👤 Summaira Yasmeen

Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF) MC4R mutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoF MC4R variants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction. Show less

Among various epithelial-to-mesenchymal transition (EMT)-related transcription factors (TFs), altered expression levels of Snail-1, Snail-2/Slug, Twist, and ZEB1 have shown a significant association in different cancers having a higher risk of metastasis. However, their role in the circulation of endometriosis patients is not well understood. Hence, the present study was designed to evaluate the crucial role of these TFs in defining the molecular pathogenesis for endometriosis progression and differentiation from control subjects. The qualitative and quantitative expression analysis of Snail-1, Snail-2/Slug, Twist, and ZEB1 were analyzed in peripheral blood samples of 75 different stages of endometriosis patients and compared with 50 control subjects. Total RNA was extracted and converted into complementary DNA (cDNA) for relative quantification of each gene transcript using SYBRGreen-based reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). The Livak method of relative quantification was used for calculating the fold change in each TF compared with endogenous control. All four selected TFs showed significantly upregulated expression levels in endometriosis patients compared with control subjects. A three-fold increase was observed for Snail-1 (p = 0.0001), and a two-fold increase was observed for Snail-2 (p = 0.01), Twist (p = 0.0002), and ZEB1 (p = 0.001) in stage III and IV compared with stage I and II of endometriosis patients. The present study revealed that EMT-related TFs play a crucial role in the pathogenesis and differentiating different stages of endometriosis patients through expression analysis of specific molecular cascades using non-invasive tools. Show less

Ovarian cancer is the most lethal gynecological malignancy. Currently, new chemotherapeutic strategies are required to improve patient outcome and survival. Biguanides, classic anti-diabetic drugs, have gained importance for theiri antitumor potency demonstrated by various studies. Olaparib is a PARP inhibitor approved for maintenance therapy following platinum-based chemotherapy. Furthermore, Snai1, a transcription factor that works as a master regulator of the epithelial/mesenchymal transition process (EMT) is involved in ovarian cancer resistance and progression. Here we aimed to demonstrate the possible cross talk between biguanides and Snail in response to olaparib combination therapy. In this study, we have shown that while in A2780CR cells biguanides reduced cell survival (single treatments ~20%; combined treatment ~44%) and cell migration (single treatments ~45%; biguanide-olaparib ~80%) significantly, A2780PAR exhibited superior efficacy with single (~60%) and combined treatments (~80%). Moreover, our results indicate that knock-down of Snail further enhances the attenuation of migration, inhibits EMT related-proteins (~90%) and induces a synergistic effect in biguanide-olaparib treatment. Altogether, this work suggests a novel treatment strategy against drug-resistant or recurrent ovarian cancer. Show less