Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caloric restriction (CR), reduced protein, methionine, or tryptophan diets; and reduced insulin and/or IGFI intracellular signaling can extend mean and/or maximum lifespan and delay deleterious age-related physiological changes in animals. Mice and flies can shift readily between the control and CR physiological states, even at older ages. Many health benefits are induced by even brief periods of CR in flies, rodents, monkeys, and humans. In humans and nonhuman primates, CR produces most of the physiologic, hematologic, hormonal, and biochemical changes it produces in other animals. In primates, CR provides protection from type 2 diabetes, cardiovascular and cerebral vascular diseases, immunological decline, malignancy, hepatotoxicity, liver fibrosis and failure, sarcopenia, inflammation, and DNA damage. It also enhances muscle mitochondrial biogenesis, affords neuroprotection; and extends mean and maximum lifespan. CR rapidly induces antineoplastic effects in mice. Most claims of lifespan extension in rodents by drugs or nutrients are confounded by CR effects. Transcription factors and co-activators involved in the regulation of mitochondrial biogenesis and energy metabolism, including SirT1, PGC-1alpha, AMPK and TOR may be involved in the lifespan effects of CR. Paradoxically, low body weight in middle aged and elderly humans is associated with increased mortality. Thus, enhancement of human longevity may require pharmaceutical interventions.
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PMID:Caloric restriction: from soup to nuts. 1985 62

Epigallocatechin gallate (EGCG), a green tea polyphenol, promotes vasodilation by phosphatidylinositol 3-kinase-dependent activation of Akt and endothelial nitric oxide synthase to stimulate production of nitric oxide. Reduction in endothelin-1 (ET-1) synthesis may also increase bioavailability of nitric oxide. We hypothesized that the phosphatidylinositol 3-kinase-dependent transcription factor FOXO1 may mediate effects of EGCG to regulate expression of ET-1 in endothelial cells. EGCG treatment (10 microm, 8 h) of human aortic endothelial cells reduced expression of ET-1 mRNA, protein, and ET-1 secretion. We identified a putative FOXO binding domain in the human ET-1 promoter 51 bp upstream from the transcription start site. Trans-activation of a human ET-1 (hET-1) promoter luciferase reporter was enhanced by coexpression of a constitutively nuclear FOXO1 mutant, whereas expression of a mutant FOXO1 with disrupted DNA binding domain did not trans-activate the hET-1 promoter. Disrupting the hET-1 putative FOXO binding domain by site-directed mutagenesis ablated promoter activity in response to overexpression of wild-type FOXO1. EGCG stimulated time-dependent phosphorylation of Akt (S(473)), FOXO1 (at Akt phosphorylation site T(24)), and AMP-activated protein kinase alpha (AMPK alpha) (T(172)). EGCG-induced nuclear exclusion of FOXO1, FOXO1 binding to the hET-1 promoter, and reduction of ET-1 expression was partially inhibited by the AMPK inhibitor Compound C. Basal ET-1 protein expression was enhanced by short interfering RNA knock-down of Akt and reduced by short interfering RNA knock-down of FOXO1 or adenovirus-mediated expression of dominant-negative Foxo1. We conclude that EGCG decreases ET-1 expression and secretion from endothelial cells, in part, via Akt- and AMPK-stimulated FOXO1 regulation of the ET-1 promoter. These findings may be relevant to beneficial cardiovascular actions of green tea.
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PMID:Green tea polyphenol epigallocatechin gallate reduces endothelin-1 expression and secretion in vascular endothelial cells: roles for AMP-activated protein kinase, Akt, and FOXO1. 1988 61

Ludwigia octovalvis is an aquatic plant widely distributed in Taiwan. It is traditionally used as a diuretic and is consumed as health drink. In this study, we evaluated the anti-proliferative activity of extracts and active constituent (chlorophyll a; CHL-a) of L. octovalvis in 3T3-L1 adipocytes; its mode of action on apoptosis was also investigated. Results showed that, among the different extracts and fractions, the ethylacetate layer (EAL) possessed the most potent anti-proliferative activity. Activity guided fractionation of the EAL obtained the bioactive constituent CHL-a (IC50: 24.10+/-0.83 nM). At concentrations 5-30 nM, CHL-a exhibited a dose-dependent accumulation of the Sub-G1 peak and caused cell cycle arrest at the G0/G1 phase. At 30 nM, it significantly reduced the cell viability, induced the appearance of DNA fragments, and enhanced the activation of caspase-3. Western blot data revealed that CHL-a decreased the level of Bcl-2, and increased the expression of CD95 (APO-1/CD95) and Bax. Furthermore, CHL-a up-regulated the AMPK and p-AMPK levels, and down-regulated the expression of PPAR-gamma. These results conclude that CHL-a possesses potent anti-proliferative activity, and its apoptotic effects on 3T3-L1 adipocytes are mediated through the activation of CD95 (APO-1/CD95) system and the AMPK signaling pathway.
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PMID:Chlorophyll a, an active anti-proliferative compound of Ludwigia octovalvis, activates the CD95 (APO-1/CD95) system and AMPK pathway in 3T3-L1 cells. 1996 29

Hypoxia (approximately 3-0.1% oxygen) is capable of rapidly inducing, via the hypoxia-inducible factor (HIF-1), a cell survival response engaging autophagy. This process is mediated by the atypical BH3-only proteins the Bcl-2/E1B 19kDa-interacting protein 3 (BNIP3/BNIP3L (NIX)) that are induced by HIF-1. These mitochondrial associated BNIP proteins also mediate mitophagy, a metabolic adaptation for survival that is able to control reactive oxygen species (ROS) production and DNA damage. In contrast, severe hypoxic conditions or anoxia (<0.1% oxygen), where the latter is often confused with physiological hypoxia, are capable of inducing a HIF-independent autophagic response, generated via an extreme nutritional stress response implicating the AMPK-mTOR and unfolded protein response (UPR) pathways. The autophagic cell death that is often observed in these extreme stress conditions should be seen as the outcome of failed adaptation.
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PMID:Hypoxia-induced autophagy: cell death or cell survival? 2002 34

Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm-deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.
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PMID:ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. 2016 76

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. DNA damage in response to genotoxic and oncogenic stresses activate the tumor suppressor pathways initiating DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence. On the other hand, DDR reasons in adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disrupt the existing cellular homeostasis. Significant metabolic changes occurred by the influence of the major tumor suppressor protein p53 and other related factors such as FOXO, AMPK, PARP, NF-kappaB and PGC-1 are discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that "metabolic syndrome" is a real disease.
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PMID:Systemic DNA damage response and metabolic syndrome as a premalignant state. 2033 25

The aim of the present study is to investigate the effects of adiponectin (APN) on hypoxia/reoxygenation (H/R) injury in cultured cardiomyocytes. Primary cardiomyocytes were obtained from neonatal rats by enzymatic digestion method and identified by immunofluorescent technique. Primary cells cultured for 72 h were used in experiment and divided into 5 groups randomly: Control group, H/R group, H/R+APN group, H/R+APN+adenine 9-beta-D-arabinfuranoside (AraA, AMPK inhibitor) group, and H/R+AraA group. The cardiocyte morphology and beating rate were observed under inverted microscope. The DNA ladder was examined by agarose gel electrophoresis, and the cell apoptosis was determined by flow cytometry. Moreover, the malondialchehyche (MDA) content in myocardial cells and the superoxide dismutase (SOD) activity in the supernatant were measured using kits, the fluorescence intensity of intracellular Ca2+ was observed by laser scanning confocal microscope, and the phosphorylation of AMPK was determined by Western blotting. Compared with control group, H/R group showed increased apoptotic rate, oxidative stress level, intracellular Ca2+ concentration and phosphorylation level of AMPK (P<0.05), while significant ameliorations in the above indices were seen in H/R+APN group. On the contrast, AraA attenuated the protective effect of APN and decreased the phosphorylation of AMPK. These results suggest that adiponectin can protect cardiomyocytes from H/R-induced oxidative stress and apoptosis through AMPK pathway.
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PMID:[Protective effects of adiponectin against hypoxia/reoxygenation injury in neonatal rat cardiomyocytes]. 2040 50

The insulin-like growth factor (IGF-I) signalling pathway is essential for metabolism, cell growth and survival. It induces expression of the mitochondrial pyrimidine nucleotide carrier 1 (PNC1) in transformed cells, but the consequences of this for cell phenotype are unknown. Here we show that PNC1 is necessary to maintain mitochondrial function by controlling mitochondrial DNA replication and the ratio of transcription of mitochondrial genes relative to nuclear genes. PNC1 suppression causes reduced oxidative phosphorylation and leakage of reactive oxygen species (ROS), which activates the AMPK-PGC1alpha signalling pathway and promotes mitochondrial biogenesis. Overexpression of PNC1 suppresses mitochondrial biogenesis. Suppression of PNC1 causes a profound ROS-dependent epithelial-mesenchymal transition (EMT), whereas overexpression of PNC1 suppresses both basal EMT and induction of EMT by TGF-beta. Overall, our findings indicate that PNC1 is essential for mitochondria maintenance and suggest that its induction by IGF-I facilitates cell growth whereas protecting cells from an ROS-promoted differentiation programme that arises from mitochondrial dysfunction.
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PMID:Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells. 2045 89

Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer's disease. PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1alpha itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets.
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PMID:Regulation of mitochondrial biogenesis. 2053 1

Ilex paraguariensis dried and minced leaves are made into a brewed tea, prepared in a sui generis manner by large populations in South America, having evolved from a tea drunk by the Guarani ethnic group to a beverage that has a social and almost ritualistic role in some South American modern societies. It is used both as a source of caffeine, in lieu or in parallel with tea and coffee, but also as a therapeutic agent for its alleged pharmacological properties. Although with some exceptions, research on biomedical properties of this herb has had a late start and strongly lags behind the impressive amount of literature on green tea and coffee. However, in the past 15 years, there was a several-fold increase in the literature studying Ilex paraguariensis properties showing effects such as antioxidant properties in chemical models and ex vivo lipoprotein studies, vaso-dilating and lipid reduction properties, antimutagenic effects, controversial association with oropharyngeal cancer, anti-glycation effects and weight reduction properties. Lately, promising results from human intervention studies have surfaced and the literature offers several developments on this area. The aim of this review is to provide a concise summary of the research published in the past three years, with an emphasis on translational studies, inflammation and lipid metabolism. Ilex paraguariensis reduces LDL-cholesterol levels in humans with Ilex paraguariensis dyslipoproteinemia and the effect is synergic with that of statins. Plasma antioxidant capacity as well as expression of antioxidant enzymes is positively modulated by intervention with Ilex paraguariensis in human cohorts. A review on the evidence implicating Ilex paraguariensis heavy consumption with some neoplasias show data that are inconclusive but indicate that contamination with alkylating agents during the drying process of the leaves should be avoided. On the other hand, several new studies confirm the antimutagenic effects of Ilex paraguariensis in different models, from DNA double breaks in cell culture models to mice studies. Novel interesting work has emerged showing significant effect on weight reduction both in mice and in rat models. Some mechanisms involved are inhibition of pancreatic lipase, activation of AMPK and uncoupling of electron transport. Intervention studies in animals have provided strong evidence of anti-inflammatory effects of Ilex paraguariensis, notably protecting cigarette-induced lung inflammation acting on macrophage migration and inactivating matrix-metalloproteinase. Research on the effects of Ilex paraguariensis in health and disease has confirmed its antioxidant, anti-inflammatory, antimutagenic and lipid-lowering activities. Although we are still waiting for the double-blind, randomized prospective clinical trial, the evidence seems to provide support for beneficial effects of mate drinking on chronic diseases with inflammatory component and lipid metabolism disorders.
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PMID:Recent advances on Ilex paraguariensis research: minireview. 2059 3


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