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Article ; Online: Current Perspective on the Role of the Circadian Clock and Extracellular Matrix in Chronic Lung Diseases.

Hahn, Kameron / Sundar, Isaac Kirubakaran

International journal of environmental research and public health

2023 Volume 20, Issue 3

Abstract: The circadian clock is a biochemical oscillator that rhythmically regulates physiological and behavioral processes such as inflammation, immunity, and metabolism in mammals. Circadian clock disruption is a key driver for chronic inflammatory as well as ... ...

Abstract	The circadian clock is a biochemical oscillator that rhythmically regulates physiological and behavioral processes such as inflammation, immunity, and metabolism in mammals. Circadian clock disruption is a key driver for chronic inflammatory as well as fibrotic lung diseases. While the mechanism of circadian clock regulation in the lung has been minimally explored, some evidence suggests that the transforming growth factor β (TGFβ) signaling pathway and subsequent extracellular matrix (ECM) accumulation in the lung may be controlled via a clock-dependent mechanism. Recent advancements in this area led us to believe that pharmacologically targeting the circadian clock molecules may be a novel therapeutic approach for treating chronic inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Here, we update the current perspective on the circadian clock role in TGFβ1 signaling and extracellular matrix production during chronic lung diseases.
MeSH term(s)	Animals ; Humans ; Chronic Disease ; Circadian Clocks/physiology ; Extracellular Matrix/metabolism ; Lung/metabolism ; Lung Diseases ; Mammals ; Pulmonary Disease, Chronic Obstructive
Chemical Substances	TGFB1 protein, human
Language	English
Publishing date	2023-01-30
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph20032455
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Article ; Online: p16-3MR: A Novel Model to Study Cellular Senescence in Cigarette Smoke-Induced Lung Injuries.

Kaur, Gagandeep / Sundar, Isaac K / Rahman, Irfan

International journal of molecular sciences

2021 Volume 22, Issue 9

Abstract: Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with ... ...

Abstract	Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16
MeSH term(s)	Aging/genetics ; Aging/pathology ; Animals ; Cellular Senescence/drug effects ; Cellular Senescence/genetics ; Cigarette Smoking/adverse effects ; Cigarette Smoking/genetics ; Cigarette Smoking/pathology ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Disease Models, Animal ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Fibronectins/genetics ; Gene Expression Regulation/genetics ; Humans ; Lung Injury/chemically induced ; Lung Injury/genetics ; Lung Injury/pathology ; Matrix Metalloproteinase 12/genetics ; Matrix Metalloproteinase 9/genetics ; Pulmonary Disease, Chronic Obstructive/chemically induced ; Pulmonary Disease, Chronic Obstructive/genetics ; Pulmonary Disease, Chronic Obstructive/pathology ; Pulmonary Emphysema/chemically induced ; Pulmonary Emphysema/genetics ; Pulmonary Emphysema/pathology ; Serpin E2/genetics
Chemical Substances	Cyclin-Dependent Kinase Inhibitor p16 ; Fibronectins ; Serpin E2 ; Serpine2 protein, mouse ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Mmp9 protein, mouse (EC 3.4.24.35) ; Matrix Metalloproteinase 12 (EC 3.4.24.65) ; matrix metallopeptidase 12, mouse (EC 3.4.24.65)
Language	English
Publishing date	2021-05-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22094834
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Article ; Online: p16-3MR

Gagandeep Kaur / Isaac K. Sundar / Irfan Rahman

International Journal of Molecular Sciences, Vol 22, Iss 4834, p

A Novel Model to Study Cellular Senescence in Cigarette Smoke-Induced Lung Injuries

2021 Volume 4834

Abstract	Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16 INK4a gene that enables detection, isolation, and selective elimination of senescent cells, thus making them a suitable model to study cellular senescence. To determine their suitability in CS-mediated lung pathologies, we exposed young (12–14 months) and old (17–20 months) p16-3MR mice to 30 day CS exposure and studied the expression of senescent genes (p16, p21, and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-exposed young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-exposed young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed alteration in the; (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-β-gal activity in CS-exposed young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model for studying the cellular senescence in CS-induced pathologies. Hence, the p16-3MR ...
Keywords	p16 ; mitochondrial dysfunction ; cellular senescence ; SASP ; cigarette smoke ; COPD ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Rev-erbα agonists suppresses TGFβ1-induced fibroblast-to-myofibroblast transition and pro-fibrotic phenotype in human lung fibroblasts.

Prasad, Chandrashekhar / Hahn, Kameron / Duraisamy, Santosh Kumar / Salathe, Matthias A / Huang, Steven K / Burris, Thomas P / Sundar, Isaac Kirubakaran

Biochemical and biophysical research communications

2023 Volume 669, Page(s) 120–127

Abstract: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by excessive scarring of the lungs that can lead to respiratory failure and death. Lungs of patients with IPF demonstrate excessive deposition of extracellular matrix (ECM) ...

Abstract	Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by excessive scarring of the lungs that can lead to respiratory failure and death. Lungs of patients with IPF demonstrate excessive deposition of extracellular matrix (ECM) and an increased presence of pro-fibrotic mediators such as transforming growth factor-beta 1 (TGFβ1), which is a major driver of fibroblast-to-myofibroblast transition (FMT). Current literature supports that circadian clock dysfunction plays an essential role in the pathophysiology of various chronic inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease, and IPF. The circadian clock transcription factor Rev-erbα is encoded by Nr1d1 that regulates daily rhythms of gene expression linked to immunity, inflammation, and metabolism. However, investigations into the potential roles of Rev-erbα in TGFβ-induced FMT and ECM accumulation are limited. In this study, we utilized several novel small molecule Rev-erbα agonists (GSK41122, SR9009, and SR9011) and a Rev-erbα antagonist (SR8278) to determine the roles of Rev-erbα in regulating TGFβ1-induced FMT and pro-fibrotic phenotypes in human lung fibroblasts. WI-38 cells were either pre-treated/co-treated with or without Rev-erbα agonist/antagonist along with TGFβ1. After 48 h, the following parameters were evaluated: secretion of COL1A1 (Slot-Blot analysis) and IL-6 (ELISA) into condition media, expressions of α-smooth muscle actin (αSMA: immunostaining and confocal microscopy), and pro-fibrotic proteins (αSMA and COL1A1 by immunoblotting), as well as gene expression of pro-fibrotic targets (qRT-PCR: Acta2, Fn1, and Col1a1). Results revealed that Rev-erbα agonists inhibited TGFβ1-induced FMT (αSMA and COL1A1), and ECM production (reduced gene expression of Acta2, Fn1, and Col1a1), and decreased pro-inflammatory cytokine IL-6 release. The Rev-erbα antagonist promoted TGFβ1-induced pro-fibrotic phenotypes. These findings support the potential of novel circadian clock-based therapeutics, such as Rev-erbα agonist, for the treatment and management of fibrotic lung diseases and disorders.
MeSH term(s)	Humans ; Myofibroblasts/metabolism ; Interleukin-6/metabolism ; Lung/pathology ; Fibrosis ; Idiopathic Pulmonary Fibrosis/pathology ; Fibroblasts/metabolism ; Phenotype ; Chronic Disease ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism
Chemical Substances	Interleukin-6 ; Nuclear Receptor Subfamily 1, Group D, Member 1
Language	English
Publishing date	2023-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2023.05.092
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Article ; Online: Proteomic Analysis of Plasma-Derived Extracellular Vesicles in Smokers and Patients with Chronic Obstructive Pulmonary Disease

Isaac K. Sundar / Dongmei Li / Irfan Rahman

ACS Omega, Vol 4, Iss 6, Pp 10649-

2019 Volume 10661

Keywords	Chemistry ; QD1-999
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	American Chemical Society
Document type	Article ; Online
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Article ; Online: Mitochondrial dysfunction is associated with Miro1 reduction in lung epithelial cells by cigarette smoke.

Sundar, Isaac K / Maremanda, Krishna P / Rahman, Irfan

Toxicology letters

2019 Volume 317, Page(s) 92–101

Abstract: Cigarette smoke (CS) is known to cause mitochondrial dysfunction leading to cellular senescence in lung cells. We determined the mechanism of mitochondrial dysfunction by CS in lung epithelial cells. CS extract (CSE) treatment differentially affected ... ...

Abstract	Cigarette smoke (CS) is known to cause mitochondrial dysfunction leading to cellular senescence in lung cells. We determined the mechanism of mitochondrial dysfunction by CS in lung epithelial cells. CS extract (CSE) treatment differentially affected mitochondrial function, such as membrane potential, mitochondrial reactive oxygen species (mtROS) and mitochrondrial mass as analyzed by FACS, and were associated with altered oxidative phosphorylation (OXPHOS) protein levels (Complexes I-IV) in primary lung epithelial cells (SAEC and NHBE), and (complexes I and II) in BEAS2B cells. There were dose- and time-dependent changes in mitochondrial respiration (oxygen consumption rate parameters i.e. maximal respiration, ATP production and spare capacity, measured by the Seahorse analyzer) in control vs. CSE treated BEAS2B and NHBE/DHBE cells. Electron microscopy (EM) analysis revealed perinuclear clustering by localization and increased mitochondrial fragmentation by fragement length analysis. Immunoblot analysis revealed CS-mediated increase in Drp1 and decrease in Mfn2 levels that are involved in mitochondrial fission/fusion process. CSE treatment reduced Miro1 and Pink1 abundance that play a crucial role in the intercellular transfer mechanism and mitophagy process. Overall, these findings highlight the role of Miro1 in context of CS-induced mitochondrial dysfunction in lung epithelial cells that may contribute to the pathogenesis of chronic inflammatory lung diseases.
MeSH term(s)	Case-Control Studies ; Cells, Cultured ; Cigarette Smoking/adverse effects ; Down-Regulation ; Energy Metabolism ; Epithelial Cells/metabolism ; Epithelial Cells/ultrastructure ; Humans ; Lung/metabolism ; Lung/ultrastructure ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Mitochondrial Proteins/metabolism ; Mitophagy ; Oxidative Stress ; Pulmonary Disease, Chronic Obstructive/etiology ; Pulmonary Disease, Chronic Obstructive/metabolism ; Pulmonary Disease, Chronic Obstructive/pathology ; Signal Transduction ; Smoke/adverse effects ; rho GTP-Binding Proteins/metabolism
Chemical Substances	Mitochondrial Proteins ; Smoke ; RHOT1 protein, human (EC 3.6.1.-) ; rho GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2019-10-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	433788-8
ISSN	1879-3169 ; 0378-4274
ISSN (online)	1879-3169
ISSN	0378-4274
DOI	10.1016/j.toxlet.2019.09.022
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Article: Age-Dependent Assessment of Genes Involved in Cellular Senescence, Telomere, and Mitochondrial Pathways in Human Lung Tissue of Smokers, COPD, and IPF: Associations With SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis.

Maremanda, Krishna P / Sundar, Isaac K / Li, Dongmei / Rahman, Irfan

Frontiers in pharmacology

2020 Volume 11, Page(s) 584637

Abstract: Background: Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial ... ...

Abstract	Background: Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of COPD and idiopathic pulmonary fibrosis (IPF). Methods: Total RNA from the human lung tissues of non-smokers, smokers, and patients with COPD and IPF were processed and analyzed using a Nanostring platform based on their ages (younger: <55 years and older: >55 years). Results: Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function ( Conclusions: Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in COPD and IPF is associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis as pharmacological targets for COVID-19.
Keywords	covid19
Language	English
Publishing date	2020-09-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2020.584637
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Article: Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis.

Maremanda, Krishna P / Sundar, Isaac K / Li, Dongmei / Rahman, Irfan

Research square

2020

Abstract: Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving ... ...

Abstract	Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with COPD and IPF compared to non-smokers. Total RNA from human lung tissues from non-smokers, smokers, and patients with COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 & 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 & 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases. Elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers, COPD and IPF subjects revealed increased protein abundance of important proteases and spike proteins like TMPRSS2, furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers, COPD and IPF subjects are more prone to COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in COPD and IPF and other smoking-related chronic lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for COVID-19 infection.
Keywords	covid19
Language	English
Publishing date	2020-06-15
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-35347/v1
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Article ; Online: Molecular clock REV-ERBα regulates cigarette smoke-induced pulmonary inflammation and epithelial-mesenchymal transition.

Wang, Qixin / Sundar, Isaac K / Lucas, Joseph H / Muthumalage, Thivanka / Rahman, Irfan

JCI insight

2021 Volume 6, Issue 12

Abstract: Cigarette smoke (CS) is the main etiological factor in the pathogenesis of emphysema/chronic obstructive pulmonary disease (COPD), which is associated with abnormal epithelial-mesenchymal transition (EMT). Previously, we have shown an association among ... ...

Abstract	Cigarette smoke (CS) is the main etiological factor in the pathogenesis of emphysema/chronic obstructive pulmonary disease (COPD), which is associated with abnormal epithelial-mesenchymal transition (EMT). Previously, we have shown an association among circadian rhythms, CS-induced lung inflammation, and nuclear heme receptor α (REV-ERBα), acting as an antiinflammatory target in both pulmonary epithelial cells and fibroblasts. We hypothesized that molecular clock REV-ERBα plays an important role in CS-induced circadian dysfunction and EMT alteration. C57BL/6J WT and REV-ERBα heterozygous (Het) and -KO mice were exposed to CS for 30 days (subchronic) and 4 months (chronic), and WT mice were exposed to CS for 10 days with or without REV-ERBα agonist (SR9009) administration. Subchronic/chronic CS exposure caused circadian disruption and dysregulated EMT in the lungs of WT and REV-ERBα-KO mice; both circadian and EMT dysregulation were exaggerated in the REV-ERBα-KO condition. REV-ERBα agonist, SR9009 treatment reduced acute CS-induced inflammatory response and abnormal EMT in the lungs. Moreover, REV-ERBα agonist (GSK4112) inhibited TGF-β/CS-induced fibroblast differentiation in human fetal lung fibroblast 1 (HFL-1). Thus, CS-induced circadian gene alterations and EMT activation are mediated through a Rev-erbα-dependent mechanism, which suggests activation of REV-ERBα as a novel therapeutic approach for smoking-induced chronic inflammatory lung diseases.
MeSH term(s)	Animals ; Epithelial-Mesenchymal Transition/drug effects ; Epithelial-Mesenchymal Transition/genetics ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism ; Pneumonia/chemically induced ; Pneumonia/metabolism ; Smoke/adverse effects
Chemical Substances	Nr1d1 protein, mouse ; Nuclear Receptor Subfamily 1, Group D, Member 1 ; Smoke
Language	English
Publishing date	2021-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.145200
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Article ; Online: Gene expression profiling of epigenetic chromatin modification enzymes and histone marks by cigarette smoke: implications for COPD and lung cancer.

Sundar, Isaac K / Rahman, Irfan

American journal of physiology. Lung cellular and molecular physiology

2016 Volume 311, Issue 6, Page(s) L1245–L1258

Abstract: Chromatin-modifying enzymes mediate DNA methylation and histone modifications on recruitment to specific target gene loci in response to various stimuli. The key enzymes that regulate chromatin accessibility for maintenance of modifications in DNA and ... ...

Abstract	Chromatin-modifying enzymes mediate DNA methylation and histone modifications on recruitment to specific target gene loci in response to various stimuli. The key enzymes that regulate chromatin accessibility for maintenance of modifications in DNA and histones, and for modulation of gene expression patterns in response to cigarette smoke (CS), are not known. We hypothesize that CS exposure alters the gene expression patterns of chromatin-modifying enzymes, which then affects multiple downstream pathways involved in the response to CS. We have, therefore, analyzed chromatin-modifying enzyme profiles and validated by quantitative real-time PCR (qPCR). We also performed immunoblot analysis of targeted histone marks in C57BL/6J mice exposed to acute and subchronic CS, and of lungs from nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). We found a significant increase in expression of several chromatin modification enzymes, including DNA methyltransferases, histone acetyltransferases, histone methyltransferases, and SET domain proteins, histone kinases, and ubiquitinases. Our qPCR validation data revealed a significant downregulation of Dnmt1, Dnmt3a, Dnmt3b, Hdac2, Hdac4, Hat1, Prmt1, and Aurkb We identified targeted chromatin histone marks (H3K56ac and H4K12ac), which are induced by CS. Thus CS-induced genotoxic stress differentially affects the expression of epigenetic modulators that regulate transcription of target genes via DNA methylation and site-specific histone modifications. This may have implications in devising epigenetic-based therapies for COPD and lung cancer.
MeSH term(s)	Acetylation ; Animals ; Bronchi/pathology ; Chromatin/metabolism ; Databases, Genetic ; Epigenesis, Genetic ; Epithelial Cells/metabolism ; Gene Expression Profiling ; Histone Acetyltransferases/metabolism ; Histone Code/genetics ; Histone Deacetylases/metabolism ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/metabolism ; Humans ; Lung/metabolism ; Lung/pathology ; Lung Neoplasms/genetics ; Mice, Inbred C57BL ; Phosphorylation ; Pulmonary Disease, Chronic Obstructive/genetics ; Smoking/genetics ; Ubiquitination
Chemical Substances	Chromatin ; Histones ; Histone Methyltransferases (EC 2.1.1.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Histone Acetyltransferases (EC 2.3.1.48) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2016-10-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00253.2016
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