Biology subjects

Mumbrekar, K. D.

Publications and source records attributed to Mumbrekar, K. D..

6 recordsLinked to original sources

bioRxiv2024

Mitochondrial genome-encoded mitomiRs regulate cellular plasticity and susceptibility to ferroptosis in triple-negative breast cancer

Ferroptosis is a distinct form of regulated cell death promoted by iron-dependent lipid peroxidation. The metabolic plasticity of cancer cells determines their sensitivity to ferroptosis. Although mitochondrial dysfunction contributes to metabolic reprogramming in cancer cells, its role in ferroptosis remains to be identified. We identified that the mitochondrial genome encodes 13 miRNAs (mitomiRs) that are highly expressed in breast cancer cell lines and patient-derived tumor samples. Expression analysis revealed that mitomiRs are upregulated in basal-like triple-negative breast cancer (TNBC) cells compared to mesenchymal stem-like TNBC cells. Interestingly, 11 out of the 13 mitomiRs bind to the 3'UTR of zinc finger E-box-binding homeobox 1 (ZEB1), a transcription factor, involved in epithelial to mesenchymal transition (EMT) in breast cancer. Using mitomiR-3 mimic, inhibitor and sponges, we confirmed that mitomiR-3 indeed regulate ZEB1 expression in TNBC cells. Increased mesenchymal features in TNBC contributed to vulnerability to pro-ferroptotic metabolic reprogramming sensitizing to cell death in in vitro and in vivo models. Some of the challenges associated with pro-ferroptotic drugs includes lack of cancer cell specificity, low targeting ability, normal tissue toxicity contributing to their limited clinical application as cancer therapeutics. Here, we identified mitomiRs which are highly expressed in TNBC subtypes with low expression in normal breast cells making them an ideal candidate for selective inhibition for targeted therapy. Further, we demonstrated that the inhibition of mitomiRs in triple-negative breast cancer cells promote pro-ferroptotic metabolic reprogramming which can be exploited as novel vulnerability for targeted ferroptotic induction in cancer cells avoiding the normal tissue toxicity. Collectively, our results indicate a novel mechanism of mitochondrial miRNA mediated ferroptosis sensitivity in TNBC subtypes which could be exploited to develop potential miRNA-based therapeutics.

cancer biology↗

bioRxiv2024

Bacterial Supplements Attenuate Pelvic Irradiation-Induced Brain Metabolic Disruptions via the Gut-Brain Axis: A Multi-Omics Investigation

Recent advancements in cancer treatments have increased patient survival rates but also led to treatment-related side effects, negatively impacting the quality of life for cancer survivors. Research has highlighted the crucial role of gut microbiota in overall health, including cognition and neurodegenerative disorders. Cancer patients receiving pelvic radiation often experience gut dysbiosis and this may induce changes in brain through the bi-directional connection between the gut microbiota and the brain, known as the microbiota-gut-brain axis. Bacterial supplements intended to enhance health, whether consumed orally or applied topically. However, the mechanism of bacterial supplements to mitigate pelvic radiation-induced metabolomic alterations is not understood. To investigate this, we employed a multi-omics approach to elucidate how these supplements might mitigate radiation-induced metabolomic changes in the rat brain. A single 6 Gy dose of pelvic radiation was administered to 3-4-month-old Sprague Dawley rats and formulated bacterial supplements were given accordingly. Faecal bacterial sequencing and brain metabolomics performed to identify the changes in the gut microbiota and brain metabolomic analysis to check the altered brain metabolites post pelvic radiation. High-throughput 16S rRNA sequencing revealed significant shifts in bacterial composition, with reduced diversity in the radiation group compared to controls, which was restored in the supplementation groups. Notably, the dominant genera in the radiation group included Methanobrevibacter, while Parasutterella and Brachyspira were prevalent in the supplementation cohorts. Untargeted metabolomic analysis identified 2,554 annotated metabolites, with 56 showing significant differences across groups. Principal Component Analysis demonstrated distinct metabolomic profiles between irradiated and control groups, with specific metabolomic pathways like retinol and glycerophospholipid metabolism altered by irradiation. Bacterial supplementation significantly attenuated these metabolomic disruptions. Therefore, bacterial supplementation could be a promising approach to addressing radiation-induced metabolomic reprogramming in the brains through gut dysbiosis in patients undergoing pelvic radiotherapy, enhancing overall well-being.

neuroscience↗

bioRxiv2023

Deciphering the Metabolic Shifts in The Hippocampus of Mice Subjected to Near Low Dose Radiation: Insights from Metabolomics and Integrated Multi-omics

Recent years have witnessed a drastic upsurge in neurological disorders, with sporadic cases contributing more than ever to their cause. Radiation exposure through diagnostic or therapeutic routes often results in neurological injuries indicative of neurodegenerative pathogenesis. Nevertheless, the impact of low doses of radiation on the brain remains a subject of extensive discussion, as research findings have presented conflicting evidence regarding potential harm and benefits. In the present study, C57/BL mice were exposed to a whole-body single dose of 0.5 Gy X-ray. Fourteen days after treatment, the animals were euthanized, and the hippocampus was isolated and processed for metabolomic analysis. Statistical and bioinformatic analysis revealed 115 metabolites altered in the radiation-exposed group, while pathway enrichment analysis unveiled alterations in tyrosine, phenylalanine, aminoacyl-tRNA metabolism, arginine biosynthesis, glutathione, arginine, proline metabolism, etc. Furthermore, a multiomics interaction network of the genes and the metabolites was constructed to gather an overview of their interaction with the neighboring genes and metabolites in different pathways. These metabolic pathways correlate with synthesizing neurotransmitters such as dopamine and neurodegenerative diseases such as Alzheimers, Parkinsons, and dementia. The present study findings unveiled metabolomic level regulation of low-dose radiation-induced neurotoxicity and its implication in the pathogenesis of neurological disorders.

neuroscience↗

bioRxiv2023

Low-dose exposure to malathion and radiation culminates in the dysregulation of multiple neuronal processes instigating neurotoxicity and activation of neurodegeneration pathways in mice hippocampus

Neurodegenerative disorders are a debilitating and persistent threat to the global elderly population carrying grim outcomes. Their genesis is often multifactorial, with a history of early exposure to xenobiotics like pesticides or diagnostic exposure to ionizing radiation. A holistic molecular insight into their mechanistic induction is still unclear upon single or combinatorial exposure to different toxicants. In the present study, one-month-old C57/BL-6J male mice were treated orally with malathion (MAL) (50mg/kg body wt. for 14 days) and/or a single whole-body radiation (IR) (0.5 Gy) on the 8th day. Post-treatment, behavioral assays were conducted to assess exploratory behavior, memory, and learning. Following sacrifice, brains were collected for histology, biochemical assays, and transcriptomic analysis. Differential expression analysis, Gene ontology, and pathway enrichment revealed several common and uniquely altered genes, biological processes, and pathways related to neurodegeneration, synaptic transmission and plasticity, neuronal survival, proliferation, and regulation of neuronal death. Increased astrogliosis was observed in the IR and co-exposure groups, with significant neuronal cell death and reduction in the expression of NeuN in all three groups. Sholl analysis and dendritic arborization/ spine density study revealed decreased total apical neuronal path length and dendritic spine density in all three groups. Decreased levels of antioxidant enzymes GST and GSH and acetylcholinesterase enzyme activity were also detected. However, there were no changes in exploratory behavior or learning and memory. Thus, explicating the molecular mechanisms behind MAL and IR can provide novel insights into the genesis of environmental factor-driven neurodegenerative pathogenesis.

neuroscience↗

bioRxiv2023

Pelvic irradiation induces behavioral and neuronal damage through gut dysbiosis in a rat model

BackgroundPelvic radiotherapy is the endorsed course of treatment for pelvic malignancies, which frequently cover pelvic primary tumor lesions as well as non-cancerous lymphatic drainage sites in the pelvic area. As a result, pelvic irradiation may indiscriminately cause harm to healthy tissues and organs in the pelvic area in individuals undergoing treatment. Some studies suggest that gut microbial dysbiosis can be correlated with the incidence of radiation-induced toxicities in cancer patients. Since, the consequences were earlier thought to be solely due to the targeted or non-targeted effect of radiation, the role of gut microbiota in the non-targeted effects of radiation and the mechanistic role of the gut-brain axis in the pelvic irradiation scenario is not well explored. Hence, the current study was carried out to explore implication of gut dysbiosis in behavioral and neuronal changes induced by pelvic irradiation. Materials and Methods3-4-month-old Sprague Dawley rats were given a single dose of 6 Gy pelvic irradiation. Fecal samples of control and treated mice were collected at different timepoints to assess microbial abundance and diversity using 16S rRNA-based metagenomic sequencing. Behavioral analysis, histological analysis of intestine, brain and gene expression analysis of brain hippocampus was performed to ascertain the indirect impact of microbial dysbiosis on cognition. ResultsFollowing pelvic irradiation, significant microbial dysbiosis and behavioral alterations were observed with distinct changes in the microbial diversity and a significant decline in the locomotor effect and anxiety level at each time point following radiation. Histological analysis revealed a significant reduction in villus distortion as well as a significant decrease in neuronal cells, matured neurons, and an increase in reactive astrocytes, suggesting that pelvic irradiation promotes neuroinflammation. Gene expression analysis revealed a significant reduction in neural plasticity. Altogether, this study demonstrated that gut dysbiosis caused by pelvic irradiation alters behavior, intestinal morphology, integrity, and brain neuronal maturation, as well as lowers the levels of neural plasticity expression. ConclusionCurrent study provides evidence for the influence of gut dysbiosis on pelvic irradiation induced cognitive impairment in a rat model.

neuroscience↗

bioRxiv2023

MiR-4521 perturbs FOXM1-mediated DNA damage response in breast cancer

Forkhead (FOX) transcription factors are involved in cell cycle control, cellular differentiation, maintenance of tissues, and aging. Mutation or aberrant expression of FOX proteins is associated with developmental disorders and cancers. FOXM1, an oncogenic transcription factor, is a promoter of cell proliferation and accelerated development of breast adenocarcinomas, squamous carcinoma of the head, neck, and cervix, and nasopharyngeal carcinoma. High FOXM1 expression is correlated with chemoresistance in patients treated with doxorubicin and Epirubicin by enhancing the DNA repair in breast cancer cells. Here, we showed that FOXM1 is a direct target of miR-4521 in breast cancer. Overexpression of miR-4521 significantly downregulated FOXM1 expression in breast cancer cells. FOXM1 regulates cell cycle progression and DNA damage response in breast cancer. We showed that miR-4521 expression leads to increased ROS levels and DNA damage in breast cancer cells. FOXM1 plays a critical role in ROS scavenging and promotes stemness which contributes to drug resistance in breast cancer. We observed that breast cancer cells stably expressing miR-4521 lead to cell cycle arrest, impaired FOXM1 mediated DNA damage response leading to increased cell death in breast cancer cells. Additionally, miR-4521-mediated FOXM1 downregulation perturbs cell proliferation, invasion, cell cycle progression, and epithelial-to-mesenchymal progression (EMT) in breast cancer. High FOXM1 expression has been associated with radio and chemoresistance contributing to poor patient survival in multiple cancers, including breast cancer. Our study showed that FOXM1 mediated DNA damage response could be targeted using miR-4521 mimics as a novel therapeutic for breast cancer.

cancer biology↗