title: Increasing NO level regulates apoptosis and inflammation in macrophages after 2-chloroethyl ethyl sulphide challenge.
abstract: Generation of nitric oxide (NO) in cellular compartments acts in a redox-dependent manner to counteract oxidative stress either by directly acting as an antioxidant through scavenging superoxide anions (O2-), to form peroxynitrite (ONOO-) or acting as a signaling molecule, altering gene expression that triggers various physiological processes. However, the molecular mechanisms of macrophage activation and NO production leads to apoptosis and inflammation after 2-chloroethyl ethyl sulphide (CEES) exposure remains unclear. We showed that CEES exposure in macrophages increased the O2-production. Also CEES exposure transiently increases the NO production and ONOO- accumulation via expression of inducible NO synthase (iNOS). Simultaneously, CEES exposure caused a significant reduction in cellular antioxidants and modulate lipid peroxidation (LPO), and protein carbonylation (PC) reactions, which was correlated with the increased level of NO and ONOO- accumulation. Mechanistic studies showed the DNA damage, 8-oxoGDNA glycosylase (OGG1) down regulation and 8-hydroxydeoxyguanosine (8-OHdG) accumulations in DNA, which was also confirmed by phosphorylation of ATM, ATR and H2A.X. Elevated levels of NO/ONOO- plays an important role in apoptosis, and alteration of cell cycle regulatory proteins in macrophages after CEES exposure. Moreover, CEES exposure to macrophage cells enhanced the transcriptional activities of inflammatory mediators such as TNFα, IL-1α, ICAM, CX3CL1, CCL8, and CXCL10, which were linked with NO/ONOO- accumulation. These results showed a mechanistic explanation of how NO/ONOO- cooperate to conduct apoptosis and inflammatory signals in macrophages after CEES challenged. Further, the protective effects of NO/ONOO- inhibitors may provide the basis for the development of a therapeutic strategy to counteract exposure to CEES.
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors.forename: Satish
authors.initials: S
authors.lastname: Sagar
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors.forename: Soumya Ranjan
authors.initials: SR
authors.lastname: Parida
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors.forename: Silpa
authors.initials: S
authors.lastname: Sabnam
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors.forename: Huma
authors.initials: H
authors.lastname: Rizwan
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors.forename: Sweta
authors.initials: S
authors.lastname: Pal
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors.forename: Mitali Madhusmita
authors.initials: MM
authors.lastname: Swain
authors.affiliation: School of Biotechnology, KIIT University, Bhubaneswar 751024, India; Department of Zoology, School of Life Sciences, Mahatma Gandhi Central University, Bihar 845401, India. Electronic address: arttatrana@yahoo.com.
authors.forename: Arttatrana
authors.initials: A
authors.lastname: Pal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D004249:DNA Damage; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D012333:RNA, Messenger; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C031278:2-chloroethyl ethyl sulfide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009151:Mustard Gas
keywords: Apoptosis; Biomolecules damage; CEES; Inflammation; NO