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Caspase-3 regulates apoptosis, and its deregulation in Non-Small Cell-Lung Carcinoma (NSCLC), and contributes to tumour growth and therapeutic resistance. Significant resistance to chemotherapy and radiation therapy, which are two frequently used treatment modalities for lung cancer, is linked to the decreased activity of caspase-3 in NSCLC. Preclinical and early clinical investigations, for example, have shown potential for targeting specific biochemical pathways involved in caspase-3 regulation, such as the Bcl-2 family of proteins or the Inhibitor of Apoptosis Proteins (IAPs). However, this study investigates the activation potential of plumbagin, a potential naphthoquinone, towards Caspase-3, which in turn targets the progression of NSCLC. The potential of naphthoquinones has already been explored and experimentally validated by several researchers in cancer-targeted drug discovery-based studies. This study focuses on exploring the physicochemical and ADMET properties of plumbagin prior to molecular docking. This renders the binding energy of the plumbagin-caspase-3 docked complex at -10.13 kcal/mol. Further, MD simulations validated the potential of Plumbagin to serve as a promising target for drug discovery against caspase-3 by analysing the computed trajectories. Given that naphthoquinones are preferred drug candidates, discovering natural chemicals that act as caspase-3 activator is a key step towards developing viable drugs for NSCLC. [ABSTRACT FROM AUTHOR]

Schizophrenia is a mental illness affecting the normal lifestyle of adults and early adolescents incurring major symptoms as jumbled speech, involvement in everyday activities eventually got reduced, patients always struggle with attention and memory, reason being both the genetic and environmental factors responsible for altered brain chemistry and structure, resulting in schizophrenia and associated orphan diseases. The network biology describes the interactions among genes/proteins encoding molecular mechanisms of biological processes, development, and diseases. Besides, all the molecular networks, protein‐protein Interaction Networks have been significant in distinguishing the pathogenesis of diseases and thereby drug discovery. The present meta‐analysis prioritizes novel disease indications viz. rare and orphan diseases associated with target Glutamate Ionotropic Receptor NMDA Type Subunit 1, GRIN1 using text mining knowledge‐based tools. Furthermore, ZINC database was virtually screened, and binding conformation of selected compounds was performed and resulted in the identification of Narciclasine (ZINC04097652) and Alvespimycin (ZINC73138787) as potential inhibitors. Furthermore, docked complexes were subjected to MD simulation studies which suggests that the identified leads could be a better potential drug to recuperate schizophrenia. [ABSTRACT FROM AUTHOR]

Asthma is a multifactorial disease with phenotypes and several clinical and pathophysiological characteristics. Besides innate and adaptive immune responses, the gut microbiome generates Treg cells, mediating the allergic response to environmental factors and exposure to allergens. Because of the complexity of asthma, microbiome analysis and other precision medicine methods are now widely regarded as essential elements of efficient disease therapy. An in-silico pipeline enables the comparative taxonomic profiling of 16S rRNA metagenomic profiles of 20 asthmatic patients and 15 healthy controls utilizing QIIME2. Further, PICRUSt supports downstream gene enrichment and pathway analysis, inferring the enriched pathways in a diseased state. A significant abundance of the phylum Proteobacteria, Sutterella, and Megamonas is identified in asthma patients and a diminished genus Akkermansia. Nasal samples reveal a high relative abundance of Mycoplasma in the nasal samples. Further, differential functional profiling identifies the metabolic pathways related to cofactors and amino acids, secondary metabolism, and signaling pathways. These findings support that a combination of bacterial communities is involved in mediating the responses involved in chronic respiratory conditions like asthma by exerting their influence on various metabolic pathways. [ABSTRACT FROM AUTHOR]

Background: Epigenetic modifications alter signaling and molecular pathways; moreover, they are an important therapeutic target. This study examined the effect of sulforaphane on molecular targets in HeLa cells., Methods: Quantitative PCR of various molecular targets was performed. Activity of epigenetic enzymes was measured by ELISA and molecular docking analysis was conducted. Promoter methylation of some tumor suppressor genes was quantified using PCR based methylation array. In-silico protein-protein interaction network analysis was performed to understand the effect of transcriptional changes., Results: Quantitative PCR demonstrated the transcriptional modulation of genes involved in proliferation, metastasis, inflammation, signal transduction pathways and chromatin modifiers. Sulforaphane reduced the enzymatic activity of DNA methyl transferases, histone deacetylases and histone methyltransferases. Molecular docking results suggest that sulforaphane competitively inhibited several DNA methyl transferases and histone deacetylases. Promoter 5'CpG methylation levels of selected tumor suppressor genes was found to be reduced which correlated with their transcriptional increase as well modulation of epigenetic enzymes. Further, protein-protein interaction network analysis discerned the participation of genes towards cancer pathways. Functional enrichment and pathway-based analysis represented the modulation of epigenetic and signaling pathways on sulforaphane treatment., Conclusions: The modulation in transcriptional status of epigenetic regulators, genes involved in tumorigenesis resulting in tumor suppressor genes demethylation and re-expression underscores the mechanism behind the anticancer effect of sulforaphane on HeLa cells.

The emergence of multi-drug resistant strains and co-occurrence of tuberculosis with HIV creates a major burden to the human health globally. Failure of primary antibacterial therapy necessitates the identification of new mycobacterial drugs. In this study, a comprehensive analysis involving bottom-up systems biology approach was applied wherein we have identified potential therapeutic targets of Mycobacterium tuberculosis infections. Our study prioritized M. tuberculosis therapeutic targets (aspartate-β-semialdeyhde dehydrogenase [ASD], dihydrodipicolinate reductase and diaminopimelate decarboxylase) based on flux and elementary mode analysis using direct mathematical modeling of the relevant metabolic pathways. Molecular docking and simulation studies of the priority target (ie, ASD) revealed the therapeutic potential of the selected natural products (Huperzine A, Rosmarinic acid, and Curcumin) based ASD inhibitors. The study highlights the crucial role of systems biology in conjunction with molecular interaction (docking) for probing novel leads against an increasingly resistant pathogen, M. tuberculousis., (© 2017 Wiley Periodicals, Inc.)