Biology subjects

Deshmukh, B.

Publications and source records attributed to Deshmukh, B..

4 recordsLinked to original sources

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

PfPPM2 signalling regulates asexual division and sexual conversion of human malaria parasite Plasmodium falciparum

Malaria parasite transits through distinct developmental stages during its life cycle in the human and mosquito host, which includes unique asynchronous division in the erythrocytes. The switch from its asexual stage to sexual forms, which is critical for disease transmission, is intricately regulated but signalling pathways involved in this process have remained unknown. In the present study, we report a novel signalling pathway involving Protein Phosphatase PfPPM2, which regulates asexual division of the parasite as well as its conversion to sexual forms. Phosphoproteomics revealed that PfPPM2 may regulate the phosphorylation of key proteins involved in chromatin remodelling and protein translation. One of the key PfPPM2-targets that emerged from these studies was Heterochromatin Protein 1 (HP1), a regulator of heritable gene silencing which contributes to both mitotic proliferation as well as sexual commitment of the parasite. We demonstrate that PfPPM2 promotes sexual conversion by regulating the interaction between HP1, H3K9me3 and chromatin and it achieves this by dephosphorylating S33 of HP1. Regulation of HP1 and Histone H3 by PfPPM2 may also contribute to division. In addition, PfPPM2 also regulates protein synthesis in the parasite by repressing the phosphorylation of initiation factor eIF2, which is likely to contribute to parasite division and possibly sexual differentiation.

microbiology↗

bioRxiv2023

Multi-protein chimeric antigens, a novel combined approach for efficiently targeting and blocking the blood stage of Plasmodium falciparum

Plasmodium falciparum-induced malaria remains a fatal disease affecting millions of people worldwide. Mainly, the blood stage of malaria is highly pathogenic and symptomatic, rapidly damaging the host organs and occasionally leading to death. Currently, no vaccines are approved for use against the blood stage of malaria. Canonical vaccines in the past have selected the most immunodominant or essential protein to block the growth of the parasite. This strategy works efficiently for low-complexity organisms such as viruses and a few bacteria but has not shown promising results for a malaria vaccine. Plasmodium has a complex life cycle and vaccine candidates especially during blood stage are ineffective due to multiple gene families showing redundancy, immune evasion, and insufficient antibody titer. Herein, we demonstrate a novel strategy of combining multiple antigens from the blood stage of Plasmodium falciparum using only the most immunodominant peptide sequences as a way of tackling polymorphism and redundancy. We created three chimeric antigens targeting eight PfEMP1 proteins (chimeric varB) and eight merozoite surface proteins (chimeric MSP and InvP) by selecting and stitching B-cell epitopes. Our chimeric constructs show naturally circulating antibodies against individual peptides using epitope-mapping microarray as well as entire proteins in malaria-infected patients. We demonstrate that anti-varB antibodies are neutralizing in nature and significantly reduce the cytoadhesion on an organ-on-chip system with a microfluidic device mimicking physiological conditions. We have applied a Deep Learning based method to quantify the number of adhered RBCs under fluidic conditions that is used to study cytoadhesion. Furthermore, the anti-MSP and InvP antibodies show complete growth inhibition in a single cycle at a combined concentration of 0.13 mg/ml. Overall, our results show that a combination of antigenic peptides from multiple antigens can function as a next-generation vaccine and effectively block the blood stage by reducing cytoadhesion and inhibiting the parasite growth.

molecular biology↗

bioRxiv2022

PfHDAC1 is an essential regulator of parasite asexual growth with its altered genomic occupancy and activity associated with artemisinin drug resistance in Plasmodium falciparum

Plasmodium falciparum is a deadly protozoan parasite and the causative agent of malaria, which accounts for close to 200 million cases and 400,000 deaths every year. It has been identified to possess a tightly regulated gene expression profile that is integrally linked to its timely development during the intraerythrocytic stage. Epigenetic modifiers of the histone acetylation code have been identified as key regulators of the parasites transcriptome. In this study, we characterize the solitary class I histone deacetylase PfHDAC1 and demonstrate that phosphorylation is required for its catalytic activity. PfHDAC1 binds to and regulates parasite genes responsible for housekeeping and stress-responsive functions. We show that PfHDAC1 activity in parasites is crucial for normal intraerythrocytic development and that its cellular abundance is correlated with parasitemia progression. We further show that PfHDAC1 has differential abundance and genomic occupancy in artemisinin drug-resistant vs sensitive parasites and that inhibition of its deacetylase activity can modulate the sensitivity of parasites to the drug. We also identify that artemisinin exposure can interfere with PfHDAC1 phosphorylation and its genomic occupancy. Collectively, our results demonstrate PfHDAC1 to be an important regulator of basic biological functions in parasites while also deterministic of responses to environmental stresses such as antimalarial drugs.

microbiology↗