Biology subjects

Lokhande, K. B.

Publications and source records attributed to Lokhande, K. B..

4 recordsLinked to original sources

bioRxiv2025

Spontaneous cancer regression as inversion of spontaneous cancer progression: Malignant melanoma remission as a case-study towards clinical applicability

The spontaneous cancer regression process (SCR) a rather rare paradoxical natural phenomenon, shows that malignant tumors can episodically undergo complete permanent elimination without treatment, and thus may be used for gaining clues to incisive therapeutic innovations. SCR of malignant breast tumors occurs subclinically across human populations ([~]22% rate), according to Scandinavian and Wisconsin Screening Registries (monitoring 0.33million and 2.95million population respectively). SCR occurs in discoid melanomas ([~]12% rate). SCR process has high novelty with no toxicity nor recurrence, and duplicating SCR process is indeed clinically desirable. We aim to probe SCR using melanoma as illustrative pilot-study, and identify candidate leads that may mimic SCR on the tumor. We investigated molecular biological of melanoma, finding two reciprocal phases: spontaneous-progression and spontaneous-regression, and showed driver genes for melanoma SCR. Then, we pursued network pharmaco-informatics analysis. We found that spontaneous melanoma eradication shows an unexpected finding, in distinct contrast to the prevalent view that immunological processes and immunotherapy are critical for melanoma regression, than targeting DNA. We found that in contradistinction, it is DNA interference process that is primary route for melanoma regression, while anti-tumor immune activation is only secondarily needed. We observed that targeting two pathways (kinase-system, inositide-system) by inhibiting two genes, arrested melanoma-progression phase, and activated the reverse phase, melanoma-regression. We investigated the interactions of possible candidate leads, indicating significant therapeutic potency. Our findings underscore the high impact possibility for leveraging the anomalous phenomenon of spontaneous cancer regression as a general oncological principle for probing targeted therapeutic interventions, with substantial clinical potentials.

cancer biology↗

bioRxiv2024

Machine Learning-Based Identification of B4GALNT1 as a Key Player in Hepatocellular Carcinoma: A Comprehensive Bioinformatics and Structural Analysis

Liver hepatocellular carcinoma (LIHC) is one of the most frequent types of malignant cancer in the globe. The identification of new biomarkers for the LIHC is critical. We used TCGA-LIHC gene expression datasets for this study. Several feature selection methods were used to find the top gene signatures that distinguish LIHC cancer from normal samples. Eleven machine learning algorithms were used on these selected characteristics, and model performance evaluation revealed that Naive Bayes Classifiers (AUC = 0.965) performs the best for a selection of 55 protein coding genes. Among 55 protein coding genes we found B4GALNT1 (Beta-1,4-N-acetyl-galactosaminyltransferase 1) which is differentially regulated in LIHC. With several evidence B4GALNT1 plays crucial role in tumorigenesis in many cancers, therefore we conducted systematic bioinformatics approach with mutational and structural analysis of B4GALNT1 in LIHC. Moreover, survival analysis, immune cell infiltration, most significant associated methylated CpG probe and access the accuracy of B4GALNT1 conducted to find the potential role of B4GALNT1. The results suggested that B4GALNT1 was significantly expressed in most cancers including LIHC. Finally, 16 missense mutations identified through cBioportal, Cosmic Database, and Human Variant Database, among which 6 mutations (P64Q, S131F, A311S, R340Q, D478H, and P507Q) found to be deleterious when analysed by in-silico prediction algorithms such as SIFT, PolyPhen2, I Mutent2 and CADD in LIHC. Molecular Dynamics simulation analysis was performed to understand the atomic details of the structure and functional changes. Results from this study suggest the impact of these missense variants on the structure of the B4GALNT1 protein and its pathogenic relevance. Our study demonstrated that B4GALNT1 may be evaluated as a novel target for liver cancer therapy because it has been found to be overexpressed in Liver and correlates with a poor prognosis.

bioinformatics↗

bioRxiv2022

Design, synthesis and biological evaluation of novel quercetin derivatives as PPAR-γ partialagonists by modulating Epithelial-mesenchymal transition in lung cancer metastasis

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-{gamma}, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT, cellular differentiation, fatty acid metabolism, insulin sensitivity and adipogenesis. Several synthetic compounds act as potent full agonist for PPAR-{gamma}. However, owing to their serious adverse effects, restricts their long-term application. Therefore, partial agonist has been greatly in demand which involves reduced and balanced PPAR-{gamma} activity. Our previous study discerned the efficacy of quercetin and its derivatives to attain favourable stabilization with PPAR-{gamma}. Here we extended this work by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC) and hydrazones (QUEINH, QUENH, QUE2FH and QUESH) and analysed their effects in modulating EMT of lung cancer cell lines via PPAR-{gamma} partial activation. QDs-treated A549 cells exhibited cell death strongly in a dose and time dependent manner at nanomolar concentration along with anti-migratory effects compared to NCI-H460 cells. Of the five derivatives we screened, QUETSC, QUE2FH and QUESH exhibited the property of partial activation as compared to the over-expressive level of rosiglitazone (RSG). Consistently, with PPAR-{gamma} partial activation, these QDs also suppressed EMT process by markedly down-regulating the levels of mesenchymal markers (Snail, Slug and Zeb-1) and concomitant up-regulation of epithelial marker (E-cadherin). In the light of these evidences; QUETSC, QUE2FH and QUESH could be used as a novel selective partial PPAR-{gamma} modulators whose pharmacological properties is distinct from RSG and may be exploited as potential therapeutic anti-metastatic agent.

cancer biology↗

bioRxiv2020

An intracellular tripeptide Arg-His-Trp of serum origin detected in MCF-7 cells is a possible agonist to β2 adrenoceptor

BackgroundThe need of agonists and antagonists of {beta}2 adrenoceptor ({beta}2AR) is warranted in various human disease conditions including cancer, cardiovascular and other metabolic disorders. However, the sources of agonists of {beta}2AR are diverse in nature. Interestingly, there is a complete gap in the exploration of agonists of {beta}2AR from serum that is a well-known component of culture media which supports growth and proliferation of normal and cancer cells in vitro. MethodsIn this paper, we employed a novel vertical tube gel electrophoresis (VTGE)-assisted purification of intracellular metabolites of MCF-7 cells grown in vitro in complete media with fetal bovine serum (FBS). Intracellular metabolites of MCF-7 cells were then analyzed by LC-HRMS. Identified intracellular tripeptides of FBS origin were evaluated for their molecular interactions with various extracellular and intracellular receptors including {beta}2AR (PDB ID: 2RH1) by employing molecular docking and molecular dynamics simulations (MDS). A known agonist of {beta}2AR, isoproterenol was used as a positive control in molecular docking and MDS analyses ResultsWe report here identification of a few novel intracellular tripeptides, namely Arg-His-Trp, (PubChem CID-145453842), Pro-Ile-Glu, (PubChem CID-145457492), Cys-Gln-Gln, (PubChem CID-71471965), Glu-Glu-Lys, (PubChem CID-11441068) and Gly-Cys-Leu (PubChem CID145455600) of FBS origin in MCF-7 cells. Molecular docking and MDS analyses revealed that among these molecules, the tripeptide Arg-His-Trp shows a favorable binding affinity with {beta}2AR (-9.8 Kcal/mol). Furthermore, agonistic effect of this tripeptide, Arg-His-Trp is significant and comparable with that of a known agonist of {beta}2AR, isoproterenol. ConclusionIn conclusion, we identified a unique Arg-His-Trp tripeptide of FBS origin in MCF-7 cells by employing a novel approach. This unique tripeptide Arg-His-Trp is suggested to be a potential agonist of {beta}2AR and it may have applications in the context of various human diseases like bronchial asthma and chronic obstructive pulmonary disease (COPD). NOVELTY & IMPACT STATEMENTSO_LIThis paper reports on a novel vertical tube gel electrophoresis (VTGE) system that assisted in the purification and identification of a few intracellular tripeptides in the in vitro grown breast cancer cells, MCF-7ls. C_LIO_LIMolecular docking and molecular dynamics simulation analyses strongly suggest that the tripeptide Arg-His-Trp among others forms the most stable ligand-protein complex with {beta}2 adrenoceptor ({beta}2AR). Its binding affinity and the nature of molecular interactions are comparable or even better than the known agonists of {beta}2AR. C_LIO_LIThis tripeptide Arg-His-Trp is predicted to show manyfold less cytotoxicity, mutagenicity, cardiotoxicity, drug-drug interactions, microsomal stability, and drug-induced liver injury over the other known agonists of {beta}2AR. C_LIO_LIThe tripeptide Arg-His-Trp is therefore suggested as an effective agonist of {beta}2AR and this may be validated in future, in preclinical and clinical models. C_LI

cell biology↗