Neha Bunkar | Dr. H.S. Gour Central University, Sagar, MP (original) (raw)

Papers by Neha Bunkar

Cellular Signalling, 2020

Clostridium perfringens, a rod-shaped, gram-positive, anaerobic, spore-forming bacterium is one o... more Clostridium perfringens, a rod-shaped, gram-positive, anaerobic, spore-forming bacterium is one of the most widely occurring bacterial pathogens, associated with a spectrum of diseases in humans. A major virulence factor during its infection is the enzyme phospholipase C encoded by the plc gene, known as Clostridium perfringens phospholipase C (CpPLC). The present study was designed to understand the role of CpPLC in inducing survival mechanisms and mitochondrial-induced epigenetic changes in a human lymphocyte cell culture model. Following exposure to CpPLC, a significant generation of mitochondrial reactive oxygen species was observed, which coincided with the changes in the expression of vital components of MAP/ERK/RTK signaling cascade that regulates the downstream cellular functions. These disturbances further led to alterations in the mitochondrial genome and functioning. This was supported by the observed upregulation in the expression of mitochondrial fission genes Drp1, Fis1, and Mff, and mitochondrial fusion genes MFN1, MFN2, and OPA1 following CpPLC exposure. CpPLC exposed cells showed upregulation of OMA1, DELE1, and HRI genes involved in the integrated stress response (ISR), which suggests that it may induce the ISR that provides a pro-survival mechanism to the host cell. CpPLC also initiated immune patho-physiologic mechanisms including mitochondrial-induced epigenetic modifications through a mitochondrial-ROS driven signaling pathway. Interestingly, epigenetic machinery not only play a pivotal role in lymphocyte homeostasis by contributing to cell-fate decisions but thought to be one of the mechanisms by which intracellular pathogens survive within the host cells. Importantly, the impairment of mtDNA repair among the CpPLC exposed cells, induced alterations within mtDNA methylation, and led to the deregulation of MT-CO1, MT-ND6, MT-ATPase 6, and MT-ATPase8 gene expression profiles that are important for mitochondrial bioenergetics and subsequent metabolic pathways. This was further confirmed by the changes in the activity of mitochondrial electron chain complexes (complex I, II, III, IV and V). The altered mtDNA methylation profile was also found to be closely associated with the varied expression of mitomiRs and their targets. CpPLC exposed cells showed up-regulation of miR24 expression and down-regulation of miR34a, miR150, and miR155, while the increased expression of mitomiR target genes i.e. of K-Ras, MYC, EGFR, and NF-kβ was also observed in these cells. Altogether, our findings provide novel insights into the derailment of redox signaling machinery in CpPLC treated lymphocytes and its role in the induction of survival mechanisms and mitochondrial-induced epigenetic modifications.

International Journal of Occupational Medicine and Environmental Health, 2015

Mitochondria play a fundamental role in regulating a variety of complex metabolic processes to ma... more Mitochondria play a fundamental role in regulating a variety of complex metabolic processes to maintain adequate energy balance for cellular existence. To orchestrate these functions, an undisturbed mitochondrial dynamics is imperative through a set of tightly guided mechanisms. Interference in key signature processes by several genetic, epigenetic and age-linked factors triggers mitochondrial dysfunction through decrease in mitochondrial biogenesis, reduced mitochondrial content, aberrant mtDNA mutations, increased oxidative stress, deficient mitophagy, energy dysfunction, decrease in anti oxidant defense and impaired calcium homeostasis. Mitochondrial dysfunction is widely implicated in origin and development of various age associated degenerative human ailments including metabolic syndromes, cardiovascular diseases, cancer, diabetes and neurodegenerative disorders. The present review revisits the mitochondrial anomalies involved in aetiology of different human diseases and also highlights the translational significance of nano-vectors aimed for selective mitochondrial engineering which might pave way for development of novel therapeutics.

Extra-pulmonary tuberculosis is often an underrated illness. Recent clinical studies have pointed... more Extra-pulmonary tuberculosis is often an underrated illness. Recent clinical studies have pointed out that lymphocyte
homeostasis is dramatically disturbed as revealed through a series of signs and symptoms. Lymphocytes, the known effector
cells of our immune system, play an important role in providing immunologic resistance against Mycobacterium infection. It is
important to have quantitative insights into the lifespan of these cells; therefore, we aimed to study the precise effect of
gastrointestinal tuberculosis infection on peripheral blood lymphocyte subpopulations and function. Our results indicated
that gastrointestinal tuberculosis could increase mitochondrial oxidative stress, lower mitochondrial DNA copy number,
promote nuclear DNA damage and repair response, decrease mitochondrial respiratory chain enzyme activities, and
upregulate Bcl-2 and caspase-3 gene expression in lymphocytes. We further revealed that Mycobacterium infection induces
autophagy for selective sequestration and subsequent degradation of the dysfunctional mitochondrion before activating
cellular apoptosis in the peripheral lymphocyte pool. Together, these observations uncover a new role of mitochondrial–
nuclear crosstalk that apparently contributes to lymphocyte homeostasis in gastrointestinal tuberculosis infection.

International Journal of Occupational Medicine and Environmental Health, 2015

December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental ... more December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental leakage of deadly poisonous methyl isocyanate (MIC) gas instigated research efforts to understand the nature, severity of health damage and sufferings of 570 000 ailing survivors of this tragedy. In a decade-long period, our systematic laboratory investigations coupled with long-term molecular surveillance studies have comprehensively demonstrated that the risk of developing an environmental associated aberrant disease phenotype, including cancer, involves complex interplay of genomic and epigenetic reprogramming. These findings poised us to translate this knowledge into an investigative framework of "molecu lar biodosimetry" in a strictly selected cohort of MIC exposed individuals. A pragmatic cancer risk-assessment strategy pursued in concert with a large-scale epidemiological study might unfold molecular underpinnings of host-susceptibility and exposureresponse relationship. The challenges are enormous, but we postulate that the study will be necessary to establish a direct initiation-promotion paradigm of environmental carcinogenesis. Given that mitochondrial retrograde signaling-induced epigenetic reprogramming is apparently linked to neoplasticity, a cutting-edge tailored approach by an expert pool of biomedical researchers will be fundamental to drive these strategies from planning to execution. Validating the epigenomic signatures will hopefully result in the development of biomarkers to better protect human lives in an overburdened ecosystem, such as India, which is continuously challenged to meet population demands. Besides, delineating the mechanistic links between MIC exposure and cancer morbidity, our investigative strategy might help to formulate suitable regulatory policies and measures to reduce the overall burden of occupational and environmental carcinogenesis.

Nanomedicine, 2014

Nanomedicine may play an important role in improving the clinical efficacy of dendritic cell-base... more Nanomedicine may play an important role in improving the clinical efficacy of dendritic cell-based immunotherapy against GI tract malignancies. Dendritic cell-based vaccines have proven their effectiveness against different established GI tract tumors, yet their success is mainly hindered by the strong tumor-induced suppressive microenvironment. The sustained and targeted release of tumor antigens to dendritic cells using different nanoengineered approaches would be an efficient strategy to overcome established immune tolerance. Encapsulation would result in low diffusivity, restricted movement, effective crosspresentation and enhanced T-cell responses. These nanotherapy-based approaches will certainly help with the designing of clinically translatable dendritic cell-based therapeutic vaccines and facilitate the selective removal of residual disease in gastrointestinal cancer patients following standard treatments.

Cellular Signalling, 2020

Clostridium perfringens, a rod-shaped, gram-positive, anaerobic, spore-forming bacterium is one o... more Clostridium perfringens, a rod-shaped, gram-positive, anaerobic, spore-forming bacterium is one of the most widely occurring bacterial pathogens, associated with a spectrum of diseases in humans. A major virulence factor during its infection is the enzyme phospholipase C encoded by the plc gene, known as Clostridium perfringens phospholipase C (CpPLC). The present study was designed to understand the role of CpPLC in inducing survival mechanisms and mitochondrial-induced epigenetic changes in a human lymphocyte cell culture model. Following exposure to CpPLC, a significant generation of mitochondrial reactive oxygen species was observed, which coincided with the changes in the expression of vital components of MAP/ERK/RTK signaling cascade that regulates the downstream cellular functions. These disturbances further led to alterations in the mitochondrial genome and functioning. This was supported by the observed upregulation in the expression of mitochondrial fission genes Drp1, Fis1, and Mff, and mitochondrial fusion genes MFN1, MFN2, and OPA1 following CpPLC exposure. CpPLC exposed cells showed upregulation of OMA1, DELE1, and HRI genes involved in the integrated stress response (ISR), which suggests that it may induce the ISR that provides a pro-survival mechanism to the host cell. CpPLC also initiated immune patho-physiologic mechanisms including mitochondrial-induced epigenetic modifications through a mitochondrial-ROS driven signaling pathway. Interestingly, epigenetic machinery not only play a pivotal role in lymphocyte homeostasis by contributing to cell-fate decisions but thought to be one of the mechanisms by which intracellular pathogens survive within the host cells. Importantly, the impairment of mtDNA repair among the CpPLC exposed cells, induced alterations within mtDNA methylation, and led to the deregulation of MT-CO1, MT-ND6, MT-ATPase 6, and MT-ATPase8 gene expression profiles that are important for mitochondrial bioenergetics and subsequent metabolic pathways. This was further confirmed by the changes in the activity of mitochondrial electron chain complexes (complex I, II, III, IV and V). The altered mtDNA methylation profile was also found to be closely associated with the varied expression of mitomiRs and their targets. CpPLC exposed cells showed up-regulation of miR24 expression and down-regulation of miR34a, miR150, and miR155, while the increased expression of mitomiR target genes i.e. of K-Ras, MYC, EGFR, and NF-kβ was also observed in these cells. Altogether, our findings provide novel insights into the derailment of redox signaling machinery in CpPLC treated lymphocytes and its role in the induction of survival mechanisms and mitochondrial-induced epigenetic modifications.

International Journal of Occupational Medicine and Environmental Health, 2015

Mitochondria play a fundamental role in regulating a variety of complex metabolic processes to ma... more Mitochondria play a fundamental role in regulating a variety of complex metabolic processes to maintain adequate energy balance for cellular existence. To orchestrate these functions, an undisturbed mitochondrial dynamics is imperative through a set of tightly guided mechanisms. Interference in key signature processes by several genetic, epigenetic and age-linked factors triggers mitochondrial dysfunction through decrease in mitochondrial biogenesis, reduced mitochondrial content, aberrant mtDNA mutations, increased oxidative stress, deficient mitophagy, energy dysfunction, decrease in anti oxidant defense and impaired calcium homeostasis. Mitochondrial dysfunction is widely implicated in origin and development of various age associated degenerative human ailments including metabolic syndromes, cardiovascular diseases, cancer, diabetes and neurodegenerative disorders. The present review revisits the mitochondrial anomalies involved in aetiology of different human diseases and also highlights the translational significance of nano-vectors aimed for selective mitochondrial engineering which might pave way for development of novel therapeutics.

Extra-pulmonary tuberculosis is often an underrated illness. Recent clinical studies have pointed... more Extra-pulmonary tuberculosis is often an underrated illness. Recent clinical studies have pointed out that lymphocyte
homeostasis is dramatically disturbed as revealed through a series of signs and symptoms. Lymphocytes, the known effector
cells of our immune system, play an important role in providing immunologic resistance against Mycobacterium infection. It is
important to have quantitative insights into the lifespan of these cells; therefore, we aimed to study the precise effect of
gastrointestinal tuberculosis infection on peripheral blood lymphocyte subpopulations and function. Our results indicated
that gastrointestinal tuberculosis could increase mitochondrial oxidative stress, lower mitochondrial DNA copy number,
promote nuclear DNA damage and repair response, decrease mitochondrial respiratory chain enzyme activities, and
upregulate Bcl-2 and caspase-3 gene expression in lymphocytes. We further revealed that Mycobacterium infection induces
autophagy for selective sequestration and subsequent degradation of the dysfunctional mitochondrion before activating
cellular apoptosis in the peripheral lymphocyte pool. Together, these observations uncover a new role of mitochondrial–
nuclear crosstalk that apparently contributes to lymphocyte homeostasis in gastrointestinal tuberculosis infection.

International Journal of Occupational Medicine and Environmental Health, 2015

December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental ... more December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental leakage of deadly poisonous methyl isocyanate (MIC) gas instigated research efforts to understand the nature, severity of health damage and sufferings of 570 000 ailing survivors of this tragedy. In a decade-long period, our systematic laboratory investigations coupled with long-term molecular surveillance studies have comprehensively demonstrated that the risk of developing an environmental associated aberrant disease phenotype, including cancer, involves complex interplay of genomic and epigenetic reprogramming. These findings poised us to translate this knowledge into an investigative framework of "molecu lar biodosimetry" in a strictly selected cohort of MIC exposed individuals. A pragmatic cancer risk-assessment strategy pursued in concert with a large-scale epidemiological study might unfold molecular underpinnings of host-susceptibility and exposureresponse relationship. The challenges are enormous, but we postulate that the study will be necessary to establish a direct initiation-promotion paradigm of environmental carcinogenesis. Given that mitochondrial retrograde signaling-induced epigenetic reprogramming is apparently linked to neoplasticity, a cutting-edge tailored approach by an expert pool of biomedical researchers will be fundamental to drive these strategies from planning to execution. Validating the epigenomic signatures will hopefully result in the development of biomarkers to better protect human lives in an overburdened ecosystem, such as India, which is continuously challenged to meet population demands. Besides, delineating the mechanistic links between MIC exposure and cancer morbidity, our investigative strategy might help to formulate suitable regulatory policies and measures to reduce the overall burden of occupational and environmental carcinogenesis.

Nanomedicine, 2014

Nanomedicine may play an important role in improving the clinical efficacy of dendritic cell-base... more Nanomedicine may play an important role in improving the clinical efficacy of dendritic cell-based immunotherapy against GI tract malignancies. Dendritic cell-based vaccines have proven their effectiveness against different established GI tract tumors, yet their success is mainly hindered by the strong tumor-induced suppressive microenvironment. The sustained and targeted release of tumor antigens to dendritic cells using different nanoengineered approaches would be an efficient strategy to overcome established immune tolerance. Encapsulation would result in low diffusivity, restricted movement, effective crosspresentation and enhanced T-cell responses. These nanotherapy-based approaches will certainly help with the designing of clinically translatable dendritic cell-based therapeutic vaccines and facilitate the selective removal of residual disease in gastrointestinal cancer patients following standard treatments.