Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor kappa B (NF-kappa B) modulates the expression of numerous genes via interaction with a specific DNA sequence termed the kappa B site. Its activity is modulated by a cytosolic inhibitor protein termed I kappa B, and its activation occurs in response to a variety of agents in a variety of cell types, most notably B and T lymphocytes. Data presented here show that an activity (designated complex I) that binds specifically to the kappa B site is induced in density-arrested Balb/c-3T3 mouse fibroblasts by platelet-derived growth factor (PDGF), a potent mitogen for these cells. Increased levels of complex I, as evaluated by electrophoretic mobility shift assays of nuclear extracts, were observed in cells treated for 1-4 h (but not 15 min) with the BB isoform of PDGF. 12-O-tetradecanoylphorbol 13-acetate (TPA) and the AA isoform of PDGF also stimulated this response and both isoforms, but not TPA, were effective in cells depleted of protein kinase C. Complex I most likely is authentic NF-kappa B, a p50-p65 heterodimer, or a closely related factor because it exhibited properties characteristic of those previously described for NF-kappa B including inducibility by deoxycholate and cycloheximide and sensitivity to I kappa B. A second kappa B binding activity (complex II), which apparently contained p50 homodimers, displayed limited induction by PDGF, whereas a third complex (complex III) migrated faster than but behaved similarly to complex I. These studies suggest that NF-kappa B or an NF-kappa B-like factor may participate in the expression of PDGF-inducible genes.
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PMID:Induction of NF-kappa B-like activity by platelet-derived growth factor in mouse fibroblasts. 142 70

The human TNF promoter contains four potential nuclear factor-kappa B (NF-kappa B)-binding sites, with the strongest binding seen for the -605 motif. Nuclear extracts from unstimulated cells of the human monocytic cell line, Mono Mac 6, contain one specific binding protein (complex II), consistent with a constitutive p50 homodimer. Stimulation of Mono Mac 6 cells with LPS will increase complex II and will strongly induce a second specific complex (complex I), which represents the p50/65 heterodimer. Treatment of Mono Mac 6 cells with pyrrolidine-dithiocarbamate (PDTC) at 300 microM will block the LPS-induced complex I almost completely and will reduce complex II to the constitutive level. Binding activity of other nuclear factors that recognize the SP-1 and c/EBP motifs of the human TNF promoter is not affected by such treatment. Northern blot analysis demonstrates that PDTC treatment will strongly reduce LPS-induced TNF transcripts. Secreted TNF protein as detected in the Wehi 164S/ActD bioassay and in a sandwich immunoassay was similarly reduced by PDTC. Kinetic analyses show that after LPS stimulation, NF-kappa B will peak at 1 h, TNF transcript prevalence at 2 h, and TNF protein at 4 h. PDTC did not shift this response to LPS to a later time, but suppressed NF-kappa B mobilization, TNF transcripts, and TNF protein over the entire 8-h observation period. Analysis of freshly isolated, LPS-stimulated blood monocytes showed a similar blockade of NF-kappa B. Furthermore, in these primary cells, induction of TNF transcripts, as determined by Northern blot analysis and by quantitative polymerase chain reaction, was prevented by PDTC as was TNF protein production. These data show that dithiocarbamates can profoundly affect cytokine expression and suggest that NF-kappa B is involved in LPS-induced TNF gene expression in human monocytes.
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PMID:Pyrrolidine dithiocarbamate inhibits NF-kappa B mobilization and TNF production in human monocytes. 825 5

Oxygen levels in the intracellular microenvironment of tissues such as heart are extremely low, at 1-2% of standard atmospheric oxygen pressure. Kinetic studies with isolated mitochondria suggest a regulatory role of oxygen under these conditions, particularly in active states at high ADP concentration, when oxygen affinity was lower than in the resting state at ADP limitation. The oxygen pressure at 50% of maximum flux, p50, was 0.035 and 0.057 kPa in heart and liver mitochondria, respiring in state 3 on substrates for complex I or II and II, respectively. p50 in the resting state 4 was 0.02 kPa. The apparent kinetic efficiency, Jmax/p50, increased from the resting to the active state, despite the decrease of oxygen affinity, 1/p50. Consequently, the relative increase of respiratory flux by ADP activation, expressed as the adenylate control ratio, declined under hypoxia, but not to the extreme of a complete loss of the scope for activation, which would occur at constant Jmax/p50. High oxygen affinity is achieved by an excess capacity of cytochrome c oxidase relative to the respiratory chain and a correspondingly low turnover rate of this enzyme, consistent with the concept of kinetic trapping of oxygen [1].
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PMID:Mitochondrial respiration in the low oxygen environment of the cell. Effect of ADP on oxygen kinetics. 969 39

The role of nuclear factor kappa B (NF-kappaB) in oxidative stress, and most recently in pro- and anti-apoptotic-related mechanistic pathways, has well been established. Because of the dual nature of NF-kappaB, the wide range of genes it regulates and the plethora of stimuli that activate it, various studies addressing the functional role of NF-kappaB proteins have resulted in a number of differing findings. The present study examined the effect of a stimulus-free environment on the frontal cortex of mice brain with the p50 subunit of NF-kappaB knocked out p50 (-/-). Homozygous p50 mice knockout (KO) and wild type (WT) were used, and at 7-9 weeks they were sacrificed and various brain regions dissected. We analyzed the levels of oxidation in the frontal cortex of both the p50 (-/-) and WT mice. There was a significant reduction in the levels of protein-bound 4-hydroxynonenal (HNE) [a lipid peroxidation product], 3-nitrotyrosine (3NT), and protein carbonyls in the p50 (-/-) mice when compared to the WT. A proteomic profile analysis identified ATP synthase gamma chain, ubiquinol-cyt-C reductase, heat shock protein 10 (Hsp10), fructose bisphosphate aldolase C, and NADH-ubiquinone oxidoreductase as proteins whose expressions were significantly increased in the p50 (-/-) mice compared to the WT. With the reduction in the levels of oxidative stress and the increase in expression of key proteins in the p50 (-/-) brain, this study suggests that the p50 subunit can potentially be targeted for the development of therapeutic interventions in disorders in which oxidative stress plays a key role.
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PMID:Proteomic analysis of brain protein expression levels in NF-kappabeta p50 -/- homozygous knockout mice. 1881 63

Sexual dimorphism is apparent in humans, however, to date no studies have investigated mitochondrial function focusing on intrinsic mitochondrial respiration (i.e., mitochondrial respiration for a given amount of mitochondrial protein) and mitochondrial oxygen affinity (p50mito) in relation to biological sex in human. A skeletal muscle biopsy was donated by nine active women, and ten men matched for maximal oxygen consumption (VO2max) and by nine endurance trained men. Intrinsic mitochondrial respiration, assessed in isolated mitochondria, was higher in women compared to men when activating complex I (CIP) and complex I+II (CI+IIP) (p < 0.05), and was similar to trained men (CIP, p = 0.053; CI+IIP, p = 0.066). Proton leak and p50mito were higher in women compared to men independent of VO2max. In conclusion, significant novel differences in mitochondrial oxidative function, intrinsic mitochondrial respiration and p50mito exist between women and men. These findings may represent an adaptation in the oxygen cascade in women to optimize muscle oxygen uptake to compensate for a lower oxygen delivery during exercise.
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PMID:Superior Intrinsic Mitochondrial Respiration in Women Than in Men. 3017 17