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)

In vivo and in vitro studies have suggested a neuroprotective role for Pituitary adenylate cyclase activating polypeptide (PACAP) against neuronal insults. Here, we showed that PACAP27 protects against neurotoxicity induced by rotenone, a mitochondrial complex I inhibitor that has been implicated in the pathogenesis of Parkinson's disease (PD). The neuroprotective effect of PACAP27 was dose-dependent and blocked by its specific receptor antagonist, PACAP6-27. The effects of PACAP27 on rotenone-induced cell death were mimicked by dibutyryl-cAMP (db-cAMP), forskolin and prevented by the PKA inhibitor H89, the ERK inhibitor PD98059 and the p38 inhibitor SB203580. PACAP27 administration blocked rotenone-induced increases in the level of caspase-3-like activity, whereas could not restore mitochondrial activity damaged by rotenone. Thus, our results demonstrate that PACAP27 has a neuroprotective role against rotenone-induced neurotoxicity in neuronal differentiated PC12 cells and the neuroprotective effects of PACAP are associated with activation of MAP kinase pathways by PKA and with inhibition of caspase-3 activity; the signaling mechanism appears to be mediated through mitochondrial-independent pathways.
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PMID:PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex I inhibitor, rotenone. 1600 91

Incidence of Parkinson's disease (PD) is lower in women compared to men (1:1.46), which is reflected in animal models. However, precise mechanisms are unclear. Administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to female mice does not lead to mitochondrial complex I inhibition as seen in males and the progressive dopaminergic cell loss in substantia nigra (SNpc) is significantly attenuated. Redox driven apoptotic signaling pathways regulated by thiol disulfide oxidoreductase(s) have been implicated in the neurodegeneration seen in PD. Oxidation of thioredoxin leads to activation of apoptosis signal regulating kinase 1 (ASK1; MAPKKK) initiating cell death cascade through MAP kinase(s). Higher constitutive expression of enzymes involved in cellular redox maintenance, such as glutathione reductase, thioredoxin, and thioredoxin reductase is observed in female brain. Exposure to MPTP activates ASK1 in male but not in female mice. Higher expression of Trx in females potentially prevents ASK1 activation. Downstream of ASK1, phosphorylation of p38 MAP kinase is seen in male but not female mice. Expression of DJ-1, the redox sensing protein is higher in females and the loss of nuclear DJ-1, followed by translocation of Daxx (death associated protein) from the nucleus to the cytosol, which promotes ASK1 mediated death cascade is not seen in females. The enzymes involved in redox maintenance potentially could play a crucial role in preventing the activation of redox driven death signaling cascade and offer neuroprotection. Theraupeutic strategies that help maintain redox homeostasis may help prevent the progressive neurodegeneration seen in PD.
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PMID:Redox activated MAP kinase death signaling cascade initiated by ASK1 is not activated in female mice following MPTP: novel mechanism of neuroprotection. 1952 88

Rotenone is a widely used pesticide that induces Parkinson's disease-like symptoms in rats and death of dopaminergic neurons in culture. Although rotenone is a potent inhibitor of complex I of the mitochondrial electron transport chain, it can induce death of dopaminergic neurons independently of complex I inhibition. Here we describe effects of rotenone in the fission yeast, Schizosaccharomyces pombe, which lacks complex I and carries out rotenone-insensitive cellular respiration. We show that rotenone induces generation of reactive oxygen species (ROS) as well as fragmentation of mitochondrial networks in treated S. pombe cells. While rotenone is only modestly inhibitory to growth of wild type S. pombe cells, it is strongly inhibitory to growth of mutants lacking the ERK-type MAP kinase, Pmk1, or protein kinase A (PKA). In contrast, cells lacking the p38 MAP kinase, Spc1, exhibit modest resistance to rotenone. Consistent with these findings, we provide evidence that Pmk1 and PKA, but not Spc1, are required for clearance of ROS in rotenone treated S. pombe cells. Our results demonstrate the usefulness of S. pombe for elucidating complex I-independent molecular targets of rotenone as well as mechanisms conferring resistance to the toxin.
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PMID:The MAP kinase Pmk1 and protein kinase A are required for rotenone resistance in the fission yeast, Schizosaccharomyces pombe. 2065 79

Persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). One of the characteristics of HCV infection is the unusual augmentation of oxidative stress, which is exacerbated by iron accumulation in the liver, as observed frequently in hepatitis C patients. Using a transgenic mouse model, in which HCC develops late in life after the preneoplastic steatosis stage, the core protein of HCV was shown to induce the overproduction of reactive oxygen species (ROS) in the liver. In excessive generation of ROS, HCV affects the steady-state levels of a mitochondrial protein chaperone, i.e. prohibitin, leading to an impaired function of the mitochondrial respiratory chain with the overproduction of ROS. Insulin resistance and hepatic steatosis, which frequently accompany HCV infection, exacerbate ROS production. On the other hand, HCV compromises some of the antioxidant systems, including heme oxygenase-1 and NADH dehydrogenase quinone 1, resulting in the provocation of oxidative stress, together with ROS overproduction, in the liver with HCV infection. Thus, HCV infection not only induces ROS but also hampers the antioxidant system in the liver, thereby exacerbating oxidative stress that would facilitate hepatocarcinogenesis. Combination with the other activated pathway, including an alteration in the intracellular signaling cascade of MAP kinase, along with HCV-associated disturbances in lipid and glucose metabolism would lead to the unusual mode of hepatocarcinogenesis, i.e. very frequent and multicentric development of HCC, in persistent HCV infection.
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PMID:Hepatocarcinogenesis in hepatitis C: HCV shrewdly exacerbates oxidative stress by modulating both production and scavenging of reactive oxygen species. 2221 30

Cell migration is a fundamental cell biological process essential both for normal development and for tissue regeneration after damage. Cells can migrate individually or as a collective. To better understand the genetic requirements for collective migration, we expressed RNA interference (RNAi) against 30 genes in the Drosophila embryonic salivary gland cells that are known to migrate collectively. The genes were selected based on their effect on cell and membrane morphology, cytoskeleton and cell adhesion in cell culture-based screens or in Drosophila tissues other than salivary glands. Of these, eight disrupted salivary gland migration, targeting: Rac2, Rab35 and Rab40 GTPases, MAP kinase-activated kinase-2 (MAPk-AK2), RdgA diacylglycerol kinase, Cdk9, the PDSW subunit of NADH dehydrogenase (ND-PDSW) and actin regulator Enabled (Ena). The same RNAi lines were used to determine their effect during regeneration of X-ray-damaged larval wing discs. Cells translocate during this process, but it remained unknown whether they do so by directed cell divisions, by cell migration or both. We found that RNAi targeting Rac2, MAPk-AK2 and RdgA disrupted cell translocation during wing disc regeneration, but RNAi against Ena and ND-PDSW had little effect. We conclude that, in Drosophila, cell movements in development and regeneration have common as well as distinct genetic requirements.
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PMID:Regulators of cell movement during development and regeneration in Drosophila. 3103 76