Biology subjects

Bhat, M. K.

Publications and source records attributed to Bhat, M. K..

5 recordsLinked to original sources

bioRxiv2025

Complex I inhibition shifts mitochondrial dynamics and regulates cancer cell survival, providing a synthetic lethal interaction

Mitochondrial remodeling has emerged as a key regulator of cancer cell metabolism, cell stemness, development of drug resistance, and induction of apoptosis. Metformin, a clinically approved inhibitor of mitochondrial complex I, has shown variable antitumor activity in preclinical and clinical settings, implying that adaptive mitochondrial responses can buffer its cytotoxic effects. Here, we show that metformin reprograms mitochondrial dynamics in liver and colorectal cancer cells, increases mitochondrial biomass, alters fusion-fission balance, and enhances biogenesis in a cell type-dependent manner. These adaptations preserve mitochondrial function and support survival under metformin-induced energetic stress. Notably, the targeted disruption of these mitochondrial adaptations induces cell death in metformin-treated cancer cells and suppresses tumor growth. Overall, the study identifies metformin-driven mitochondrial remodeling as a central adaptive axis to complex I inhibition and provides a rationale for co-targeting mitochondrial dynamics and metabolism to enhance the anticancer efficacy of metformin.

cancer biology↗

bioRxiv2025

Obese serum factors aggravate DNA damage, alter DNA damage response, and promote proliferation in colon cancer cells

HighlightsO_LIObese serum aggravates DNA damage and reduces levels of DNA repair molecules in colon cancer cells. C_LIO_LIObese serum activates DDR mechanisms by upregulating P-p53ser15 and pchk2. C_LIO_LIATM-/- mice are prone to AOM/DSS induced colon polyp formation. C_LIO_LIObese serum contributes to the survival phenotype of colon cancer cells. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/642555v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@7be6dforg.highwire.dtl.DTLVardef@72794borg.highwire.dtl.DTLVardef@1795a57org.highwire.dtl.DTLVardef@1a36b9_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG Clinical data indicate a positive link between obesity and DNA damage, which has also been implicated in various pathological conditions. Obesity increases the risk of occurrence and progression of cancers including colon cancer. The underlying mechanisms of the association between obesity-induced alterations in DNA damage response and colon cancer remain unexplored. The present study attempts to investigate the functional status of cellular DNA damage response in an obese environment and its association with colon cancer. To address this, cells were cultured in media supplemented with serum collected from mice fed a normal fat-diet and high-fat diet. Subsequently, the DNA damage response and phenotypic parameters were evaluated. Experimental results revealed that cells cultured in HFD serum exhibited increased DNA damage and reduced levels of DNA repair molecules together with activation of DDR by upregulating levels of pH2AX, P-p53ser15, and pchk2 proteins. Moreover, the cell growth assay revealed a rapid proliferation of cells cultured in HFD serum. Furthermore, HFD mice administered with azoxymethane/dextran sodium sulfate (AOM/DSS) exhibited a higher occurrence of colon polyps compared to normal diet-fed mice. Interestingly, in ATM knockout mice (ATM-a key DDR-related molecule) a higher occurrence of polyps was detected compared to ATM wild-type mice, suggesting a possible association of ATM with polyp formation. Thus, by perturbing DDR, repair pathways, and increasing cell survival, obesity creates a favorable environment for the proliferation of cells. Collectively, this study advances understanding of obesity-altered DDR and its association with cancer cell proliferation.

cancer biology↗

bioRxiv2024

Hypercholesterolemia-induced impairment in sorafenib functionality is overcome by avasimibe co-treatment

Avasimibe; a cholesterol-lowering drug with a proven safety in clinical trials, has recently been repositioned as an anticancer agent in various preclinical investigations. A study from our group reported that hypercholesterolemia promotes hepatocellular carcinoma (HCC) cell survival and hampers the anticancer effect of sorafenib, a kinase inhibitor. In the present study, we demonstrate that in HCC under hypercholesterolemic conditions the anticancer property of sorafenib is potentiated by avasimibe (AVA) co-treatment. Further, to elucidate the role of hypercholesterolemia on sorafenib efficacy, in vitro and in vivo models of HCC were used. In vitro, co-treatment of both drugs synergistically inhibited HCC cell viability and induced cell death under normal and hypercholesterolemic conditions. At the molecular level, downregulation of ERK signalling and induction of endoplasmic reticulum stress are likely to contribute to the combinatorial cytotoxic effect of sorafenib and avasimibe in vitro. In mice, fed on a high-cholesterol diet (HCD), the efficacy of sorafenib was restored by co-administration of AVA. Collectively, these findings suggest that impairment in the efficacy of sorafenib because of hypercholesterolemic phenotype could be restored by AVA co-treatment, which may have implications towards treatment strategy. HighlightsO_LICholesterol impedes sorafenib efficacy in Hepatocellular carcinoma cells. C_LIO_LIAvasimibe restores the functionality of sorafenib under hypercholesterolemic environment. C_LIO_LICombine treatment of sorafenib and avasimibe synergistically enhances cytotoxicity in hepatocellular carcinoma. C_LIO_LISorafenib and avasimibe treatment in the presence of LDLc.is associated with diminished ERK activation and increased ER stress. C_LI

cancer biology↗

bioRxiv2020

PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Reveals Important Insights into the Outbreak

The PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Consortium has achieved its initial goal of completing the sequencing of 1000 SARS-CoV-2 genomes from nasopharyngeal and oropharyngeal swabs collected from individuals testing positive for COVID-19 by Real Time PCR. The samples were collected across 10 states covering different zones within India. Given the importance of this information for public health response initiatives investigating transmission of COVID-19, the sequence data is being released in GISAID database. This information will improve our understanding on how the virus is spreading, ultimately helping to interrupt the transmission chains, prevent new cases of infection, and provide impetus to research on intervention measures. This will also provide us with information on evolution of the virus, genetic predisposition (if any) and adaptation to human hosts. One thousand and fifty two sequences were used for phylodynamic, temporal and geographic mutation patterns and haplotype network analyses. Initial results indicate that multiple lineages of SARS-CoV-2 are circulating in India, probably introduced by travel from Europe, USA and East Asia. A2a (20A/B/C) was found to be predominant, along with few parental haplotypes 19A/B. In particular, there is a predominance of the D614G mutation, which is found to be emerging in almost all regions of the country. Additionally, mutations in important regions of the viral genome with significant geographical clustering have also been observed. The temporal haplotype diversities landscape in each region appears to be similar pan India, with haplotype diversities peaking between March-May, while by June A2a (20A/B/C) emerged as the predominant one. Within haplotypes, different states appear to have different proportions. Temporal and geographic patterns in the sequences obtained reveal interesting clustering of mutations. Some mutations are present at particularly high frequencies in one state as compared to others. The negative estimate Tajimas D (D = -2.26817) is consistent with the rapid expansion of SARS-CoV-2 population in India. Detailed mutational analysis across India to understand the gradual emergence of mutants at different regions of the country and its possible implication will help in better disease management.

genomics↗

bioRxiv2020

Phylogenomic analysis of SARS-CoV-2 genomes from western India reveals unique linked mutations

India has become the third worst-hit nation by the COVID-19 pandemic caused by the SARS-CoV-2 virus. Here, we investigated the molecular, phylogenomic, and evolutionary dynamics of SARS-CoV-2 in western India, the most affected region of the country. A total of 90 genomes were sequenced. Four nucleotide variants, namely C241T, C3037T, C14408T (Pro4715Leu), and A23403G (Asp614Gly), located at 5UTR, Orf1a, Orf1b, and Spike protein regions of the genome, respectively, were predominant and ubiquitous (90%). Phylogenetic analysis of the genomes revealed four distinct clusters, formed owing to different variants. The major cluster (cluster 4) is distinguished by mutations C313T, C5700A, G28881A are unique patterns and observed in 45% of samples. We thus report a newly emerging pattern of linked mutations. The predominance of these linked mutations suggests that they are likely a part of the viral fitness landscape. A novel and distinct pattern of mutations in the viral strains of each of the districts was observed. The Satara district viral strains showed mutations primarily at the 3' end of the genome, while Nashik district viral strains displayed mutations at the 5' end of the genome. Characterization of Pune strains showed that a novel variant has overtaken the other strains. Examination of the frequency of three mutations i.e., C313T, C5700A, G28881A in symptomatic versus asymptomatic patients indicated an increased occurrence in symptomatic cases, which is more prominent in females. The age-wise specific pattern of mutation is observed. Mutations C18877T, G20326A, G24794T, G25563T, G26152T, and C26735T are found in more than 30% study samples in the age group of 10-25. Intriguingly, these mutations are not detected in the higher age range 61-80. These findings portray the prevalence of unique linked mutations in SARS-CoV-2 in western India and their prevalence in symptomatic patients. ImportanceElucidation of the SARS-CoV-2 mutational landscape within a specific geographical location, and its relationship with age and symptoms, is essential to understand its local transmission dynamics and control. Here we present the first comprehensive study on genome and mutation pattern analysis of SARS-CoV-2 from the western part of India, the worst affected region by the pandemic. Our analysis revealed three unique linked mutations, which are prevalent in most of the sequences studied. These may serve as a molecular marker to track the spread of this viral variant to different places.

genomics↗