ABSTRACT
Chagas disease (CD) is endemic in large parts of Central and South America, as well as in Texas and the southern regions of the United States. Successful parasites, such as the causative agent of CD, Trypanosoma cruzi have adapted to specific hosts during their phylogenesis. In this work, we have assembled an interactive network of the complex relations that occur between molecules within T. cruzi. An expert curation strategy was combined with a text-mining approach to screen 10,234 full-length research articles and over 200,000 abstracts relevant to T. cruzi. We obtained a scale-free network consisting of 1055 nodes and 874 edges, and composed of 838 proteins, 43 genes, 20 complexes, 9 RNAs, 36 simple molecules, 81 phenotypes, and 37 known pharmaceuticals. Further, we deployed an automated docking pipeline to conduct large-scale docking studies involving several thousand drugs and potential targets to identify network-based binding propensities. These experiments have revealed that the existing FDA-approved drugs benznidazole (Bz) and nifurtimox (Nf) show comparatively high binding energies to the T. cruzi network proteins (e.g., PIF1 helicase-like protein, trans-sialidase), when compared with control datasets consisting of proteins from other pathogens. We envisage this work to be of value to those interested in finding new vaccines for CD, as well as drugs against the T. cruzi parasite.
ABSTRACT
Cervical cancer is one of the leading causes of women's mortality in developing countries. The prevalence of cervical cancer is higher in developing countries like India and continents like Africa. Hyper-methylation of tumor suppressor genes through human papillomavirus (HPV) infection is known to be one of the major causes of cervical cancer. The promoter hypermethylation of the cell adhesion molecule 1 (CADM1) and suppressor of cytokine signalling (SOCS1) genes due to DNMT1 overexpression leads to their epigenetic silencing followed by gene repression causing cervical cancer. In silico study on the inhibition effect of capsaicin on DNMT1 was simulated by different servers. The binding energy was observed to be -7.8 kcal/mol. In vitro studies on the effect of capsaicin on aberrant methylation of CADM1 and SOCS1 were performed on the adenocarcinoma cervical cancer cell line, HeLa. The IC50 of capsaicin was observed to be 160 µM through crystal violet assay. DNA methylation of the CADM1 and SOCS1 was analyzed by methylation-specific PCR along with their reversal using capsaicin (20 µM) by treating the cells for 72 h and 6 days. In silico results suggested that capsaicin has an inhibitory effect on DNMT1, which regulates DNA methylation leading to the hypermethylation of CADM1 and SOCS1 genes. The in vitro studies suggested that hypermethylation leads to the inhibition of CADM1 and SOCS1 expression, which could be reversed using capsaicin with visible changes in methylation-specific and unmethylation-specific bands in MS-PCR, respectively. The present study shows the reversal of methylation of CADM1 and SOCS1 after 72 h which showed a further increase in case of 6 days of treatment using 20 µM capsaicin, which makes capsaicin a potent candidate for causing demethylation of CADM1 and SOCS1 genes that may lead to the reactivation of the downregulated gene.
