Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00369 (ROS)
 19,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AMP-activated protein kinase influences cellular metabolism, glucose-regulated gene expression, and insulin secretion of pancreatic beta cells. Its sustained activation by culture at low glucose concentrations or in the presence of 5-aminoimidazole-4-carboxamide riboside (AICAR) was shown to trigger apoptosis in beta cells. This study shows that both low glucose- and AICAR-induced apoptosis are associated with increased formation of mitochondrial superoxide-derived radicals and decreased mitochondrial activity. Mitochondrial dysfunction was reflected by an increased oxidized state of the mitochondrial flavins (FMN/FAD) but not of NAD(P)H. It was accompanied by suppression of glucose oxidation and glucose-induced insulin secretion, while palmitate oxidation appeared unaffected. When the cellular accumulation of superoxide-derived radicals was quenched by the ROS scavengers vitamin E, N-acetylcysteine, or the SOD-mimetic compound MnTBAP, apoptosis was significantly inhibited. Both low glucose and AICAR also elevated the expression of BH3-domain-only Bcl-2 antagonists, and induced caspase-3 activation, causing caspase-dependent truncation of Bcl-2. Overexpression of recombinant human Bcl-2 prevented caspase-3 activation, endogenous Bcl-2 processing, and apoptosis, but did not attenuate oxygen radical formation, AMPK activation, or JNK phosphorylation. We conclude that apoptosis by prolonged AMPK activation in beta cells results from enhanced production of mitochondria-derived oxygen radicals and onset of the intrinsic mitochondrial apoptosis pathway, followed by caspase activation and Bcl-2 cleavage which may amplify the death signal.
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PMID:Increased oxygen radical formation and mitochondrial dysfunction mediate beta cell apoptosis under conditions of AMP-activated protein kinase stimulation. 1715 94

This study was undertaken to examine the effect of low and high concentrations of H2O2 on cancer cell proliferation and apoptosis, and AMPK signaling pathways in HT-29 human colon cancer cells. Nontoxic doses of H2O2 (10 microM) induced cancer cell proliferation, whereas the toxic level of 1,000 microM H2O2 induced apoptosis. The stimulation of cell proliferation was accompanied with an increase in cyclooxygenase-2 (COX-2), and apoptosis induced by high-dose H2O2 was correlated with the activation of AMPK and negatively correlated with COX-2 expression. These results suggest that ROS at nontoxic levels can stimulate cancer cell growth by regulating AMP-activated protein kinase (AMPK) and/or COX-2, and the abundant exogenous ROS linked to the growth inhibition through modulating AMPK signaling pathways.
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PMID:Differential modulation of AMPK signaling pathways by low or high levels of exogenous reactive oxygen species in colon cancer cells. 1734 7

Deletion mutations of mitochondrial DNA (mtDNA) accumulate somatically on a cell-by-cell basis with age, resulting in decreased cell function in muscle and substantia nigra. In osteosarcoma cells deletions incapacitate mitochondria and induce the autophagic transcript ATG12, which is involved in an early step of the mammalian autophagy pathway. We discuss here which consequences of mtDNA deletions could induce ATG12, and provide two new pieces of data. Our previous studies demonstrated that mtDNA deletions decreased mitochondrial ATP production and proteasomal function, induced the AMPK transcript (likely as a consequence of bioenergetic depletion), and decreased the intracellular concentration of 20 amino acids (possibly as a consequence of decreased proteasomal activity). Deletions eliminate essential tRNAs for mitochondrial protein synthesis, as well as essential components of mitochondrial multisubunit enzymes; therefore, the increased level of ATG12 could result from decreased bioenergetic function, increased oxidative damage, or decreased mitochondrial protein synthesis. However, the bioenergetic inhibitor rotenone does not induce ATG12. We show here that chloramphenicol, which inhibits mitochondrial protein synthesis, induces ATG12, and that mtDNA deletions result in an increased burden of oxidatively damaged protein. Thus, mtDNA deletions could induce ATG12 through a mechanism such as the following: deletions > mitochondrial protein synthesis inhibition or ROS > proteasome inhibition > amino acid depletion > ATG12.
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PMID:Mitochondrial DNA deletions and chloramphenicol treatment stimulate the autophagic transcript ATG12. 1715 91

Metabolic disorders such as obesity are major obstacles in improving the average life span. Therefore, a therapeutic approach using natural compounds has been proposed as a novel strategy for preventing metabolic disorders. Ginsenoside Rh2 is one of the ginsenosides that exert anti-diabetes, anti-inflammatory, and anti-cancer effects. However, the anti-obesity effects of Ginsenoside Rh2 remain unclear. Here, we investigated the anti-obesity ability of ginsenoside Rh2 using cell culture systems. Ginsenoside Rh2 effectively inhibited adipocyte differentiation via PPAR-gamma inhibition. Next, to find specific target molecules based on this result, we used cell culture systems to examine whether AMPK activation was involved in the anti-obesity ability of ginsenoside Rh2 since several published papers have indicated that AMPK signaling is involved in the regulation of metabolic disorders. Ginsenoside Rh2 significantly activated AMPK in 3T3-L1 adipocytes. In addition, we also examined the effect of AMPK on lipolysis molecules such as CPT-1 and UCP-2 by using an AMPK inhibitor. Ginsenoside Rh2 effectively induced CPT-1 and UCP-2 and this induction was abolished by AMPK inhibitor treatment. Moreover, we observed that ROS is an important upstream signal for AMPK activation during ginsenoside Rh2 treatment. Taken together, these results indicate that ginsenoside Rh2 is the most effective candidate for preventing metabolic disorders such as obesity and that it acts via the AMPK signaling pathway. Thus, AMPK signaling might contribute toward improving human health.
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PMID:Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3T3-L1 adipocyte. 1797 Dec 95

Hypercapnia (elevated CO(2) levels) occurs as a consequence of poor alveolar ventilation and impairs alveolar fluid reabsorption (AFR) by promoting Na,K-ATPase endocytosis. We studied the mechanisms regulating CO(2)-induced Na,K-ATPase endocytosis in alveolar epithelial cells (AECs) and alveolar epithelial dysfunction in rats. Elevated CO(2) levels caused a rapid activation of AMP-activated protein kinase (AMPK) in AECs, a key regulator of metabolic homeostasis. Activation of AMPK was mediated by a CO(2)-triggered increase in intracellular Ca(2+) concentration and Ca(2+)/calmodulin-dependent kinase kinase-beta (CaMKK-beta). Chelating intracellular Ca(2+) or abrogating CaMKK-beta function by gene silencing or chemical inhibition prevented the CO(2)-induced AMPK activation in AECs. Activation of AMPK or overexpression of constitutively active AMPK was sufficient to activate PKC-zeta and promote Na,K-ATPase endocytosis. Inhibition or downregulation of AMPK via adenoviral delivery of dominant-negative AMPK-alpha(1) prevented CO(2)-induced Na,K-ATPase endocytosis. The hypercapnia effects were independent of intracellular ROS. Exposure of rats to hypercapnia for up to 7 days caused a sustained decrease in AFR. Pretreatment with a beta-adrenergic agonist, isoproterenol, or a cAMP analog ameliorated the hypercapnia-induced impairment of AFR. Accordingly, we provide evidence that elevated CO(2) levels are sensed by AECs and that AMPK mediates CO(2)-induced Na,K-ATPase endocytosis and alveolar epithelial dysfunction, which can be prevented with beta-adrenergic agonists and cAMP.
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PMID:AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and human cells by promoting Na,K-ATPase endocytosis. 1818 52

5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a phylogenetically conserved serine/threonine protein kinase. AMPK may inhibit cell growth and proliferation and also regulates apoptosis. 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a cell-permeable AMPK activator. Activation of AMPK with AICAR has been shown to induce apoptosis of the rat hepatoma cell line FTO2B cells and almost completely inhibited HepG2 cells growth. In this study, a HepG2 cell line, which was transfected with a vector containing human CYP2E1 cDNA (E47 cells), was treated with AICAR. Cell proliferation was blocked, and apoptosis and necrosis were elevated as assessed by cellular morphology, DNA content assay, and lactate dehydrogenase leakage. AICAR treatment significantly increases CYP2E1 activity (20-fold) and expression (5.5-fold) in E47 cells. Iodotubericidin, which inhibits the conversion of AICAR to its activated form AICAR monophosphate, the antioxidants trolox and MnTMPyP, and 4-methylpyrazole, an inhibitor of CYP2E1, all can protect the E47 cells from AICAR-induced necrosis. Production of intracellular reactive oxygen species was increased by AICAR treatment in E47 cells. The cytotoxicity mechanism of AICAR in E47 cells is suggested to include AMPK activation, p53 phosphorylation, p21 expression, overexpression of CYP2E1, and intracellular ROS accumulation.
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PMID:Overexpression of CYP2E1 induces HepG2 cells death by the AMP kinase activator 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). 1847 82

Like insulin, muscle contraction (in vitro or in situ) and exercise increase glucose uptake into skeletal muscle. However, the contraction/exercise pathway of glucose uptake in skeletal muscle is an independent pathway to that of insulin. Indeed, skeletal muscle glucose uptake is normal during exercise in those who suffer from insulin resistance and diabetes. Thus, the pathway of contraction-mediated glucose uptake into skeletal muscle provides an attractive potential target for pharmaceutical treatment and prevention of such conditions, especially as skeletal muscle is the major site of impaired glucose disposal in insulin resistance. The mechanisms regulating skeletal muscle glucose uptake during contraction have not been fully elucidated. Potential regulators include Ca(2+) (via CaMK's and/or CaMKK), AMPK, ROS, and NO signaling, with some redundancy likely to be evident within the system. In this review, we attempt to briefly synthesize current evidence regarding the potential mechanisms involved in regulating skeletal muscle glucose uptake during contraction, focusing on ROS and NO signaling. While reading this review, it will become clear that this is an evolving field of research and that much more work is required to elucidate the mechanism(s) regulating skeletal muscle glucose uptake during contraction.
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PMID:Skeletal muscle glucose uptake during exercise: a focus on reactive oxygen species and nitric oxide signaling. 1939 Nov 63

AMPK (AMP-activated protein kinase) is a key regulator of cellular energy because of its capacity to detect changes in the concentration of AMP. Recent evidence, however, indicates the existence of alternative mechanisms of activation of this protein. Mitochondrial ROS (reactive oxygen species), generated as a result of the interaction between nitric oxide and mitochondrial cytochrome c oxidase, activate AMPKalpha1 in HUVECs (human umbilical-vein endothelial cells) at a low oxygen concentration (i.e. 3%). This activation is independent of changes in AMP. In the present study we show, using HUVECs in which AMPKalpha1 has been silenced, that this protein is responsible for the expression of genes involved in antioxidant defence, such as manganese superoxide dismutase, catalase, gamma-glutamylcysteine synthase and thioredoxin. Furthermore, peroxisome proliferator-activated-coactivator-1, cAMP-response-element-binding protein and Foxo3a (forkhead transcription factor 3a) are involved in this signalling pathway. In addition, we show that silencing AMPKalpha1 in cells results in a reduced mitochondrial and eNOS (endothelial NO synthase) content, reduced cell proliferation, increased accumulation of ROS and apoptosis. Thus AMPKalpha1 in HUVECs regulates both their mitochondrial content and their antioxidant defences. Pharmacological activation of AMPKalpha1 in the vascular endothelium may be beneficial in conditions such as metabolic syndrome, Type 2 diabetes and atherosclerosis, not only because of its bioenergetic effects but also because of its ability to counteract oxidative stress.
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PMID:AMPKalpha1 regulates the antioxidant status of vascular endothelial cells. 1944 39

Peroxisome proliferator-activated receptor (PPARgamma), a ligand-dependent transcription factor, negatively modulates high glucose effects. We postulated that rosiglitazone (RSG), an activator of PPARgamma prevents the upregulation of vascular endothelial growth factor (VEGF) and collagen IV by mesangial cells exposed to high glucose. Primary cultured rat mesangial cells were growth-arrested in 5.6 mM (NG) or 25 mM D-glucose (HG) for up to 48 hours. In HG, PPARgamma mRNA and protein were reduced within 3 h, and enhanced ROS generation, expression of p22(phox), VEGF and collagen IV, and PKC-zeta membrane association were prevented by RSG. In NG, inhibition of PPARgamma caused ROS generation and VEGF expression that were unchanged by RSG. Reduced AMP-activated protein kinase (AMPK) phosphorylation in HG was unchanged with RSG, and VEGF expression was unaffected by AMPK inhibition. Hence, PPARgamma is a negative modulator of HG-induced signaling that acts through PKC-zeta but not AMPK and regulates VEGF and collagen IV expression by mesangial cells.
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PMID:Rosiglitazone prevents high glucose-induced vascular endothelial growth factor and collagen IV expression in cultured mesangial cells. 1960 56

AICAR (5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, Acadesine, AICA riboside) is an activator of AMP-activated protein kinase (AMPK). The results of recent studies suggest that AICAR, in addition to its application for treating metabolic disorders, may also have therapeutic potential for treating neuroinflammatory diseases where reactive microglia play an etiological role. However, the molecular mechanisms of action by which AICAR exerts its anti-inflammatory effects still remain unclear or controversial. In this paper we attempt to evaluate the effects of AICAR on non-stimulated and LPS-activated rat primary microglial cell cultures. The presented evidence supports the conclusion that AMPK activated by AICAR is involved in regulation of ROS and cytokine production (IL-1 beta, TNF-alpha (6h), IL-10 and TGF-beta) as well as arginase I and PGC-1alpha expression. Furthermore, we found that the effects of AICAR on IL-6 and TNF-alpha (12, 24h) release and on the expression of iNOS and NF-kappaB p65 are not AMPK-dependent because the pre-treatment of LPS-activated microglia with compound C (a pharmacological inhibitor of AMPK) did not reverse the effect of AICAR. The results of the presented study provide additional data about AMPK-dependent and -independent mechanisms whereby AICAR may modulate inflammatory response of microglia.
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PMID:AICAR (5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside) increases the production of toxic molecules and affects the profile of cytokines release in LPS-stimulated rat primary microglial cultures. 1985 24


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