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Metformin AND AMPK

Pamela T Soliman, Qian Zhang, Russell R Broaddus, Shannon N Westin, David Iglesias, Mark F Munsell, Rosemarie Schmandt, Melinda Yates, Lois Ramondetta, Karen H Lu
OBJECTIVE: Metformin reduces cancer incidence and improves overall survival in diabetic patients. In preclinical studies, metformin decreases endometrial cancer (EC) cell growth by activation of AMPK/mTOR inhibition. We sought to determine the effects of metformin on serum/tumor biomarkers in women with EC. METHODS: In this prospective trial, newly diagnosed EC patients underwent pre-treatment blood draw/endometrial biopsy, were administered oral metformin 850mg daily for ≥7days, and underwent post-treatment blood draw/definitive surgery...
October 13, 2016: Gynecologic Oncology
Qilong Wang, Miao Zhang, Gloria Torres, Shengnan Wu, Changhan Ouyang, Zhonglin Xie, Ming-Hui Zou
Metformin is a widely used anti-diabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells.Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE(-/-) mice...
October 13, 2016: Diabetes
Luciano Galdieri, Himavanth Gatla, Ivana Vancurova, Ales Vancura
AMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de-novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetyl-CoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription...
October 12, 2016: Journal of Biological Chemistry
Nathaniel B Bone, Zhongyu Liu, Jean-Francois Pittet, Jaroslaw W Zmijewski
Catecholamines, including β-adrenergic and dopaminergic neurotransmitters, have an essential role in regulating the "fight or flight" reflex and also affects immune cell proinflammatory action. However, little is known about whether catecholamines prevent dysfunction of metabolic pathways associated with inflammatory organ injury, including development of acute lung injury (ALI). We hypothesize that selected catecholamines may reduce metabolic alterations in LPS-stimulated macrophages and in the lungs of mice subjected to endotoxin-induced ALI, a situation characterized by diminished activity of AMP-activated protein kinase (AMPK)...
October 12, 2016: Journal of Leukocyte Biology
Rosa Lauretta, Giulia Lanzolla, Patrizia Vici, Luciano Mariani, Costanzo Moretti, Marialuisa Appetecchia
Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth...
2016: International Journal of Endocrinology
Marie Daugan, Amélie Dufaÿ Wojcicki, Benoit d'Hayer, Vincent Boudy
Since epidemiologic data have highlighted the positive effects of metformin to reduce cancer incidence and mortality, many in vitro and in vivo studies as well as a large number of clinical trials have been conducted in order to study its potential. The many anticancer actions of metformin lead to a cytostatic effect. Two distinct but not exclusive mechanisms can be implicated in these actions. First, by decreasing insulinemia and glycaemia, metformin can block the PI3K/MAPK signalling pathway implicated in cell growth...
October 5, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Madina Naimi, Filip Vlavcheski, Brennan Murphy, Tomas Hudlicky, Evangelia Tsiani
Compounds that increase the activity of the energy sensor AMP-activated kinase (AMPK) have the potential to regulate blood glucose levels. Although rosemary extract (RE) has been reported to activate AMPK and reduce blood glucose levels in vivo, the chemical components responsible for these effects are not known. In the present study, we measured the levels of the polyphenol carnosic acid (CA) in RE and examined the effects and the mechanism of action of CA on glucose transport system in muscle cells. High performance liquid chromatography (HPLC) was used to measure the levels of CA in RE...
September 22, 2016: Clinical and Experimental Pharmacology & Physiology
Bo-Hwa Choi, Da-Hyun Lee, Jin Kim, Ju-Hee Kang, Chang-Shin Park
Generally, both lipopolysaccharide (LPS)- and hypoxia-induced nuclear factor kappa B (NF-κB) effects are alleviated through differential posttranslational modification of NF-κB phosphorylation after pretreatment with 5´-AMP-activated protein kinase (AMPK) activators such as 5´-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or the hypoglycemic agent metformin. We found that AICAR or metformin acts as a regulator of LPS/NF-κB-or hypoxia/NF-κB-mediated cyclooxygenase induction by an AMPK-dependent mechanism with interactions between p65-NF-κB phosphorylation and acetylation, including in a human bladder cancer cell line (T24)...
September 2016: International Neurourology Journal
Linda A Villani, Brennan K Smith, Katarina Marcinko, Rebecca J Ford, Lindsay A Broadfield, Alex E Green, Vanessa P Houde, Paola Muti, Theodoros Tsakiridis, Gregory R Steinberg
OBJECTIVE: The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear. METHODS: Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed...
October 2016: Molecular Metabolism
Jian Jin, Sun Woo Lim, Long Jin, Ji Hyun Yu, Hyun Seon Kim, Byung Ha Chung, Chul Woo Yang
Background/Aims: Metformin (MET) is a first-line drug for type 2 diabetes mellitus (DM); its effect on new-onset diabetes after transplantation caused by immunosuppressant therapy is unclear. We compared the effects of MET on DM caused by tacrolimus (TAC) or sirolimus (SRL). Methods: DM was induced by injection of TAC (1.5 mg/kg) or SRL (0.3 mg/kg) for 2 weeks in rats, and MET (200 mg/kg) was injected for 2 more weeks. The effects of MET on DM caused by TAC or SRL were evaluated using an intraperitoneal glucose tolerance test (IPGTT) and by measuring plasma insulin concentration, islet size, and glucose-stimulated insulin secretion (GSIS)...
September 30, 2016: Korean Journal of Internal Medicine
Don-Kyu Kim, Yong-Hoon Kim, Yoon Seok Jung, Ki-Sun Kim, Jae-Ho Jeong, Yong-Soo Lee, Jae-Min Yuk, Byung-Chul Oh, Hyon E Choy, Steven Dooley, Martina U Muckenthaler, Chul-Ho Lee, Hueng-Sik Choi
Small heterodimer partner (SHP) is a transcriptional corepressor regulating diverse metabolic processes. Here, we show that SHP acts as an intrinsic negative regulator of iron homeostasis. SHP-deficient mice maintained on a high-iron diet showed increased serum hepcidin levels, decreased expression of the iron exporter ferroportin as well as iron accumulation compared to WT mice. Conversely, overexpression of either SHP or AMP-activated protein kinase (AMPK), a metabolic sensor inducing SHP expression, suppressed BMP6-induced hepcidin expression...
September 30, 2016: Scientific Reports
Bin Zhao, Xiaoke Wang, Jun Zheng, Hailiang Wang, Jun Liu
Considerable evidence has demonstrated that metformin can activate 5'-AMP-activated protein kinase (AMPK) signaling pathway, which plays a critical role in protection of endothelial cell permeability. Hence, the present study evaluated the effects of metformin on blood brain barrier permeability and AQP4 expression in vitro, and assessed the effects of metformin treatment on tumor-induced brain edema in vivo. Hypoxia or VEGF exposure enhanced bEnd3 endothelial cell monolayer permeability and attenuated the expression of tight junction proteins including Occludin, Claudin-5, ZO-1, and ZO-2...
2016: American Journal of Translational Research
Qiyuan Yang, Xingwei Liang, Xiaofei Sun, Lupei Zhang, Xing Fu, Carl J Rogers, Anna Berim, Shuming Zhang, Songbo Wang, Bo Wang, Marc Foretz, Benoit Viollet, David R Gang, Buel D Rodgers, Mei-Jun Zhu, Min Du
Promoting brown adipose tissue (BAT) development is an attractive strategy for the treatment of obesity, as activated BAT dissipates energy through thermogenesis; however, the mechanisms controlling BAT formation are not fully understood. We hypothesized that as a master regulator of energy metabolism, AMP-activated protein kinase (AMPK) may play a direct role in the process and found that AMPKα1 (PRKAA1) ablation reduced Prdm16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of α-ketoglutarate (αKG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the Prdm16 promoter...
October 11, 2016: Cell Metabolism
Jingfang Zou, Liangli Hong, Chaohuan Luo, Zhi Li, Yuzhang Zhu, Tianliang Huang, Yongneng Zhang, Huier Yuan, Yaqiu Hu, Tengfei Wen, Wanling Zhuang, Bozhi Cai, Xin Zhang, Jiexiong Huang, Jidong Cheng
Metformin is an oral biguanide commonly used for the treating type II diabetes and has recently been demonstrated to possess anti-proliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Our study demonstrated a marked loss of AMP-activated protein kinase (AMPK) phosphorylation and nuclear FOXO1 protein in estrogen-dependent endometrial cancer (EC) tumors compared to normal control endometrium...
September 16, 2016: Cancer Science
Wei-Wan Zheng, Xin-Yuan Li, Hui-Bin Liu, Zi-Rui Wang, Qing-Qing Hu, Yu-Xia Li, Bin-Lin Song, Jie Lou, Qiu-Shi Wang, He-Ping Ma, Zhi-Ren Zhang
Recent studies suggest that the epithelial sodium channel (ENaC) is expressed in the endothelial cells. To test whether high salt affects the NO production via regulation of endothelial ENaC, human umbilical vein endothelial cells (HUVECs) were incubated in solutions containing either normal or high sodium (additional 20 mM NaCl). Our data showed that high sodium treatment significantly increased α-, β-, and γ-ENaC expression levels in HUVECs. Using the cell-attached patch-clamp technique, we demonstrated that high sodium treatment significantly increased ENaC open probability (P O )...
2016: Oxidative Medicine and Cellular Longevity
Jordi Camps, Anna Hernández-Aguilera, Anabel García-Heredia, Noemí Cabré, Fedra Luciano-Mateo, Meritxell Arenas, Jorge Joven
Metformin is a biguanide used in the treatment of type 2 diabetes mellitus and obesity. The main mechanism of action is to decrease the intestinal glucose absorption and the hepatic glucose production. It does not influence insulin secretion. Metformin also increases the affinity of the insulin receptor, reduces high insulin levels and improves insulin resistance. Additionally, it promotes weight loss. Metformin is a pleiotropic compound but acts, largely, by activating 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK)...
September 15, 2016: Current Clinical Pharmacology
Sreenithya Ravindran, Vinitha Kuruvilla, Kerry Wilbur, Shankar Munusamy
Metformin, a well-known anti-diabetic agent, is very effective in lowering blood glucose in patients with type 2 diabetes with minimal side-effects. Metformin is also being recommended in the treatment of obesity and polycystic ovary syndrome. Metformin elicits its therapeutic effects mainly via activation of AMP-activated kinase (AMPK) pathway. Renal cells under hyperglycemic or proteinuric conditions exhibit inactivation of cell defense mechanisms such as AMPK and autophagy, and activation of pathologic pathways such as mammalian target of rapamycin (mTOR), endoplasmic reticulum (ER) stress, epithelial-to-mesenchymal transition (EMT), oxidative stress, and hypoxia...
September 14, 2016: Journal of Cellular Physiology
Soundharrajan Ilavenil, Da Hye Kim, Mayakrishnan Vijayakumar, Srisesharam Srigopalram, Sang Gun Roh, Mariadhas Valan Arasu, Jong Suk Lee, Ki Choon Choi
BACKGROUND: From ancient times, marine algae have emerged as alternative medicine and foods, contains the rich source of natural products like proteins, vitamins, and secondary metabolites, especially Chlorella vulgaris (C. vulgaris) contains numerous anti-inflammatory, antioxidants and wound healing substances. Type 2 diabetes mellitus is closely associated with adipogenesis and their factors. Hence, we aimed to investigate the chemical constituents and adipogenic modulatory properties of C...
2016: Biological Research
Guizuo Wang, Yang Song, Wei Feng, Lu Liu, Yanting Zhu, Xinming Xie, Yilin Pan, Rui Ke, Shaojun Li, Fangwei Li, Lan Yang, Manxiang Li
Evidence suggests that an imbalance between oxidation and antioxidation is involved in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Activation of AMP-activated protein kinase (AMPK) has been shown to inhibit the occurrence of ALI/ARDS. However, it is unknown whether activation of AMPK benefits ALI/ARDS by restoration of the oxidant and antioxidant balance, and which mechanisms are responsible for this process. The present study aimed to address these issues. Lipopolysaccharide (LPS) induced pronounced pathological changes of ALI in mice; these were accompanied by elevated production of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) compared with control mice...
September 2016: Experimental and Therapeutic Medicine
Lu Liu, Yilin Pan, Yang Song, Xiaofan Su, Rui Ke, Lan Yang, Li Gao, Manxiang Li
The aims of the present study were to examine the effect of adenosine monophosphate-activated protein kinase (AMPK) activation on airway smooth muscle cells (ASMCs) proliferation and to address its potential mechanisms. Platelet derived growth factor (PDGF) activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, and this in turn up-regulated S-phase kinase-associated protein 2 (Skp2) and consequently reduced cyclin dependent kinase inhibitor 1B (p27) leading to ASMCs proliferation...
September 4, 2016: European Journal of Pharmacology
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