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Search Results: 1 - 10 of 403509 matches for " M. Prakash Hande "
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Anti-proliferative activity of silver nanoparticles
PV AshaRani, M Prakash Hande, Suresh Valiyaveettil
BMC Cell Biology , 2009, DOI: 10.1186/1471-2121-10-65
Abstract: Normal human lung fibroblasts (IMR-90) and human glioblastoma cells (U251) were exposed to different doses of Ag-nps in vitro. Uptake of Ag-nps occurred mainly through endocytosis (clathrin mediated process and macropinocytosis), accompanied by a time dependent increase in exocytosis rate. The electron micrographs revealed a uniform intracellular distribution of Ag-np both in cytoplasm and nucleus. Ag-np treated cells exhibited chromosome instability and mitotic arrest in human cells. There was efficient recovery from arrest in normal human fibroblasts whereas the cancer cells ceased to proliferate. Toxicity of Ag-np is mediated through intracellular calcium (Ca2+) transients along with significant alterations in cell morphology and spreading and surface ruffling. Down regulation of major actin binding protein, filamin was observed after Ag-np exposure. Ag-np induced stress resulted in the up regulation of metallothionein and heme oxygenase -1 genes.Here, we demonstrate that uptake of Ag-np occurs mainly through clathrin mediated endocytosis and macropinocytosis. Our results suggest that cancer cells are susceptible to damage with lack of recovery from Ag-np-induced stress. Ag-np is found to be acting through intracellular calcium transients and chromosomal aberrations, either directly or through activation of catabolic enzymes. The signalling cascades are believed to play key roles in cytoskeleton deformations and ultimately to inhibit cell proliferation.The convergence of nanotechnology with nanomedicine has added new hope in the therapeutic and pharmaceutical field. The unique nature of nanoparticles is being exploited by scientists, in hope of developing novel diagnostic and antimicrobial agents [1]. Silver nanoparticles (Ag-np) are widely used in medicine, physics, material sciences and chemistry [2]. However, the rapid progress in nanotechnology was accompanied by insufficient data on biohazard identification. Exposure to nanomaterials occurs through inhalatio
Telomere-Mediated Chromosomal Instability Triggers TLR4 Induced Inflammation and Death in Mice
Rabindra N. Bhattacharjee,Birendranath Banerjee,Shizuo Akira,M. Prakash Hande
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011873
Abstract: Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC?/? mice) display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR) are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation.
Genome Integrity - a new open access journal
Razqallah Hakem, M Prakash Hande, John Petrini, Predrag Slijepcevic
Genome Integrity , 2010, DOI: 10.1186/2041-9414-1-1
Abstract: By launching Genome Integrity, the first open access journal dedicated to the field of DNA damage response and associated processes, we aim to provide interested scientists with the journal that enables (i) immediate online access to articles as soon as they are accepted for publication and (ii) free and universal online access resulting in dissemination to the widest possible audience. We believe that the current lack of opportunities for immediate and free dissemination of articles focusing on the above area of research will make Genome Integrity a viable and competitive journal. We would like to note that Genome Integrity articles will be archived in PubMed [1] and all freely accessible full-text repositories. This complies with the policies of a number of funding bodies including the Wellcome Trust, NIH and Howard Hughes Medical Institute [2-5].The scope of Genome Integrity is wide and ambitious. We aim to attract articles focusing on all aspects of DNA damage response mechanisms, including mechanisms of DNA damage induction, sensing, signalling and repair, cell cycle check-point control, telomere maintenance and control of apoptosis. The journal also welcomes submissions which focus on mechanisms of chromosome stability maintenance and the effects of genotoxic stress on this stability. A growing area of research within the field is understanding DNA damage processing in the context of interphase nucleus chromatin and the journal certainly aims to attract authors interested in the mechanisms underlying these processes. Genome Integrity also intends to encourage publications from authors interested in exploring the effects of normal and pathological DNA damage responses on tissue homeostasis, cellular and organismal ageing and tumorigenesis in humans and in animal models. In brief, Genome Integrity will publish articles exploring fundamental, as well as translational, aspects of all processes behind DNA damage response, genome and chromosome stability maintenance
Hydrogen peroxide induced genomic instability in nucleotide excision repair-deficient lymphoblastoid cells
Kalpana Gopalakrishnan, Grace Low, Aloysius Ting, Prarthana Srikanth, Predrag Slijepcevic, M Prakash Hande
Genome Integrity , 2010, DOI: 10.1186/2041-9414-1-16
Abstract: Loss of functional XPB or XPD but not XPA led to enhanced sensitivity towards H2O2-induced cell death. XP-deficient lymphoblastoid cells exhibited increased susceptibility to H2O2-induced DNA damage with XPD showing the highest susceptibility and lowest repair capacity. Furthermore, XPB- and XPD-deficient lymphoblastoid cells displayed enhanced DNA damage at the telomeres. XPA- and XPB-deficient lymphoblastoid cells also showed differential regulation of XPD following H2O2 treatment.Taken together, our data implicate a role for the NER in H2O2-induced oxidative stress management and further corroborates that oxidative stress is a significant contributing factor in XP symptoms. Resistance of XPA-deficient lymphoblastoid cells to H2O2-induced cell death while harbouring DNA damage poses a potential cancer risk factor for XPA patients. Our data implicate XPB and XPD in the protection against oxidative stress-induced DNA damage and telomere shortening, and thus premature senescence.The nucleotide excision repair (NER) pathway is a versatile DNA repair mechanism that recognizes and efficiently removes an array of structurally diverse DNA lesions including ultraviolet (UV)-induced lesions, intra-strand crosslinks and bulky chemical adducts such as those induced by compounds in tobacco smoke. The NER comprises of more than three dozen genes working in spatial and temporal concert and is differentiated into two sub-pathways - the global genome-NER (GG-NER) and transcription coupled repair (TCR) - that differ only in damage recognition [1,2].Inherited defects in the NER predispose an individual to genetic disorders featuring genomic instability and segmental progeria - Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and Trichothiodystrophy (TTD). XP is a rare autosomal recessive congenital disorder that arises from mutations in XP proteins, XPA - XPG, and a variant form XPV. XP patients are predisposed to sun-induced cutaneous cancer incidence by more than a thousand-fold
Stable expression of promyelocytic leukaemia (PML) protein in telomerase positive MCF7 cells results in alternative lengthening of telomeres phenotype
Jacklyn W Y Yong, Xiujun Yeo, Md Khan, Martin B Lee, M Prakash Hande
Genome Integrity , 2012, DOI: 10.1186/2041-9414-3-5
Abstract: Stable over-expression of both types of PML does not affect the telomere maintenance in the ALT cells. We report novel observations in PML over-expressed telomerase-positive MCF7 cells: 1) APBs are detected in telomerase-positive MCF7 cells following over-expression of wild-type PML and 2) rapid telomere elongation is observed in MCF7 cells that stably express either wild-type PML or PML C/C-. We also show that the telomerase activity in MCF7 cells can be affected depending on the type of PML protein over-expressed.Our data suggests that APBs might not be essential for the ALT pathway as MCF7 cells that do not contain APBs exhibit long telomeres. We propose that wild-type PML can either definitively dominate over telomerase or enhance the activity of telomerase, and PML C/C- can allow for the co-existence of both telomerase and ALT pathways. Our findings add another dimension in the study of telomere maintenance as the expression of PML alone (wild-type or otherwise) is able to change the dynamics of the telomerase pathway.Telomeres are specialised chromatin structures capping the ends of chromosomes [1]. They consist of TTAGGG repeats and function to protect the ends of the DNA. Human telomeres in somatic cells lose about 50 to 150 base pairs with each round of cellular division. When telomeres shorten to a critical length, cells will enter a state of permanent growth arrest termed as replicative senescence. Cellular senescence limits the proliferative capacity of cells and this suppresses tumourigenesis [2]. To overcome cellular senescence and to achieve immortality, cancer cells maintain telomeres through the activation of the telomerase enzyme. Some cancer cells also use the lesser-known telomere maintenance pathway-the Alternative Lengthening of Telomeres pathway, ALT [3,4].Cancer cells that employ the ALT pathway for telomere maintenance exhibit distinct hallmarks from cells that use telomerase [5]. These cells exhibit heterogeneous telomeres, with length vary
Differential regulation of intracellular factors mediating cell cycle, DNA repair and inflammation following exposure to silver nanoparticles in human cells
PV AshaRani, Swaminathan Sethu, Hui Lim, Ganapathy Balaji, Suresh Valiyaveettil, M Prakash Hande
Genome Integrity , 2012, DOI: 10.1186/2041-9414-3-2
Abstract: We report that silver nanoparticles are capable of adsorbing cytosolic proteins on their surface that may influence the function of intracellular factors. Gene and protein expression profiles of Ag-np exposed cells revealed up regulation of many DNA damage response genes such as Gadd 45 in both the cell types and ATR in cancer cells. Moreover, down regulation of genes necessary for cell cycle progression (cyclin B and cyclin E) and DNA damage response/repair (XRCC1 and 3, FEN1, RAD51C, RPA1) was observed in both the cell lines. Double strand DNA damage was observed in a dose dependant manner as evidenced in γH2AX foci assay. There was a down regulation of p53 and PCNA in treated cells. Cancer cells in particular showed a concentration dependant increase in phosphorylated p53 accompanied by the cleavage of caspase 3 and PARP. Our results demonstrate the involvement of NFκB and MAP kinase pathway in response to Ag-np exposure. Up regulation of pro-inflammatory cytokines such as interleukins (IL-8, IL-6), macrophage colony stimulating factor, macrophage inflammatory protein in fibroblasts following Ag-np exposure were also observed.In summary, Ag-np can modulate gene expression and protein functions in IMR-90 cells and U251 cells, leading to defective DNA repair, proliferation arrest and inflammatory response. The observed changes could also be due to its capability to adsorb cytosolic proteins on its surface.Wide spread use of nanoparticles has increased the risk of nanoparticle induced toxic effects in the environment and in humans. The rate of exposure increased progressively over the years when engineered nanomaterials were extensively used in a variety of industries. Intentional manipulation of nanoparticle surfaces with biomolecules and chemicals to cater various applications resulted in nanomaterials with unforeseeable activity. Large scale production and improper waste disposal may elevate human exposure to them and subsequent accumulation of these nanomaterial
Inhibition of poly (ADP-Ribose) polymerase-1 in telomerase deficient mouse embryonic fibroblasts increases arsenite-induced genome instability
Resham L Gurung, Lakshmidevi Balakrishnan, Rabindra N Bhattacharjee, Jayapal Manikandan, Srividya Swaminathan, M Prakash Hande
Genome Integrity , 2010, DOI: 10.1186/2041-9414-1-5
Abstract: Inhibition of PARP in telomerase deficient MEFs induced an increase in arsenite-induced DNA damage as compared to control cells. Combined inhibition also resulted in enhanced genomic instability, demonstrated by elevated micronuclei induction and chromosomal aberrations with decreased cell survival. In addition, telomerase inhibition in PARP-1 deficient MEFs led to greater telomere shortening and increased genomic instability.Our study demonstrated that the co-inhibition of PARP-1 and telomerase in MEFs rendered cells more susceptible to DNA damaging agents. Hence, these results offer support for the use of combined inhibition of PARP-1 and telomerase as a strategy to minimise the problems associated with long-term telomerase inhibition in cancer therapeutics.Telomeres are specialised dynamic structures at the ends of linear eukaryotic chromosomes consisting of non-coding DNA repeats (TTAGGG)n and associated proteins [1,2]. These terminal DNA-protein complexes function as protective caps preventing chromosomal end-to-end fusions and the recognition of chromosomal ends as damaged DNA [3]. Telomeres shorten with each cell division, eventually triggering senescence [4,5]. In contrast, majority of tumour cells overcome telomere-mediated senescence via the activation of telomerase enzyme [6].Telomerase contains two core components, an RNA subunit (hTERC and mTERC in human and mouse respectively), which provides the template for replenishment of telomeres [7] and a catalytic protein subunit, telomerase reverse transcriptase (hTERT or mTERT) that adds telomeric repeats to existing telomeres [8]. Deletion of mTERC in mice resulted in the shortening of telomeres leading to increased genomic instability and reduction in growth rate [9-11]. In addition, these studies have also demonstrated that no phenotypic differences occur in the first generation mice lacking mTERC component. The abrogation of telomerase results in the reduction in cell proliferation only after telomeres ar
Synergistic Interaction of Rnf8 and p53 in the Protection against Genomic Instability and Tumorigenesis
Marie-Jo Halaby,Anne Hakem,Li Li,Samah El Ghamrasni,Shriram Venkatesan,Prakash M. Hande,Otto Sanchez,Razqallah Hakem
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003259
Abstract: Rnf8 is an E3 ubiquitin ligase that plays a key role in the DNA damage response as well as in the maintenance of telomeres and chromatin remodeling. Rnf8?/? mice exhibit developmental defects and increased susceptibility to tumorigenesis. We observed that levels of p53, a central regulator of the cellular response to DNA damage, increased in Rnf8?/? mice in a tissue- and cell type–specific manner. To investigate the role of the p53-pathway inactivation on the phenotype observed in Rnf8?/? mice, we have generated Rnf8?/?p53?/? mice. Double-knockout mice showed similar growth retardation defects and impaired class switch recombination compared to Rnf8?/? mice. In contrast, loss of p53 fully rescued the increased apoptosis and reduced number of thymocytes and splenocytes in Rnf8?/? mice. Similarly, the senescence phenotype of Rnf8?/? mouse embryonic fibroblasts was rescued in p53 null background. Rnf8?/?p53?/? cells displayed defective cell cycle checkpoints and DNA double-strand break repair. In addition, Rnf8?/?p53?/? mice had increased levels of genomic instability and a remarkably elevated tumor incidence compared to either Rnf8?/? or p53?/? mice. Altogether, the data in this study highlight the importance of p53-pathway activation upon loss of Rnf8, suggesting that Rnf8 and p53 functionally interact to protect against genomic instability and tumorigenesis.
Thymoquinone Induces Telomere Shortening, DNA Damage and Apoptosis in Human Glioblastoma Cells
Resham Lal Gurung,Shi Ni Lim,Aik Kia Khaw,Jasmine Fen Fen Soon,Kirthan Shenoy,Safiyya Mohamed Ali,Manikandan Jayapal,Swaminathan Sethu,Rajamanickam Baskar,M. Prakash Hande
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012124
Abstract: A major concern of cancer chemotherapy is the side effects caused by the non-specific targeting of both normal and cancerous cells by therapeutic drugs. Much emphasis has been placed on discovering new compounds that target tumour cells more efficiently and selectively with minimal toxic effects on normal cells.
Genomic Instability, Defective Spermatogenesis, Immunodeficiency, and Cancer in a Mouse Model of the RIDDLE Syndrome
Toshiyuki Bohgaki equal contributor,Miyuki Bohgaki equal contributor,Renato Cardoso,Stephanie Panier,Dimphy Zeegers,Li Li,Grant S. Stewart,Otto Sanchez,M. Prakash Hande,Daniel Durocher,Anne Hakem ,Razqallah Hakem
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001381
Abstract: Eukaryotic cells have evolved to use complex pathways for DNA damage signaling and repair to maintain genomic integrity. RNF168 is a novel E3 ligase that functions downstream of ATM,γ-H2A.X, MDC1, and RNF8. It has been shown to ubiquitylate histone H2A and to facilitate the recruitment of other DNA damage response proteins, including 53BP1, to sites of DNA break. In addition, RNF168 mutations have been causally linked to the human RIDDLE syndrome. In this study, we report that Rnf168?/? mice are immunodeficient and exhibit increased radiosensitivity. Rnf168?/? males suffer from impaired spermatogenesis in an age-dependent manner. Interestingly, in contrast to H2a.x?/?, Mdc1?/?, and Rnf8?/? cells, transient recruitment of 53bp1 to DNA double-strand breaks was abolished in Rnf168?/? cells. Remarkably, similar to 53bp1 inactivation, but different from H2a.x deficiency, inactivation of Rnf168 impairs long-range V(D)J recombination in thymocytes and results in long insertions at the class-switch junctions of B-cells. Loss of Rnf168 increases genomic instability and synergizes with p53 inactivation in promoting tumorigenesis. Our data reveal the important physiological functions of Rnf168 and support its role in both γ-H2a.x-Mdc1-Rnf8-dependent and -independent signaling pathways of DNA double-strand breaks. These results highlight a central role for RNF168 in the hierarchical network of DNA break signaling that maintains genomic integrity and suppresses cancer development in mammals.
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