1.AMPK activators: mechanisms of action and physiological activities.
Joungmok KIM ; Goowon YANG ; Yeji KIM ; Jin KIM ; Joohun HA
Experimental & Molecular Medicine 2016;48(4):e224-
AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, which coordinates metabolic pathways and thus balances nutrient supply with energy demand. Because of the favorable physiological outcomes of AMPK activation on metabolism, AMPK has been considered to be an important therapeutic target for controlling human diseases including metabolic syndrome and cancer. Thus, activators of AMPK may have potential as novel therapeutics for these diseases. In this review, we provide a comprehensive summary of both indirect and direct AMPK activators and their modes of action in relation to the structure of AMPK. We discuss the functional differences among isoform-specific AMPK complexes and their significance regarding the development of novel AMPK activators and the potential for combining different AMPK activators in the treatment of human disease.
AMP-Activated Protein Kinases*
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Homeostasis
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Humans
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Metabolic Networks and Pathways
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Metabolism
2.AMPK activators: mechanisms of action and physiological activities.
Joungmok KIM ; Goowon YANG ; Yeji KIM ; Jin KIM ; Joohun HA
Experimental & Molecular Medicine 2016;48(4):e224-
AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, which coordinates metabolic pathways and thus balances nutrient supply with energy demand. Because of the favorable physiological outcomes of AMPK activation on metabolism, AMPK has been considered to be an important therapeutic target for controlling human diseases including metabolic syndrome and cancer. Thus, activators of AMPK may have potential as novel therapeutics for these diseases. In this review, we provide a comprehensive summary of both indirect and direct AMPK activators and their modes of action in relation to the structure of AMPK. We discuss the functional differences among isoform-specific AMPK complexes and their significance regarding the development of novel AMPK activators and the potential for combining different AMPK activators in the treatment of human disease.
AMP-Activated Protein Kinases*
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Homeostasis
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Humans
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Metabolic Networks and Pathways
;
Metabolism
3.Neuroprotective Effects of AMP-Activated Protein Kinase on Scopolamine Induced Memory Impairment.
Soo Jeong KIM ; Jun Ho LEE ; Hwan Suck CHUNG ; Joo Hyun SONG ; Joohun HA ; Hyunsu BAE
The Korean Journal of Physiology and Pharmacology 2013;17(4):331-338
AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, is activated in response to cellular stress when intracellular levels of AMP increase. We investigated the neuroprotective effects of AMPK against scopolamine-induced memory impairment in vivo and glutamate-induced cytotoxicity in vitro. An adenovirus expressing AMPK wild type alpha subunit (WT) or a dominant negative form (DN) was injected into the hippocampus of rats using a stereotaxic apparatus. The AMPK WT-injected rats showed significant reversal of the scopolamine induced cognitive deficit as evaluated by escape latency in the Morris water maze. In addition, they showed enhanced acetylcholinesterase (AChE)-reactive neurons in the hippocampus, implying increased cholinergic activity in response to AMPK. We also studied the cellular mechanism by which AMPK protects against glutamate-induced cell death in primary cultured rat hippocampal neurons. We further demonstrated that AMPK WT-infected cells increased cell viability and reduced Annexin V positive hippocampal neurons. Western blot analysis indicated that AMPK WT-infected cells reduced the expression of Bax and had no effects on Bcl-2, which resulted in a decreased Bax/Bcl-2 ratio. These data suggest that AMPK is a useful cognitive impairment treatment target, and that its beneficial effects are mediated via the protective capacity of hippocampal neurons.
Acetylcholinesterase
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Adenoviridae
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AMP-Activated Protein Kinases
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Animals
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Annexin A5
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Apoptosis
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Blotting, Western
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Cell Death
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Cell Survival
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Energy Metabolism
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Hippocampus
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Memory
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Neurons
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Neuroprotective Agents
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Rats
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Scopolamine Hydrobromide
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United Nations
4.Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase.
Chang Eun PARK ; Min Jung KIM ; Jong Hwa LEE ; Byung Il MIN ; Hyunsu BAE ; Wonchae CHOE ; Sung Soo KIM ; Joohun HA
Experimental & Molecular Medicine 2007;39(2):222-229
trans-Resveratrol (t-RVT), a naturally occurring polyphenol found in Polygonum cuspidatum, grape, and red wine, has been reported to have anti- inflammatory, cardioprotective, and cancer chemopreventive properties. However antidiabetic effect of t-RVT has not yet been reported. In this study, we show that t-RVT increases glucose uptake in C2C12 myotubes by activating AMP-activated protein kinase (AMPK), uncovering an antidiabetic potential of t-RVT for the first time. AMPK plays a central role in the regulation of glucose and lipid metabolism, and hence it is considered a novel therapeutic target for metabolic syndrome such as type 2 diabetes. t-RVT significantly induced glucose uptake in C2C12 cells, via AMPK activation, but not a phosphatidylinositol-3 kinase (PI-3 kinase) signal pathway. The induced glucose uptake was attenuated by pretreatment with a pharmacological inhibitor for AMPK, indicating that the effect of t-RVT primarily depends on AMPK activation. However, in the presence of insulin, t-RVT also potentiated the effect of insulin on glucose uptake via AMPK activation, which led to further activation of PI-3 kinase/Akt signal pathway.
1-Phosphatidylinositol 3-Kinase/metabolism
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AMP-Activated Protein Kinases
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Animals
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Biological Transport/drug effects
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Cell Line
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Enzyme Activation/drug effects
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Glucose/*metabolism
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Insulin/metabolism
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Mice
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Models, Biological
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Multienzyme Complexes/*metabolism
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Muscle Fibers, Skeletal/*drug effects/enzymology/metabolism
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Protein-Serine-Threonine Kinases/*metabolism
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Proto-Oncogene Proteins c-akt/metabolism
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Stilbenes/*pharmacology
5.Baicalein protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis through inhibition of reactive oxygen species production and CHOP induction.
Ji Hyun CHOI ; A Young CHOI ; Hana YOON ; Wonchae CHOE ; Kyung Sik YOON ; Joohun HA ; Eui Ju YEO ; Insug KANG
Experimental & Molecular Medicine 2010;42(12):811-822
Baicalein is one of the major flavonoids in Scutellaria baicalensis Georgi and possesses various effects, including cytoprotection and anti-inflammation. Because endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia, we investigated the effects of baicalein on apoptotic death of HT22 mouse hippocampal neuronal cells induced by thapsigargin (TG) and brefeldin A (BFA), two representative ER stress inducers. Apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) were measured by flow cytometry. Expression level and phosphorylation status of ER stress-associated proteins and activation and cleavage of apoptosis-associated proteins were analyzed by Western blot. Baicalein reduced TG- and BFA-induced apoptosis of HT22 cells and activation and cleavage of apoptosis-associated proteins, such as caspase-12 and -3 and poly(ADP-ribose) polymerase. Baicalein also reduced the TG- and BFA-induced expression of ER stress-associated proteins, including C/EBP homologous protein (CHOP) and glucose-regulated protein 78, the cleavage of X-box binding protein-1 and activating transcription factor 6alpha, and the phosphorylation of eukaryotic initiation factor-2alpha and mitogen-activated protein kinases, such as p38, JNK, and ERK. Knock-down of CHOP expression by siRNA transfection and specific inhibitors of p38 (SB203580), JNK (SP600125), and ERK (PD98059) as well as anti-oxidant (N-acetylcysteine) reduced TG- or BFA-induced cell death. Baicalein also reduced TG- and BFA-induced ROS accumulation and MMP reduction. Taken together, these results suggest that baicalein could protect HT22 neuronal cells against ER stress-induced apoptosis by reducing CHOP induction as well as ROS accumulation and mitochondrial damage.
Animals
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*Apoptosis
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Brefeldin A/pharmacology
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Cell Line
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Cytoprotection
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DNA-Binding Proteins/metabolism
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Endoplasmic Reticulum/drug effects/*physiology
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Flavanones/*pharmacology
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Heat-Shock Proteins/biosynthesis
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Hippocampus/cytology
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Membrane Potential, Mitochondrial/drug effects
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Mice
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Mitogen-Activated Protein Kinases/metabolism
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Neurons/*drug effects/physiology
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Reactive Oxygen Species/*metabolism
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Signal Transduction/drug effects
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Thapsigargin/pharmacology
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Transcription Factor CHOP/*biosynthesis
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Transcription Factors/metabolism
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Unfolded Protein Response/drug effects