Biology subjects

Pathak, L.

Publications and source records attributed to Pathak, L..

5 recordsLinked to original sources

bioRxiv2026

Squalene as a Candidate Signalling Molecule: Computational Evidence for a Predicted KEAP1 Interaction and Implications for Stress-Induced Altruistic Stem-Cell Niche Protection

Stem and progenitor cells exposed to cytotoxic stress must preserve both their own viability and the functional integrity of their surrounding niche. Previous investigations from our laboratory have described stress-adapted altruistic stem-cell phenotypes and demonstrated the cytoprotective potential of squalene in normal haematopoietic and mesenchymal progenitor cells through preservation of glutathione homeostasis. More recent studies have associated hypoxia-driven changes in squalene metabolism with intracellular squalene accumulation and protection against lipid peroxidation, while independent experimental evidence has implicated NRF2 in squalene-mediated cytoprotection. However, the molecular basis through which squalene may engage the NRF2 regulatory pathway remains incompletely understood. Here, we investigated the structural feasibility of a potential interaction between squalene and the KEAP1 Kelch domain using molecular docking across three human KEAP1 crystal structures (PDB IDs: 6TYM, 6SP4 and 5CGJ). The docking protocol was evaluated through native-ligand redocking, yielding RMSD values of 0.826, 0.277 and 0.303 A, respectively. Squalene was consistently accommodated within the canonical hydrophobic cavity, with predicted docking scores of 7.905, 7.513 and 6.756 kcal/mol. The predicted interaction environment was predominantly hydrophobic and involved residues including Arg415, Arg380 and Asn414, without conventional hydrogen-bond formation. These findings support the structural feasibility of squalene accommodation within the KEAP1 Kelch domain and provide a testable hypothesis connecting stress-responsive squalene metabolism with potential KEAP1 NRF2 regulation. However, docking alone does not establish direct binding, physiological accessibility, KEAP1 inhibition or functional NRF2 activation. Further biophysical, molecular-dynamics and cellular investigations are required to establish the biological significance of the predicted interaction.

cancer biology↗

bioRxiv2023

Fusobacterium nucleatum present in the saliva of oral cancer subjects can activate niche defense of oral squamous cell carcinoma

Oral cancer is a subset of head and neck cancer (HNC), has a high incidence rate in this malignancy group. Cancer Stem Cells (CSCs) are population of the heterogeneous malignant cells present within oral tumor microenvironment. CSCs stemness permits them to control several signaling pathways and so play a role in cancer progression and relapse. A number of studies have recently demonstrated the presence of specific oral bacteria populations and their lipopolysaccharides (LPS) in the tumor microenvironment. The precise mechanism of action in the initiation, progression, and relapse of oral cancer by the oral bacteria are yet to be determined. We previously reported pathogenic bacterial internalization in CSCs. Based on the findings; we have developed an in-vitro model to investigate how oral microbiota may integrate into the tumor microenvironments CSC population and control its activity. Notably, we found that live bacteria and their LPS, mostly Fusobacterium nucleatum isolated from clinical subjects, were capable of invading CSCs in the in-vitro experimental design setup. Post the host-pathogen interaction; it enabled the activation of a niche modulatory tumor stemness defense (TSD) phenotype in the CSCs. These aggressive CSCs with the TSD phenotype have been found to have a critical role in the progression and relapse of oral cancer.

cancer biology↗

bioRxiv2022

Targeting tumor stemness switch phenotype by activating pathogen induced stem cell niche defense

Cancer stem cells (CSCs) reside in their tumor microenvironment (TME) niches, which are often hypoxic. Previously, we found that hypoxia and oxidative stress prevalent in TME may reprogram CSCs to a highly aggressive and inflammatory phenotype, the tumor stemness switch (TSS) phenotype. We previously reported a "stem cell niche defense" mechanism in bone marrow and lung mesenchymal stem cell niche against pathogen. Pathogen induced bystander apoptosis (PIBA) of stem cells harboring intracellular pathogen may be part of this defense mechanism. We speculate that the TSS phenotype may also activate this niche defense mechanism to defend their TME niche against pathogen and therefore could be exploited to target CSCs. Here we report that CSCs of TSS phenotype enriched in post-hypoxia ABCG2+ CSCs of several cell lines of diverse tumors including oral squamous cell carcinoma cell line SCC-25 exhibited bystander apoptosis when infected with either Bacillus Calmette Guerin (BCG) or mutant Mycobacterium tuberculosis (Mtb) strain 18b. The conditioned media (CM) of the infected cells not only exhibited marked anti-tumor activity in vivo, but also showed significant anti-microbial activity. A detailed mechanisms study revealed that some of the infected ABCG2+ CSCs underwent pyroptosis and released a high mobility group box protein 1 (HMGB1)/p53 death signal that can induce a toll like receptor (TLR) 2/4 mediated bystander apoptosis. Thus, our findings suggest that PIBA can be utilized to activate the "niche defense" mechanism in TSS phenotype, which not only target the TSS, but also exhibit marked anti-tumor activity in vivo.

cancer biology↗

bioRxiv2020

Stem cell basis of a host driven transmission of antigen packed aerosols: a novel mechanism of natural vaccination for tuberculosis

Natural vaccination against pathogens are known to be achieved by herd-immunity i.e. infected human host provide immunity to the community by spreading the pathogen. Whether, infected human hosts transmit vesicle packed aerosols of pathogens antigen for natural vaccination of the community has not yet been considered. We have explored a traditional healing method of aerosol-inoculation against small pox and tuberculosis in the Sualkuchi-Hajo cultural complex of Kamarupa, an ancient Indian region known for tantra-based healing and spirituality. In the aerosol-inoculation method against TB, selected persons with TB (later identified as smear negative TB subject) are encouraged to spread good nigudah in the community by Kirtan chanting; the good Nigudah are thought to be present within bad-nigudah or invisible krimis (tiny flesh eating living being mentioned in ancient Indias medicinal text Caraka Samhita and Atharva Veda). A 15-years of contact TB investigation study, as well as laboratory study of aerosol obtained from smear negative PTB (SN-PTB) subjects led to the identification of good Nigudah as extracellular vesicles (EVs) filled with Mtb-antigen ESAT-6. We then developed a mouse model of aerosol-inoculation using SN-PTB subject derived aerosol EVs, and identified Mtb infected mesenchymal stem cells (MSCs) of the lung as the putative source of the ESAT-6+ EVs. These Mtb infected MSCs reprogram to altruistic stem cell (ASC) phenotype, which then secrete ESAT-6+ EVs to the aerosols; healthy mice receiving the aerosol develop Mtb specific herd immunity. These results expedite our ongoing work on the innate defense mechanism of ASCs against pathogen, and provide a novel mechanism of natural vaccination, where the host extracts appropriate antigens from a pathogen, and then spread it in the community via aerosols.

immunology↗

bioRxiv2020

Coronavirus activates a stem cell-mediated defense mechanism that accelerates the activation of dormant tuberculosis: implications for the COVID-19 pandemic

We postulate that similar to bacteria, adult stem cells may also exhibit an innate defense mechanism to protect their niche. Here, we provide preliminary data on stem cell based innate defense against a mouse model of coronavirus, murine hepatitis virus-1 (MHV-1) infection. In a mouse model of mesenchymal stem cell (MSC) mediated Mycobacterium tuberculosis (Mtb) dormancy, MHV-1 infection in the lung exhibited 20 fold lower viral loads than the healthy control mice, suggesting the potential enhancement of an anti-MHV-1 defense by Mtb. This defense mechanism involves the in vivo expansion and reprogramming of CD271+MSCs in the lung to an enhanced stemness phenotype. The reprogrammed MSCs facilitate the activation of stemness genes, intracellular Mtb replication, and extracellular release of Mtb. The conditioned media of the reprogrammed MSCs exhibit direct anti-viral activity in an in vitro model of MHV-1 induced toxicity to type II alveolar epithelial cells. Thus, our data suggest that reprogrammed MSCs exert a unique innate defense against MHV-1 by activating dormant Mtb. The molecular details of this anti-viral defense mechanism against coronavirus could be further studied to develop a vaccine against COVID-19.

microbiology↗