Genistein modulates signaling pathways and targets several epigenetic markers in hela cells

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Background: Several epigenetic changes are responsible for transcriptional alterations of signaling pathways and tumour suppressor genes (TSGs) contributing to carcinogenesis. This study was aimed to examine the effect of the phytochemical, genistein on various molecular targets in HeLa cells. Methods: Quantitative PCR was used to analyze the expression of various molecular targets. Biochemical assays were employed to study the epigenetic enzymes. To correlate the transcriptional status of the selected TSGs and epigenetic modulation, their promoter 5’CpG methylation levels were evaluated by quantitative methylation array followed by methylation specific restriction digestion. Results: The expression of several genes involved in the cell cycle regulation, migration, inflammation, phosphatidylinositol 3-kinase (PI3K) and mitogen activated kinase-like protein (MAPK) pathway were found to be modulated including CCNB1, TWIST1, MMP14, TERT, AKT1, PTPRR, FOS and IL1A. Genistein modulated the expression of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), demethylases, and histone phosphorylases. Furthermore, genistein decreased the activity of DNMTs, HDACs, and HMTs and reduced global DNA methylation levels. Promoter methylation of several TSGs, including FHIT, RUNX3, CDH1, PTEN, and SOC51, was lowered with corresponding transcriptional increase. Network analysis indicated similar effect of genistein. Conclusion: This study presents a comprehensive mechanism of action of genistein showcasing effective epigenetic modulation and widespread transcriptional changes resulting in restoration of tumour suppressor gene expression. This study corroborates the development of genistein as a candidate for anti-cancer therapy

Investigation of Precise Molecular Mechanistic Action of Tobacco-Associated Carcinogen ‘NNK’ Induced Carcinogenesis: A System Biology Approach

Cancer is the second deadliest disease listed by the WHO. One of the major causes of cancer disease is tobacco and consumption possibly due to its main component, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A plethora of studies have been conducted in the past aiming to decipher the association of NNK with other diseases. However, it is strongly linked with cancer development. Despite these studies, a clear molecular mechanism and the impact of NNK on various system-level networks is not known. In the present study, system biology tools were employed to understand the key regulatory mechanisms and the perturbations that will happen in the cellular processes due to NNK. To investigate the system level influence of the carcinogen, NNK rewired protein–protein interaction network (PPIN) was generated from 544 reported proteins drawn out from 1317 articles retrieved from PubMed. The noise was removed from PPIN by the method of modulation. Gene ontology (GO) enrichment was performed on the seed proteins extracted from various modules to find the most affected pathways by the genes/proteins. For the modulation, Molecular COmplex DEtection (MCODE) was used to generate 19 modules containing 115 seed proteins. Further, scrutiny of the targeted biomolecules was done by the graph theory and molecular docking. GO enrichment analysis revealed that mostly cell cycle regulatory proteins were affected by NNK

Topological and system‑level protein interaction network (pin) analyses to deduce molecular mechanism of curcumin

Curcumin is an important bioactive component of turmeric and also one of the important natural products, which has been investigated extensively. The precise mode of action of curcumin and its impact on system level protein networks are still not well studied. To identify the curcumin governed regulatory action on protein interaction network (PIN), an interectome was created based on 788 key proteins, extracted from PubMed literatures, and constructed by using STRING and Cytoscape programs. The PIN rewired by curcumin was a scale-free, extremely linked biological system. MCODE plug-in was used for sub-modulization analysis, wherein we identified 25 modules; ClueGo plug-in was used for the pathway’s enrichment analysis, wherein 37 enriched signalling pathways were obtained. Most of them were associated with human diseases groups, particularly carcinogenesis, inflammation, and infectious diseases. Finally, the analysis of topological characteristic like bottleneck, degree, GO term/pathways analysis, bio-kinetics simulation, molecular docking, and dynamics studies were performed for the selection of key regulatory proteins of curcumin-rewired PIN. The current findings deduce a precise molecular mechanism that curcumin might exert in the system. This comprehensive in-silico study will help to understand how curcumin induces its anti-cancerous, anti-inflammatory, and anti-microbial effects in the human body

Isolation, characterization and antifungal docking studies of wortmannin isolated from Penicillium radicum

During the search for a potent antifungal drug, a cell-permeable metabolite was isolated from a soil isolate taxonomically identified as Penicillium radicum. The strain was found to be a potent antifungal agent. Production conditions of the active compound were optimized and the active compound was isolated, purified, characterized and identified as a phosphoinositide 3-kinase (PI3K) inhibitor, commonly known as wortmannin (Wtmn). This is very first time we are reporting the production of Wtmn from P. radicum. In addition to its previously discovered anticancer properties, the broad spectrum antifungal property of Wtmn was re-confirmed using various fungal strains. Virtual screening was performed through molecular docking studies against potential antifungal targets, and it was found that Wtmn was predicted to impede the actions of these targets more efficiently than known antifungal compounds such as voriconazole and nikkomycin i.e. 1) mevalonate-5-diphosphate decarboxylase (1FI4), responsible for sterol/isoprenoid biosynthesis; 2) exocyst complex component SEC3 (3A58) where Rho-and phosphoinositide-dependent localization is present and 3) Kre2p/Mnt1p a Golgi alpha1,2-mannosyltransferase (1S4N) involved in the biosynthesis of yeast cell wall glycoproteins). We conclude that Wtmn produced from P. radicum is a promising lead compound which could be potentially used as an efficient antifungal drug in the near future after appropriate structural modifications to reduce toxicity and improve stability.Peer reviewe

Prediction of T cell epitopes for the utility of vaccine development from structural proteins of dengue virus variants using <i style="">in silico </i>methods

193-198The spread of dengue virus, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) has increased significantly in the past two decades and thus has been a major concern of public health globally. Dengue virus infection can lead to a wide range of manifestations in the form of undifferentiated fever, classic dengue fever, DHF with plasma leakage, which leads to hypovelmic shock DSS. A new strategy for developing prophylactic and therapeutic application of pathogen-specific immunity was provided from epitope-based vaccines; it is a critical requirement for the identification and selection of T cell epitopes that act as vaccine target. Immunoinformatics serves as a valuable tool to screen and select antigenic peptide sequences as potential T cell epitopes for binding affinity with HLA alleles. We studied dengue variants conserved epitopes in three structural proteins, capsid, envelope and precursor membrane, which recognize some highest binding affinity HLA. A total of 45 promiscuous nanomer candidate epitopes for HTL are recognized against MHC Class II and 28 promiscuous epitopes are recognized against CTL for MHC class I. This computational prediction analysis will improve our understanding of T cell immune response and help in identifying the antigenic peptide for formulation of antigen based diagnostic kit and peptide based subunit vaccine design against dengue virus

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Not AvailableWith the availability of complete genome sequences of many cyanobacterial species, it is becoming feasible to study the broad prospective of the environmental adaptation and the overall changes at transcriptional and translational level in these organisms. In the evolutionary phase, niche-specific competitive forces have resulted in specific features of the cyanobacterial genomes. In this study, functional composition of the 84 different cyanobacterial genomes and their adaptations to different environments was examined by identifying the genomic composition for specific cellular processes, which reflect their genomic functional profile and ecological adaptation.It was identified that among cyanobacterial genomes, metabolic genes have major share over other categories and differentiation of genomic functional profilewas observed for the species inhabiting different habitats.The cyanobacteria of freshwater and other habitats accumulate large number of poorly characterized genes.Strain specific functionswere also reported in many cyanobacterial members, of which an important featurewas the occurrence of phage-related sequences. From this study, it can be speculated that habitat is one of the major factors in giving the shape of functional composition of cyanobacterial genomes towards their ecological adaptations. © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Not Availabl