control rats; HSD, normal rats fed with high salt diet; UNX, uninephrectomized rats; UNX+HSD, uninephrectomized rats fed with high salt diet. N = 5–6; *P<0.05, **P<0.01, ***P<0.001 vs. Control; ^SP<0.05, ^SSP<0.01 vs. HSD; ^UP<0.05, ^UUP<0.01, ^UUUP<0.001 vs. UNX.</p

Probable mechanism showing high salt diet intake evokes cardiac dysfunction in uninephrectomy.

<p>UNX combined with HSD intake upregulates AT1R, LTCCs leading to increased cardiovascular reactivity and decreased BRS; upregulates miR-25, miR-155 and miR-451 and downregulates miR-99b affecting SERCA2, AKT and AMPK leading to impaired excitation-coupling cycle, fibrosis and hypertrophy culminating in cardiac dysfunction.</p

Mallory-Weiss Syndrome complicating pregnancy – A rare near miss

Mallory-Weiss syndrome (MWS) rarely occurs during pregnancy and can lead to massive bleed if occurring in the third trimester. Unrecognized MWS may lead to life threatening hemorrhage and shock affecting maternal and fetal well-being. We describe a rare case of MWS in a pregnant patient at 36 weeks of gestation with underlying pre-eclampsia, acute kidney injury, and hemodynamic instability. The possibility of mucosal tears should be kept in mind in the absence of an obvious source of bleeding

Combined Transcriptomic and Proteomic Profiling to Unravel Osimertinib, CARP-1 Functional Mimetic (CFM 4.17) Formulation and Telmisartan Combo Treatment in NSCLC Tumor Xenografts

The epidermal growth factor receptor (EGFR) is highly expressed in many non-small cell lung cancers (NSCLC), necessitating the use of EGFR-tyrosine kinase inhibitors (TKIs) as first-line treatments. Osimertinib (OSM), a third-generation TKI, is routinely used in clinics, but T790M mutations in exon 20 of the EGFR receptor lead to resistance against OSM, necessitating the development of more effective therapeutics. Telmisartan (TLM), OSM, and cell cycle and apoptosis regulatory protein 1 (CARP-1) functional mimetic treatments (CFM4.17) were evaluated in this study against experimental H1975 tumor xenografts to ascertain their anti-cancer effects. Briefly, tumor growth was studied in H1975 xenografts in athymic nude mice, gene and protein expressions were analyzed using next-generation RNA sequencing, proteomics, RT-PCR, and Western blotting. TLM pre-treatment significantly reduced the tumor burden when combined with CFM-4.17 nanoformulation and OSM combination (TLM_CFM-F_OSM) than their respective single treatments or combination of OSM and TLM with CFM 4.17. Data from RNA sequencing and proteomics revealed that TLM_CFM-F_OSM decreased the expression of Lamin B2, STAT3, SOD, NFKB, MMP-1, TGF beta, Sox-2, and PD-L1 proteins while increasing the expression of AMPK proteins, which was also confirmed by RT-PCR, proteomics, and Western blotting. According to our findings, the TLM_CFM-F_OSM combination has a superior anti-cancer effect in the treatment of NSCLC by affecting multiple resistant markers that regulate mitochondrial homeostasis, inflammation, oxidative stress, and apoptosis