WITHDRAWN: The effect of ischemia on expression quantitative trait loci (eQTL) in human myocardium and insights into myocardial injury etiology.

26 February, 2024. Research Square has withdrawn this preprint as it was submitted and made public without the full consent of all the authors and without the full consent of the principle investigator of the registered clinical trial. Therefore, this work should not be cited as a reference.

Modulation of interaction of BRCA1-RAD51 and BRCA1-AURKA protein complexes by natural metabolites using as possible therapeutic intervention toward cardiotoxic effects of cancer drugs: an in-silico approach.

Breast cancer type 1 susceptibility protein (BRCA1) plays an important role in maintaining genome stability and is known to interact with several proteins involved in cellular pathways, gene transcription regulation and DNA damage response. More than 40% of inherited breast cancer cases are due to BRCA1 mutation. It is also a prognostic marker in non-small cell lung cancer patients as well as a gatekeeper of cardiac function. Interaction of mutant BRCA1 with other proteins is known to disrupt the tumor suppression mechanism. Two directly interacting proteins with BRCA1 namely, DNA repair protein RAD51 (RAD51) and Aurora kinase A (AURKA), known to regulate homologous recombination (HR) and G/M cell cycle transition, respectively, form protein complex with both wild and mutant BRCA1. To analyze the interactions, protein-protein complexes were generated for each pair of proteins. In order to combat the cardiotoxic effects of cancer drugs, pharmacokinetically screened natural metabolites derived from plant, marine and bacterial sources and along with FDA-approved cancer drugs as control, were subjected to molecular docking. Piperoleine B and dihydrocircumin were the best docked natural metabolites in both RAD51 and AURKA complexes, respectively. Molecular dynamics simulation (MDS) analysis and binding free energy calculations for the best docked natural metabolite and drug for both the mutant BRCA1 complexes suggested better stability for the natural metabolites piperolein B and dihydrocurcumin as compared to drug. Thus, both natural metabolites could be further analyzed for their role against the cardiotoxic effects of cancer drugs through wet lab experiments.Communicated by Ramaswamy H. Sarma.

Discovering Innovative Drugs Targeting Both Cancer and Cardiovascular Disease by Shared Protein-Protein Interaction Network Analyses.

Cancer and cardiovascular disease (CVD) have a common co-occurrence. Both diseases display overlapping pathophysiology and risk factors, suggesting shared biological mechanisms. Conditions such as obesity, diabetes, hypertension, smoking, poor diet, and inadequate physical activity can cause both heart disease and cancer. The burgeoning field of onco-cardiology aims to develop diagnostics and innovative therapeutics for both diseases through targeting shared mechanisms and molecular targets. In this overarching context, this expert review presents an analysis of the protein-protein interaction (PPI) networks for onco-cardiology drug discovery. Several PPI complexes such as MDM2-TP53 and CDK4-pRB have been studied for their tumor-suppressive functions. In addition, XIAP-SMAC, RAC1-GEF, Sur-2ESX, and TP53-BRCA1 are other PPI complexes that offer potential breakthrough for onco-cardiology therapeutics innovation. As both cancer and CVD share biological mechanisms to a certain degree, the PPI network analyses for onco-cardiology drug discovery are promising for addressing comorbid diseases in the spirit of systems medicine. We discuss the emerging architecture of PPI networks in cancer and CVD and prospects and challenges for their exploitation toward therapeutics applications. Finally, we emphasize that PPIs that were once thought to be undruggable have become potential new class of innovative drug targets.

Modulation of interaction of mutant TP53 and wild type BRCA1 by alkaloids: a computational approach towards targeting protein-protein interaction as a futuristic therapeutic intervention strategy for breast cancer impediment.

Protein-protein interactions (PPI) are a new emerging class of novel therapeutic targets. In order to probe these interactions, computational tools provide a convenient and quick method towards the development of therapeutics. Keeping this in view the present study was initiated to analyse interaction of tumour suppressor protein p53 (TP53) and breast cancer associated protein (BRCA1) as promising target against breast cancer. Using computational approaches such as protein-protein docking, hot spot analyses, molecular docking and molecular dynamics simulation (MDS), stepwise analyses of the interactions of the wild type and mutant TP53 with that of wild type BRCA1 and their modulation by alkaloids were done. Protein-protein docking method was used to generate both wild type and mutant complexes of TP53-BRCA1. Subsequently, the complexes were docked using sixteen different alkaloids, fulfilling ADMET and Lipinski's rule of five criteria, and were compared with that of a well-known inhibitor of PPI, namely nutlin. The alkaloid dicentrine was found to be the best docked alkaloid among all the docked alklaloids as well as that of nutlin. Furthermore, MDS analyses of both wild type and mutant complexes with the best docked alkaloid i.e. dicentrine, revealed higher stability of mutant complex than that of the wild one, in terms of average RMSD, RMSF and binding free energy, corroborating the results of docking. Results suggested more pronounced interaction of BRCA1 with mutant TP53 leading to increased expression of mutated TP53 thus showing a dominant negative gain of function and hampering wild type TP53 function leading to tumour progression.

Chitosan immobilized novel peroxidase from Azadirachta indica: Characterization and application.

In the present paper, a peroxidase was purified from the leaves of a medicinal tree, namely Azadirachta indica, to 45.2 folds with overall recovery of 61%. Based on the subunit size, the purified peroxidase was suggested to be a monomeric structure of size 50kDa and exhibited good thermostability as it was fully stable at 65°C for 1hr and also retained about 73% activity at 70°C till 30min. The substrate affinity was found to be in order of guaiacol>pyrogallol>o-dianisidine. The purified peroxidase was found to be insensitive towards high concentrations of Na+, Ca2+, Mg2+ and Mn2+. Heavy metals, namely Cs2+, Co2+ and Cd2+ activated the peroxidase while that of Hg2+ deactivated the peroxidase in concentration dependent manner. The purified peroxidase exhibited tolerance towards organic solvents in order of ethanol>butanol>isopropanol>acetone. Immobilization of purified peroxidase by entrapment into chitosan beads led to shift in its optimum pH from pH 5 to 7 and considerable enhancement in dye decolorization ability as compared to that of free enzyme. Thus, based on all the above properties, it may be suggested that the purified A. indica peroxidase is a promising candidate for industrial applications.

Citrus Functional Genomics and Molecular Modeling in Relation to Citrus sinensis (Sweet Orange) Infection with Xylella fastidiosa (Citrus Variegated Chlorosis).

Citrus are among the economically most important fruit tree crops in the world. Citrus variegated chlorosis (CVC), caused by Xylella fastidiosa infection, is a serious disease limiting citrus production at a global scale. With availability of citrus genomic resources, it is now possible to compare citrus expressed sequence tag (EST) data sets and identify single-nucleotide polymorphisms (SNPs) within and among different citrus cultivars that can be exploited for citrus resistance to infections, citrus breeding, among others. We report here, for the first time, SNPs in the EST data sets of X. fastidiosa-infected Citrus sinensis (sweet orange) and their functional annotation that revealed the involvement of eight C. sinensis candidate genes in CVC pathogenesis. Among these genes were xyloglucan endotransglycosylase, myo-inositol-1-phosphate synthase, and peroxidase were found to be involved in plant cell wall metabolism. These have been further investigated by molecular modeling for their role in CVC infection and defense. Molecular docking analyses of the wild and the mutant (SNP containing) types of the selected three enzymes with their respective substrates revealed a significant decrease in the binding affinity of substrates for the mutant enzymes, thus suggesting a decrease in the catalytic efficiency of these enzymes during infection, thereby facilitating a favorable condition for infection by the pathogen. These findings offer novel agrigenomics insights in developing future molecular targets and strategies for citrus fruit cultivation in ways that are resistant to X. fastidiosa infection, and by extension, with greater harvesting efficiency and economic value.

Treponema pallidum putative novel drug target identification and validation: rethinking syphilis therapeutics with plant-derived terpenoids.

Syphilis, a slow progressive and the third most common sexually transmitted disease found worldwide, is caused by a spirochete gram negative bacteria Treponema pallidum. Emergence of antibiotic resistant T. pallidum has led to a search for novel drugs and their targets. Subtractive genomics analyses of pathogen T. pallidum and host Homo sapiens resulted in identification of 126 proteins essential for survival and viability of the pathogen. Metabolic pathway analyses of these essential proteins led to discovery of nineteen proteins distributed among six metabolic pathways unique to T. pallidum. One hundred plant-derived terpenoids, as potential therapeutic molecules against T. pallidum, were screened for their drug likeness and ADMET (absorption, distribution, metabolism, and toxicity) properties. Subsequently the resulting nine terpenoids were docked with five unique T. pallidum targets through molecular modeling approaches. Out of five targets analyzed, D-alanine:D-alanine ligase was found to be the most promising target, while terpenoid salvicine was the most potent inhibitor. A comparison of the inhibitory potential of the best docked readily available natural compound, namely pomiferin (flavonoid) with that of the best docked terpenoid salvicine, revealed that salvicine was a more potent inhibitor than that of pomiferin. To the best of our knowledge, this is the first report of a terpenoid as a potential therapeutic molecule against T. pallidum with D-alanine:D-alanine ligase as a novel target. Further studies are warranted to evaluate and explore the potential clinical ramifications of these findings in relation to syphilis that has public health importance worldwide.