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  1. Article: Exploiting the damaging effects of ROS for therapeutic use by deactivating cell-free chromatin: the alchemy of resveratrol and copper.

    Mittra, Indraneel

    Frontiers in pharmacology

    2024  Volume 15, Page(s) 1345786

    Abstract: Cell-free chromatin particles (cfChPs) that circulate in blood, or those that are released locally from dying cells, have myriad pathological effects. They can horizontally transfer themselves into healthy cells to induce DNA damage and activate ... ...

    Abstract Cell-free chromatin particles (cfChPs) that circulate in blood, or those that are released locally from dying cells, have myriad pathological effects. They can horizontally transfer themselves into healthy cells to induce DNA damage and activate inflammatory and apoptotic pathways. It has been proposed that repeated and lifelong assault on healthy cells by cfChPs may be the underlying cause of ageing and multiple age related disorders including cancer. The damaging effects of cfChPs can be minimized by deactivating them via the medium of ROS generated by admixing the nutraceuticals resveratrol (R) and copper (Cu). The antioxidant R acts as a pro-oxidant in the presence of Cu by its ability to catalyse the reduction of Cu(II) to Cu(I) with the generation of ROS via a Fenton-like reaction which can deactivate extra-cellular cfChPs. This perspective article explores the possibility of using the damaging potential of ROS for therapeutic purposes. It discusses the ability of ROS generating nutraceuticals R-Cu to deactivate the extracellular cfChPs without damaging effects on the genomic DNA. As cfChPs play a key role in activation of various disease associated pathways, R-Cu mediated deactivation of these pathways may open up multiple novel avenues for therapy. These findings have considerable translational implications which deserve further investigation by the way of well-designed randomised clinical trials.
    Language English
    Publishing date 2024-02-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2024.1345786
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cytokine Storm as a Cellular Response to dsDNA Breaks: A New Proposal.

    Shabrish, Snehal / Mittra, Indraneel

    Frontiers in immunology

    2021  Volume 12, Page(s) 622738

    Abstract: Pathogenesis of cytokine storm is poorly understood. In this article we propose a new mechanism and suggest innovative therapeutic avenues for its prevention. We have reported that particles of cell-free chromatin (cfCh) that are released from the ... ...

    Abstract Pathogenesis of cytokine storm is poorly understood. In this article we propose a new mechanism and suggest innovative therapeutic avenues for its prevention. We have reported that particles of cell-free chromatin (cfCh) that are released from the billions of cells that die in the body everyday can illegitimately integrate into genomes of healthy cells to trigger dsDNA breaks. The latter leads to apoptosis and/or intense activation of inflammatory cytokines in the affected cells. We hypothesise that a similar phenomenon of dsDNA breaks and inflammation is involved in cytokine storm. The abundant cfCh particles that are released from dying host cells following viral/microbial invasion initiate a cascading effect of more cell death resulting in a vicious cycle of further DNA damage, apoptosis and hyper-inflammation which culminate in cytokine storm. We propose that this unrelenting vicious cycle of cellular DNA damage and cytokine storm may be the underlying cause of high mortality from severe COVID-19. We discuss results of our preclinical studies wherein we have shown that endotoxin induced cytokine storm in mice can be reversed by three different agents that have the ability to inactivate cfCh. These agents may be worthy of investigation in clinical trials to reduce mortality from COVID-19.
    MeSH term(s) Apoptosis ; COVID-19/immunology ; Cell Death ; Cytokine Release Syndrome/immunology ; DNA Breaks, Double-Stranded ; Endotoxins/metabolism ; Free Radicals/metabolism ; Humans ; Inflammation/immunology ; SARS-CoV-2/physiology
    Chemical Substances Endotoxins ; Free Radicals
    Language English
    Publishing date 2021-02-01
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.622738
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells.

    Mehrotra, Sonam / Mittra, Indraneel

    Genes

    2020  Volume 11, Issue 9

    Abstract: Genome instability is a crucial and early event associated with an increased predisposition to tumor formation. In the absence of any exogenous agent, a single human cell is subjected to about 70,000 DNA lesions each day. It has now been shown that ... ...

    Abstract Genome instability is a crucial and early event associated with an increased predisposition to tumor formation. In the absence of any exogenous agent, a single human cell is subjected to about 70,000 DNA lesions each day. It has now been shown that physiological cellular processes including DNA transactions during DNA replication and transcription contribute to DNA damage and induce DNA damage responses in the cell. These processes are also influenced by the three dimensional-chromatin architecture and epigenetic regulation which are altered during the malignant transformation of cells. In this review, we have discussed recent insights about how replication stress, oncogene activation, chromatin dynamics, and the illegitimate recombination of cell-free chromatin particles deregulate cellular processes in cancer cells and contribute to their evolution. The characterization of such endogenous sources of genome instability in cancer cells can be exploited for the development of new biomarkers and more effective therapies for cancer treatment.
    MeSH term(s) Animals ; Biomarkers, Tumor/genetics ; Chromatin/genetics ; DNA Replication/genetics ; Genomic Instability/genetics ; Humans ; Mutation/genetics ; Neoplasms/genetics
    Chemical Substances Biomarkers, Tumor ; Chromatin
    Language English
    Publishing date 2020-09-21
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2527218-4
    ISSN 2073-4425 ; 2073-4425
    ISSN (online) 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes11091101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Circulating nucleic acids: a new class of physiological mobile genetic elements.

    Mittra, Indraneel

    F1000Research

    2015  Volume 4, Page(s) 924

    Abstract: Mobile genetic elements play a major role in shaping biotic genomes and bringing about evolutionary transformations. Herein, a new class of mobile genetic elements is proposed in the form of circulating nucleic acids (CNAs) derived from the billions of ... ...

    Abstract Mobile genetic elements play a major role in shaping biotic genomes and bringing about evolutionary transformations. Herein, a new class of mobile genetic elements is proposed in the form of circulating nucleic acids (CNAs) derived from the billions of cells that die in the body every day due to normal physiology and that act intra-corporeally. A recent study shows that CNAs can freely enter into healthy cells, integrate into their genomes by a unique mechanism and cause damage to their DNA. Being ubiquitous and continuously arising, CNA-induced DNA damage may be the underlying cause of ageing, ageing-related disabilities and the ultimate demise of the organism. Thus, DNA seems to act in the paradoxical roles of both preserver and destroyer of life. This new class of mobile genetic element may be relevant not only to multi-cellular organisms with established circulatory systems, but also to other multi-cellular organisms in which intra-corporeal mobility of nucleic acids may be mediated via the medium of extra-cellular fluid.
    Language English
    Publishing date 2015
    Publishing country England
    Document type Journal Article
    ZDB-ID 2699932-8
    ISSN 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.7095.1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Circulating nucleic acids

    Indraneel Mittra

    F1000Research, Vol

    a new class of physiological mobile genetic elements [version 1; referees: 2 approved]

    2015  Volume 4

    Abstract: Mobile genetic elements play a major role in shaping biotic genomes and bringing about evolutionary transformations. Herein, a new class of mobile genetic elements is proposed in the form of circulating nucleic acids (CNAs) derived from the billions of ... ...

    Abstract Mobile genetic elements play a major role in shaping biotic genomes and bringing about evolutionary transformations. Herein, a new class of mobile genetic elements is proposed in the form of circulating nucleic acids (CNAs) derived from the billions of cells that die in the body every day due to normal physiology and that act intra-corporeally. A recent study shows that CNAs can freely enter into healthy cells, integrate into their genomes by a unique mechanism and cause damage to their DNA. Being ubiquitous and continuously arising, CNA-induced DNA damage may be the underlying cause of ageing, ageing-related disabilities and the ultimate demise of the organism. Thus, DNA seems to act in the paradoxical roles of both preserver and destroyer of life. This new class of mobile genetic element may be relevant not only to multi-cellular organisms with established circulatory systems, but also to other multi-cellular organisms in which intra-corporeal mobility of nucleic acids may be mediated via the medium of extra-cellular fluid.
    Keywords Aging ; Cellular Death & Stress Responses ; Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publishing date 2015-09-01T00:00:00Z
    Publisher F1000 Research Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article: Cell-free chromatin particles released from dying cells inflict mitochondrial damage and ROS production in living cells.

    Raghuram, Gorantla V / Tripathy, Bhabesh Kumar / Avadhani, Kartikeya / Shabrish, Snehal / Khare, Naveen Kumar / Lopes, Relestina / Pal, Kavita / Mittra, Indraneel

    Cell death discovery

    2024  Volume 10, Issue 1, Page(s) 30

    Abstract: Mitochondrial damage and the resultant oxidative stress are associated with neurodegenerative diseases, ageing, and cancer. However, the triggers of mitochondrial damage remain unclear. We previously reported that cell-free chromatin particles (cfChPs) ... ...

    Abstract Mitochondrial damage and the resultant oxidative stress are associated with neurodegenerative diseases, ageing, and cancer. However, the triggers of mitochondrial damage remain unclear. We previously reported that cell-free chromatin particles (cfChPs) released from the billions of cells that die in the body every day can readily enter healthy cells and damage their DNA. Here, we show that cfChPs isolated from the sera of healthy individuals, when applied to NIH3T3 mouse fibroblast cells, cause physical damage to mitochondrial DNA (mtDNA). cfChPs also induce ultrastructural changes, increase mitochondrial mass, alter mitochondrial shape, upregulate mitochondrial outer membrane protein translocase of the outer membrane 20, and change mitochondrial membrane potential. Furthermore, a marked increase was observed in mitochondrial superoxide (ROS) production, as detected by MitoSOX Red, and intracellular superoxide dismutase-1 activation. ROS production was also activated when a conditioned medium containing cfChPs released from hypoxia-induced dying NIH3T3 cells was applied to healthy NIH3T3 cells. ROS activation was significantly reduced when the conditioned medium was pre-treated with three different cfChP-deactivating agents: anti-histone antibody-complexed nanoparticles, DNase I, and the novel pro-oxidant combination of the nutraceuticals resveratrol and copper. Given that 1 × 10
    Language English
    Publishing date 2024-01-15
    Publishing country United States
    Document type Journal Article
    ISSN 2058-7716
    ISSN 2058-7716
    DOI 10.1038/s41420-023-01728-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Correction: Therapeutic interventions on human breast cancer xenografts promote systemic dissemination of oncogenes.

    Raghuram, Gorantla V / Pal, Kavita / Sriram, Gaurav / Khan, Afzal / Joshi, Ruchi / Jadhav, Vishalkumar / Shinde, Sushma / Shaikh, Alfina / Rane, Bhagyeshri / Kangne, Harshada / Mittra, Indraneel

    PloS one

    2024  Volume 19, Issue 3, Page(s) e0301650

    Abstract: This corrects the article DOI: 10.1371/journal.pone.0298042.]. ...

    Abstract [This corrects the article DOI: 10.1371/journal.pone.0298042.].
    Language English
    Publishing date 2024-03-28
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0301650
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Cell-free chromatin: A newly described mediator of systemic inflammation.

    Chaudhary, Shahid / Mittra, Indraneel

    Journal of biosciences

    2019  Volume 44, Issue 2

    Abstract: Recent research has shown that cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body everyday can enter into healthy cells, integrate into their genomes and induce dsDNA breaks and apoptotic responses. ... ...

    Abstract Recent research has shown that cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body everyday can enter into healthy cells, integrate into their genomes and induce dsDNA breaks and apoptotic responses. Genomic integration of cfCh activates NF κ B suggesting a novel mechanism of induction of systemic inflammation. Since DNA damage and inflammation are underlying pathologies in multiple devastating acute and chronic disease conditions, the discovery of agents that can inactivate cfCh may provide therapeutic possibilities.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/pharmacology ; Antibodies, Neutralizing/pharmacology ; Apoptosis/drug effects ; Apoptosis/genetics ; Biological Transport ; Chromatin/chemistry ; Chromatin/drug effects ; Chromatin/pathology ; DNA Breaks, Double-Stranded/drug effects ; Deoxyribonuclease I/pharmacology ; Extracellular Space/chemistry ; Gene Expression Regulation ; Histones/antagonists & inhibitors ; Histones/genetics ; Histones/metabolism ; Humans ; Inflammation/prevention & control ; Jurkat Cells/transplantation ; Mice ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Resveratrol/analogs & derivatives ; Resveratrol/pharmacology ; Signal Transduction
    Chemical Substances Anti-Inflammatory Agents ; Antibodies, Neutralizing ; Chromatin ; H2AX protein, human ; Histones ; NF-kappa B ; Deoxyribonuclease I (EC 3.1.21.1) ; Resveratrol (Q369O8926L)
    Language English
    Publishing date 2019-06-09
    Publishing country India
    Document type Journal Article ; Review
    ZDB-ID 756157-x
    ISSN 0973-7138 ; 0250-5991
    ISSN (online) 0973-7138
    ISSN 0250-5991
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Cell-free chromatin particles released from dying cancer cells activate immune checkpoints in human lymphocytes: implications for cancer therapy.

    Shabrish, Snehal / Pal, Kavita / Khare, Naveen Kumar / Satsangi, Dharana / Pilankar, Aishwarya / Jadhav, Vishalkumar / Shinde, Sushma / Raphael, Nimisha / Sriram, Gaurav / Lopes, Relestina / Raghuram, Gorantla V / Tandel, Harshali / Mittra, Indraneel

    Frontiers in immunology

    2024  Volume 14, Page(s) 1331491

    Abstract: Immune checkpoint blockade is the exciting breakthrough in cancer, but how immune checkpoints are activated is unknown. We have earlier reported that cell-free chromatin particles (cfChPs) that circulate in blood of cancer patients, or those that are ... ...

    Abstract Immune checkpoint blockade is the exciting breakthrough in cancer, but how immune checkpoints are activated is unknown. We have earlier reported that cell-free chromatin particles (cfChPs) that circulate in blood of cancer patients, or those that are released locally from dying cancer cells, are readily internalized by healthy cells with biological consequences. Here we report that treatment of human lymphocytes with cfChPs isolated from sera of cancer patients led to marked activation of the immune checkpoints PD-1, CTLA-4, LAG-3, NKG2A, and TIM-3. This finding was corroborated
    MeSH term(s) Humans ; Animals ; Mice ; Chromatin ; HeLa Cells ; Immunotherapy ; Lymphocytes ; Neoplasms/therapy
    Chemical Substances Chromatin
    Language English
    Publishing date 2024-01-11
    Publishing country Switzerland
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1331491
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells

    Mehrotra, Sonam / Mittra, Indraneel

    Genes. 2020 Sept. 21, v. 11, no. 9

    2020  

    Abstract: Genome instability is a crucial and early event associated with an increased predisposition to tumor formation. In the absence of any exogenous agent, a single human cell is subjected to about 70,000 DNA lesions each day. It has now been shown that ... ...

    Abstract Genome instability is a crucial and early event associated with an increased predisposition to tumor formation. In the absence of any exogenous agent, a single human cell is subjected to about 70,000 DNA lesions each day. It has now been shown that physiological cellular processes including DNA transactions during DNA replication and transcription contribute to DNA damage and induce DNA damage responses in the cell. These processes are also influenced by the three dimensional-chromatin architecture and epigenetic regulation which are altered during the malignant transformation of cells. In this review, we have discussed recent insights about how replication stress, oncogene activation, chromatin dynamics, and the illegitimate recombination of cell-free chromatin particles deregulate cellular processes in cancer cells and contribute to their evolution. The characterization of such endogenous sources of genome instability in cancer cells can be exploited for the development of new biomarkers and more effective therapies for cancer treatment.
    Keywords DNA ; DNA damage ; DNA replication ; biomarkers ; chromatin ; endogenous sources ; epigenetics ; genetic instability ; humans ; neoplasm cells ; neoplasms ; oncogenes ; transcription (genetics)
    Language English
    Dates of publication 2020-0921
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2527218-4
    ISSN 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes11091101
    Database NAL-Catalogue (AGRICOLA)

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