Neuroprotective Effect of Melatonin in a Neonatal Hypoxia–Ischemia Rat Model Is Regulated by the AMPK/mTOR Pathway
Efe NacarkucukMaría E. BernisAnna‐Sophie BremerKora GrzelakMargit ZweyerElke MaesHannah BurkardHemmen Sabir
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Melatonin has been shown to be neuroprotective in different animal models of neonatal hypoxic-ischemic brain injury. However, its exact molecular mechanism of action remains unknown. Our aim was to prove melatonin's short- and long-term neuroprotection and investigate its role on the AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway following neonatal hypoxic-ischemic brain injury.Keywords:
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Adenosine 5’-monophosphate (AMP) activated protein kinase (AMPK) is a highly conserved sensor of cellular energy. AMPK has been recognized as a key regulator of mammalian metabolic function and has emerged as an attractive target for the treatment of metabolic disorders, including obesity and type 2 diabetes. The synthesis and biological evaluation of novel 3-(4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoic acid derivatives as AMPK activators are described. The in vivo proof of principle for plasma glucose lowering effect is exemplified with a lead compound from this series. Keywords: AMP-activated protein kinase (AMPK), AMPK activators, Thienopyrimidinone derivatives, Type-2 diabetes mellitus, db/db mice model.
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김상현, Kazuhiko Higashida, 김기진. SAMS-GFP 펩티드에 의한 AMP-activated protein kinase 기능 차단이 골격근 내 당 수송에 미치는 영향. 운동과학, 제20권 제3호. 205-214, 2011. 운동시 골격근 내 당 수송은 주로 AMP-activated protein kinase(AMPK)와 Ca2+/calmodulin-dependent protein kinase(CaMK) 신호전달체계를 통해 이루어진다. AMPK의 세 가지 subunit 중 α 는 α1과 α2 isoform이 존재하는데, α2가 골격근 내 주요 isoform으로 알려져 있다. 그렇지만 AMPKα2를 knockout(KO) 하더라도 AMPKα1의 효과까지는 완벽하게 차단되지 않을 뿐 아니라 AMPKα1의 활성이 오히려 반등하게 된다. 따라서 최근 AMPKα2 KO 생쥐를 이용하여 AMPK가 운동시골격근 내 당 수송에 중요한 역할을 하지 않는다는 연구결과는 골격근 내 당 수송에 대한 AMPK 역할을 확실히 규명하는데 한계가 있다. 이에 본 연구는 가성 펩티드(pseudo peptide)인 SAMS-GFP를 이용하여 AMPKα1과 α2의 기능을 완전히 차단한 후 AMPK가 골격근내 당 수송에 어떠한 역할을 하는지 알아보았다. 이를 위해 electric pulse-mediated gene transfer 기술을 이용하여 SAMS-GFP peptide를 epitrochlearis 근육에 과 발현 시켰다. 그 결과 SAMS-GFP 저해 펩티드(inhibitory peptide)는 AICAR에 의해 증가된 골격근 내 당 수송을 완벽히 차단하였다. 그리고 저산소증과 근 수축에 의해 각각 6.5배 그리고 4.3배 증가된 당 수송이 SAMS-GFP 유전자에 의해 각각 50% 가까이 감소되었다. 또한 SAMS-GFP 저해 펩티드는 GLUT4 생합성에 아무런 영향을 미치지 않았다. 이러한 결과를 종합해 볼 때 AMPK가 근 수축에 따른 골격근 내 당 수송에 CaMK 신호전달체계와 함께 여전히 핵심적인 역할을 하며, SAMS-GFP 저해 펩티드가 AMPKα2 KO 생쥐와는 달리 AMPKα1과 AMPKα2 기능을 모두 완벽하게 차단하였다는 것을 알 수 있다.
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5'-Adenosine monophosphate-activated protein kinase (AMPK) is a potential therapeutic target for various medical conditions. We here identify a small-molecule compound (RX-375) that activates AMPK and inhibits fatty acid synthesis in cultured human hepatocytes. RX-375 does not bind to AMPK but interacts with prohibitins (PHB1 and PHB2), which were found to form a complex with AMPK. RX-375 induced dissociation of this complex, and PHBs knockdown resulted in AMPK activation, in the cultured cells. Administration of RX-375 to obese mice activated AMPK and ameliorated steatosis in the liver. High-throughput screening based on disruption of the AMPK-PHB interaction identified a second small-molecule compound that activates AMPK, confirming the importance of this interaction in the regulation of AMPK. Our results thus indicate that PHBs are previously unrecognized negative regulators of AMPK, and that compounds that prevent the AMPK-PHB interaction constitute a class of AMPK activator.
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Adenosine 5'-monophosphate-activated protein activated protein kinase (AMPK), a heterotrimeric complex, is an important kinase to regulate glycolipid metabolism and energy balance involved in a variety physiological processes in human body. Many research indicated that the function and activity of AMPK were closely related to inflammation, diabetes and cancers. Recent reports show that inhibition of metformin (a first-line drug) on hepatic glucose in patients with hyperglycemia is associated with AMPK pathway, suggesting that targeting AMPK may be one of the effective strategies for the prevention and treatment of a variety of chronic diseases. Here, we review research progress on the structure, activation and regulation of AMPK in glycolipid metabolism to provide an insight into the basic and clinical research of diabetes therapy.AMP 激活的蛋白激酶 (AMP-activated protein kinase，AMPK) 是一种异源三聚体复合物，作为机体能量平衡和糖脂代谢的重要激酶参与多种生理过程的调节。研究表明，炎症、糖尿病和癌症等多种慢性疾病也与AMPK功能和活性调节有密切关系。新近发现，糖尿病一线用药二甲双胍抑制肝糖产生改善病人高血糖的作用与AMPK激活有关，提示靶向AMPK 可能是预防和治疗多种慢性疾病的有效策略之一。文中从AMPK 的结构与活性、AMPK在糖代谢调控中的作用和AMPK 在血脂代谢调控中的作用3 个方面综述了AMPK 研究的进展，旨在为糖脂代谢调控的基础和临床研究提供依据。.
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Adenosine monophosphate–activated protein kinase (AMPK), a serine/threonine protein kinase, is known as “intracellular energy sensor and regulator.” AMPK regulates multiple cellular processes including protein and lipid synthesis, cell proliferation, invasion, migration, and apoptosis. Moreover, AMPK plays a key role in the regulation of “Warburg effect” in cancer cells. AMPK activity is down-regulated in most tumor tissues compared with the corresponding adjacent paracancerous or normal tissues, indicating that the decline in AMPK activity is closely associated with the development and progression of cancer. Therefore, understanding the mechanism of AMPK deactivation during cancer progression is of pivotal importance as it may identify AMPK as a valid therapeutic target for cancer treatment. Here, we review the mechanisms by which AMPK is down-regulated in cancer.
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