A5103002081- DNA Repair Mechanisms
- Synthesis of Organic Compounds
- Phytochemicals and Medicinal Plants
- Ubiquitin and proteasome pathways
- Synthesis and Biological Activity
- Nutrition and Health in Aging
- Telomeres, Telomerase, and Senescence
- Complementary and Alternative Medicine Studies
- Synthesis and Reactions of Organic Compounds
- Nuclear Structure and Function
- Biomedical and Chemical Research
- Carcinogens and Genotoxicity Assessment
- Genomics and Chromatin Dynamics
- Adipokines, Inflammation, and Metabolic Diseases
- Hemoglobinopathies and Related Disorders
- Cancer-related molecular mechanisms research
- Chemical Synthesis and Analysis
- Plant Genetic and Mutation Studies
- Cytokine Signaling Pathways and Interactions
- Genetic and Kidney Cyst Diseases
- Cholesterol and Lipid Metabolism
- Radiopharmaceutical Chemistry and Applications
- X-ray Diffraction in Crystallography
- Muscle Physiology and Disorders
- Monoclonal and Polyclonal Antibodies Research
Chameli Devi Institute of Pharmacy
2024
The University of Texas Southwestern Medical Center
2010-2024
Mubarak Al Kabeer Hospital
2007-2024
Southwestern Medical Center
2013-2024
Jai Prakash Vishwavidyalaya
2015-2023
Center for Human Genetics
2023
National Institute of Mental Health and Neurosciences
2021
Scheer Memorial Adventist Hospital
2020
Guru Gobind Singh Indraprastha University
2020
Banaras Hindu University
2017
The human MOF gene encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac). Here we show reduced levels of H4K16ac correlate with defective DNA damage response (DDR) and double-strand break (DSB) repair to ionizing radiation (IR). defect, however, is not due altered expression proteins involved in DDR. Abrogation IR-induced DDR by depletion inhibited blocking deacetylation. was found be associated the DNA-dependent kinase catalytic subunit (DNA-PKcs), nonhomologous...
Heat shock proteins (HSPs) are highly conserved among all organisms from prokaryotes to eukaryotes.In mice, the HSP genes Hsp70.1 and Hsp70.3 induced by both endogenous exogenous stressors, such as heat toxicants.In order determine whether specifically influence genomic instability, mice deficient for (Hsp70.1/3؊/؊ mice) were generated gene targeting.Mouse embryonic fibroblasts (MEFs) prepared Hsp70.1/3 ؊/؊ did not synthesize or after heat-induced stress.While Hsp70.1/3؊/؊ mutant fertile,...
We have determined that hMOF, the human ortholog of Drosophila MOF gene (males absent on first), encoding a protein with histone acetyltransferase activity, interacts ATM (ataxia-telangiectasia-mutated) protein. Cellular exposure to ionizing radiation (IR) enhances hMOF-dependent acetylation its target substrate, lysine 16 (K16) H4 independently function. Blocking IR-induced increase in at K16, either by expression dominant negative mutant ΔhMOF or RNA interference-mediated hMOF knockdown,...
The mammalian ortholog of the Drosophila MOF (males absent on first) gene product is a histone H4 lysine 16-specific acetyltransferase. Recent studies have shown that depletion human (hMOF) in cell lines leads to genomic instability, spontaneous chromosomal aberrations, cycle defects, altered nuclear morphology, reduced transcription certain genes, and defective DNA damage response ionizing radiation (IR). Here we show plays an essential role mammals during embryogenesis oncogenesis....
Abstract All cells have intricately coupled sensing and signaling mechanisms that regulate the cellular outcome following exposure to genotoxic agents such as ionizing radiation (IR). In IR-induced pathway, specific protein events, ataxia-telangiectasia mutated (ATM) activation histone H2AX phosphorylation (γ-H2AX), are mechanistically well characterized. How these can be altered, especially by clinically relevant agents, is not clear. Here we show hyperthermia, an effective radiosensitizer,...
The human LMNA gene encodes the essential nuclear envelope proteins lamin A and C (lamin A/C). Mutations in result altered morphology, but how this impacts mechanisms that maintain genomic stability is unclear. Here, we report A/C-deficient cells have a normal response to ionizing radiation are sensitive agents cause interstrand cross-links (ICLs) or replication stress. In treatment with ICL (cisplatin, camptothecin, mitomycin), displayed γ-H2AX focus formation higher frequency of delayed...
The protein products of several rad checkpoint genes Schizosaccharomyces pombe (rad1+, rad3 +, rad9 rad17 rad26 and hus1 +) play crucial roles in sensing changes DNA structure, function the maintenance telomeres. When mammalian homologue S. Rad9 was inactivated, increases chromosome end-to-end associations frequency telomere loss were observed. This instability correlated with enhanced S- G2-phase-specific cell killing, delayed kinetics γ-H2AX focus appearance disappearance, reduced...
AbstractChromosomes in PTEN deficient cells display both numerical as well structural alterations including regional amplification. We found that displayed a normal DNA damage response (DDR) evidenced by the ionizing radiation (IR)-induced phosphorylation of Ataxia Telangiectasia Mutated (ATM) its effectors. also had no defect Rad51 expression or repair kinetics post irradiation. In contrast, caffeine treatment specifically increased IR-induced chromosome aberrations and mitotic index only...
Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and phosphorylated colocalizes with γ-H2AX, ATM, 53BP1 foci. Mutation site (MOF-T392A) impedes in S G2 but not G1 cells. Expression MOF-T392A also blocks reduction DSB-associated seen wild-type S/G2 cells,...
Cachexia syndrome consists of adipose and muscle loss, often despite normal food intake. We hypothesized that cachexia-associated wasting is driven in part by tumor humoral factors induce adipocyte lipolysis. developed an assay to purify secreted from a cachexia-inducing colon cancer line increases lipolysis adipocytes identified leukemia inhibitory factor (LIF) mass spectrometry. Recombinant LIF induced vitro. Peripheral administered mice caused >50% loss tissue >10% reduction body weight...
In order to survive, cells have evolved highly effective repair mechanisms deal with the potentially lethal DNA damage produced by exposure endogenous as well exogenous agents. Ionizing radiation induces damage, especially double-strand breaks (DSBs), that is sensed cellular machinery and then subsequently repaired either of two different DSB mechanisms: (1) non-homologous end joining, which re-ligates broken ends (2) homologous recombination, employs an undamaged identical sequence a...
The effects of ketoconazole, a lanosterol demethylase and cytochrome P450 inhibitor, on the regulation 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34, reductase) activity sterol biosynthesis were studied in rat intestinal epithelial cell cultures (IEC-6). Incubation cells with 0.15-2 microM ketoconazole resulted concentration-dependent inhibition activity. As drug concentration approached 15 microM, returned to control values, at 30 stimulation enzyme was observed. had no...
Despite our understanding that medial smooth muscle hypertrophy is a central feature of vascular remodeling, the molecular pathways underlying this pathology are still not well understood. Work over past decade has illustrated potential role for multifunctional calmodulin-dependent kinase CaMKII in cell contraction, growth, and migration. Here we demonstrate enriched (VSM) inhibition blocks ANG II-dependent VSM vitro vivo. Specifically, systemic with KN-93 prevented II-mediated hypertension...
Mycobacterium tuberculosis utilizes many mechanisms to establish itself within the macrophage, and bacterially derived cAMP is important in modulating host cellular response. Although genome of M. endowed with a number mammalian-like adenylyl cyclases, only single phosphodiesterase has been identified that can decrease levels produced by bacterium. We present crystal structure full-length sole phosphodiesterase, Rv0805, found tuberculosis, whose orthologs are genomes slow growing pathogenic...
Telomeres are associated with the nuclear matrix and thought to be heterochromatic. We show here that in human cells overexpression of green fluorescent protein-tagged heterochromatin protein 1 (GFP-HP1) or nontagged HP1 isoforms HP1(Hsalpha) HP1(Hsbeta), but not HP1(Hsgamma), results decreased association a catalytic unit telomerase (hTERT) telomeres. However, reduction G overhangs overall telomere sizes was found overexpressing any these three proteins. Cells HP1(Hsbeta) also display...
The authors reviewed preoperative MRI and EEG findings in relation to postsurgical outcome 17 patients with refractory epilepsy due tuberous sclerosis complex (TSC). Resecting concordant (main tuber) abnormalities offered seizure freedom (8/9, 89%; median follow-up 25 months) comparable other focal etiologies. Patients nonconcordant did less well (3/8, 38%, free; p = 0.027, OR 13).
In this study, antidepressant-like activity of Emblica offcinalis Gaertn. fruits (Family: Euphorbiaceae) was evaluated in Swiss young male albino mice employing tail suspension test and forced swim test.Aqueous extract (200 400 mg/kg) the administered orally for 14 successive days to mice. On day 14, 60 min after administration, animals were subjected test.The significantly decreased immobility period both test, indicating significant activity. The lower dose showed better action. efficacy...
Cachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukemia inhibitory factor (LIF) which induces cachexia. We characterized how LIF promotes cachexia-associated weight loss anorexia mice through JAK-dependent changes hypothalamic tissues.Cachexia was induced vivo heterotopic allotransplanted administration cells or intraperitoneal recombinant absence...
The brains of ataxia telangiectasia (AT) patients display an aberrant loss Purkinje cells (PCs) that is postulated to contribute the observed deficits in motor coordination as well learning and cognitive function. AT have mutations mutated (ATM) gene [Savitsky et al. (1995) Science 268:1749-1753]. However, Atm-deficient mice, neurological defects are limited, PCs not deformed or lost [Barlow (1996) Cell 86:159-171]. Here we report PC-specific deletion mouse males absent on first (mMof)...
Ataxia telangiectasia patients develop lymphoid malignancies of both B- and T-cell origin. Similarly, ataxia mutated (Atm)-deficient mice exhibit severe defects in maturation eventually thymomas. The function ATM is known to be influenced by the mammalian orthologue Drosophila MOF (males absent on first) gene. Here, we report effect T-cell-specific ablation mouse Mof (Mof) gene leucocyte trafficking survival. Conditional MofFlox/Flox (MofF/F) expressing Cre recombinase under control Lck...
Adipose tissue inflammation is observed in multiple metabolically-altered states including cancer-associated cachexia and obesity. Although a syndrome of adipose loss obesity disease excess, both pathologies demonstrate increases circulating levels IL-6 family cytokines, β-adrenergic signaling, adipocyte lipolysis. While β-adrenergic-stimulated lipolysis well described, there limited mechanistic insight into how cancer cachexia-associated inflammatory cytokines contribute to under pathologic...
Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed 50% patients with solid tumors. Management CC limited by the absence biomarkers knowledge molecules that drive its phenotype. To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 which produced an unambiguous phenotype or non-cachexia. Whole-exome sequencing revealed 8 10 lines, but none non-cachexia possessed mutations...