Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We showed previously that type I interferon causes a down-regulation of mitochondrial gene expression. We show here that IFN treatment leads to functional impairment of mitochondria. Western blot analysis indicated that interferon treatment reduces the steady-state level of cytochrome b in murine L-929 cells. Interferon produced a reduction in cytochrome c oxidase and NADH-cytochrome c reductase activities of isolated mitochondria as well as inhibiting electron transport in isolated mitochondria and in intact cells. Several mitochondrial mRNAs are affected by interferon treatment in human Daudi lymphoblastoid cells, which are highly sensitive to the antiproliferative effects of interferon. Electron transport in Daudi cells was also inhibited by interferon both in intact cells and isolated mitochondria with a dose response identical to that for the antiproliferative response. In contrast, a Daudi strain resistant to the antiproliferative effects of interferon showed no down-regulation of mRNA expression and no inhibition of electron transport. Possibly as a consequence of the inhibitory effect on mitochondrial gene expression, treatment with interferon causes a reduction in cellular ATP levels. The inhibition of cellular growth by interferon may thus be partly a consequence of a reduction in cellular ATP levels.
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PMID:Inhibition of mitochondrial function by interferon. 866 94

Nitric oxide synthase (NOS) isoenzymes generate nitric oxide (NO), a sensitive multifunctional intercellular signal molecule. High NO levels are produced by an inducible NOS (iNOS) in activated macrophages in response to proinflammatory agents, many of which also regulate local bone metabolism. NO is a potent inhibitor of osteoclast bone resorption, whereas inhibitors of NOS promote bone resorption both in vitro and in vivo. The possibility that osteoclasts, like macrophages, express a regulated iNOS and produce NO as a potential autocrine signal following inflammatory stimulation was investigated in well-characterized avian marrow-derived osteoclast-like cells. NO production (reflected by medium nitrite levels) was markedly elevated in these cells by the proinflammatory agents lipopolysaccharide (LPS) and the synergistic action of IL-1 alpha, TNF alpha, and IFN gama. inhibitors of NOS activity (aminoguanidine, L-NAME) or iNOS induction (dexamethasone, TGF beta) reduced LPS-stimulated nitrite production. LPS also increased the NOS-associated diaphorase activity of these cells and their reactivity with anti-iNOS antibodies. RT-PCR cloning, using avian osteoclast-like cell RNA and human iNOS primers, yielded a novel 900 bp cDNA with high sequence homology (76%) to human, rat, and mouse iNOS genes. In probing osteoclast-like cell RNA with the PCR-derived iNOS cDNA, a 4.8 kb mRNA species was detected whose levels were greatly increased by LPS. Induction of iNOS mRNA by LPS, or by proinflammatory cytokines, occurred prior to the rise of medium nitrite in time course studies and was diminished by dexamethasone. Moreover, osteoclast-like cells demonstrated an upregulation of NO production and iNOS mRNA by IL-8 and IL-10, regulatory mechanism's not previously described. It is concluded that osteoclast-like cells express a novel iNOS that is upregulated by inflammatory mediators, leading to NO production. Therefore, NO may serve as both a paracrine and autocrine signal for modulating osteoclast bone resorption.
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PMID:Proinflammatory agents, IL-8 and IL-10, upregulate inducible nitric oxide synthase expression and nitric oxide production in avian osteoclast-like cells. 870 87