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AMPK AND metformin

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https://www.readbyqxmd.com/read/28915708/targeting-metabolism-and-amp-activated-kinase-with-metformin-to-sensitize-non-small-cell-lung-cancer-nsclc-to-cytotoxic-therapy-translational-biology-and-rationale-for-current-clinical-trials
#1
REVIEW
Michael Troncone, Stephanie M Cargnelli, Linda A Villani, Naghmeh Isfahanian, Lindsay A Broadfield, Laura Zychla, Jim Wright, Gregory Pond, Gregory R Steinberg, Theodoros Tsakiridis
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915611/metformin-increases-chemo-sensitivity-via-gene-downregulation-encoding-dna-replication-proteins-in-5-fu-resistant-colorectal-cancer-cells
#2
Sung-Hee Kim, Soon-Chan Kim, Ja-Lok Ku
Metformin is most widely prescribed for type 2 diabetes. Recently, evidences have shown that metformin has anticancer effects on pancreatic-, colorectal-, ovarian-, and other cancers. Because metformin has less adverse effects and is inexpensive, it could be a useful chemo-therapeutic agent with anticancer effects. In this study, we demonstrated metformin inhibited by cell proliferation, cell migration ability, clonogenic ability, and cancer stem cell population. Metformin also induced cell cycle arrest in parental-(SNU-C5), and 5-Fu resistant-colorectal cancer cell line (SNU-C5_5FuR)...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915221/metformin-exerts-beneficial-effects-in-hemorrhagic-shock-in-an-ampk%C3%AE-1-independent-manner
#3
Paul Kim, Giovanna Piraino, Michael O'Connor, Paul W Hake, Vivian Wolfe, Patrick Lahni, Basilia Zingarelli
Despite therapeutic advances in hemorrhagic shock, mortality from multiple organ failure remains high. AMP-activated protein kinase (AMPK) is involved in cellular energy homeostasis. Two catalytic subunits, α1 and α2, have been identified, with α1 subunit largely expressed in major organs. Here, we hypothesized that genetic deficiency of AMPKα1 worsens hemorrhage-induced multiple organ failure. We also investigated whether treatment with metformin, a clinically used drug for metabolic homeostasis, affords beneficial effects...
September 14, 2017: Shock
https://www.readbyqxmd.com/read/28913567/two-cell-embryos-are-more-sensitive-than-blastocysts-to-ampk-dependent-suppression-of-anabolism-and-stemness-by-commonly-used-fertility-drugs-a-diet-supplement-and-stress
#4
Alan Bolnick, Mohammed Abdulhasan, Brian Kilburn, Yufen Xie, Mindie Howard, Paul Andresen, Alexandra M Shamir, Jing Dai, Elizabeth E Puscheck, Eric Secor, Daniel A Rappolee
PURPOSE: This study tests whether metformin or diet supplement BR-DIM-induced AMP-activated protein kinase (AMPK) mediated effects on development are more pronounced in blastocysts or 2-cell mouse embryos. METHODS: Culture mouse zygotes to two-cell embryos and test effects after 0.5-1 h AMPK agonists' (e.g., Met, BR-DIM) exposure on AMPK-dependent ACCser79P phosphorylation and/or Oct4 by immunofluorescence. Culture morulae to blastocysts and test for increased ACCser79P, decreased Oct4 and for AMPK dependence by coculture with AMPK inhibitor compound C (CC)...
September 15, 2017: Journal of Assisted Reproduction and Genetics
https://www.readbyqxmd.com/read/28905939/curcumin-administration-suppresses-collagen-synthesis-in-the-hearts-of-rats-with-experimental-diabetes
#5
Shuang Guo, Xiang-Wen Meng, Xiao-Song Yang, Xiu-Fen Liu, Chang-Han Ou-Yang, Chao Liu
Cardiac fibrosis is considered the initial change of diabetic cardiomyopathy (DCM). We have shown that curcumin alleviates collagen deposition in DCM, but the mechanism remains unknown. In this study we sought to investigate the effects of curcumin on cardiac fibrosis in vivo and in vitro and to elucidate the underlying mechanisms. Experimental diabetes was induced in rats by injection of low-dose streptozotocin (STZ) combined with high energy diet. The rats were orally treated with curcumin (300 mg·kg(-1)·d(-1)) for 16 weeks...
September 14, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28900501/metformin-sensitizes-leukemia-cells-to-vincristine-via-activation-of-amp-activated-protein-kinase
#6
Yong Yi, Linfeng Gao, Min Wu, Juan Ao, Chunyan Zhang, Xiaodong Wang, Min Lin, Johann Bergholz, Yujun Zhang, Zhi-Xiong Jim Xiao
Vincristine is extensively used chemotherapeutic medicine to treat leukemia. However, it remains a critical clinical problem with regard to its toxicity and drug-resistance. AMP-activated protein kinase (AMPK) is an energy sensor that is pivotal in maintaining cell metabolic homeostasis. It is reported that AMPK is involved in vincristine-induced apoptosis. However, whether AMPK is involved in chemotherapy-resistance is largely unclear. It is well-documented that metformin, a widely used medicine to treat type II diabetes, possesses anti-cancer activities, yet whether metformin affects leukemia cell viability via vincristine is unknown...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28894049/the-pathophysiological-basis-of-the-protective-effects-of-metformin-in-heart-failure
#7
Aleksandra Dziubak, Grażyna Wójcicka
Metformin, currently recommended as the drug of first choice in type 2 diabetes mellitus (T2DM), is one of the few antihiperglycemic drugs to reduce cardiovascular risk. Nonetheless, due to the risk of lactic acidosis during metformin therapy, its usage in patients with diabetes and heart failure (HF) is still a matter of debate. The aim of this review is to present data supporting the possibility of using metformin in the treatment of diabetic patients with concomitant heart failure. In the failing heart, metformin through the mechanism related to AMP-activated protein kinase (AMPK) activity, improves free fatty acids (FFA) and glucose metabolism, mitochondrial biogenesis, as well as nitric oxide (NO)-NO synthase pathway...
August 24, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28847008/effects-of-metformin-on-inflammation-oxidative-stress-and-bone-loss-in-a-rat-model-of-periodontitis
#8
Aurigena Antunes de Araújo, Aline de Sousa Barbosa Freitas Pereira, Caroline Addison Carvalho Xavier de Medeiros, Gerly Anne de Castro Brito, Renata Ferreira de Carvalho Leitão, Lorena de Souza Araújo, Paulo Marcos Matta Guedes, Sarah Hiyari, Flávia Q Pirih, Raimundo Fernandes de Araújo Júnior
AIM: To evaluate the effects of metformin (Met) on inflammation, oxidative stress, and bone loss in a rat model of ligature-induced periodontitis. MATERIALS & METHODS: Male albino Wistar rats were divided randomly into five groups of twenty-one rats each, and given the following treatments for 10 days: (1) no ligature + water, (2) ligature + water, (3) ligature + 50 mg/kg Met, (4) ligature + 100 mg/kg Met, and (5) ligature + 200 mg/kg Met. Water or Met was administered orally...
2017: PloS One
https://www.readbyqxmd.com/read/28821394/activation-of-ampk-is-neuroprotective-in-the-oxidative-stress-by-advanced-glycosylation-end-products-in-human-neural-stem-cells
#9
Chien-Hung Lin, Yi-Chuan Cheng, Christopher J Nicol, Kuan-Hung Lin, Chia-Hui Yen, Ming-Chang Chiang
Advanced glycosylation end products (AGEs) formation is correlated with the pathogenesis of diabetic neuronal damage, but its links with oxidative stress are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). Once activated, AMPK regulates many pathways central to metabolism and energy balance including, glucose uptake, glycolysis and fatty acid oxidation. AMPK is also present in neurons, but its role remains unclear...
August 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28817623/metformin-attenuates-myocardial-ischemia-reperfusion-injury-via-up-regulation-of-antioxidant-enzymes
#10
Xiaoling Wang, Lei Yang, Licheng Kang, Jing Li, Liang Yang, Jincai Zhang, Jie Liu, Mengmeng Zhu, Qiong Zhang, Yanna Shen, Zhi Qi
The objective was to examine the protective effect of metformin (Met) on myocardial ischemia-reperfusion (IR) injury and whether the mechanism was related to the AMPK/ antioxidant enzymes signaling pathway. Rat Langendorff test and H2O2-treated rat cardiomyocytes (H9c2) were used in this study. Met treatment significantly improved left ventricular (LV) function, reduced infarct size and CK-MB release in comparison with IR group. Decreased TUNEL staining positive cells were also observed in IR+Met group ex vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28816632/the-liver-circadian-clock-modulates-biochemical-and-physiological-responses-to-metformin
#11
Emma Henriksson, Anne-Laure Huber, Erin K Soto, Anna Kriebs, Megan E Vaughan, Drew Duglan, Alanna B Chan, Stephanie J Papp, Madelena Nguyen, Megan E Afetian, Katja A Lamia
Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Although metformin is a relatively safe and effective drug, its clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic use of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice...
August 2017: Journal of Biological Rhythms
https://www.readbyqxmd.com/read/28801594/deficiency-in-catechol-o-methyltransferase-is-linked-to-a-disruption-of-glucose-homeostasis-in-mice
#12
Megumi Kanasaki, Swayam Prakash Srivastava, Fan Yang, Ling Xu, Sumiyo Kudoh, Munehiro Kitada, Norikazu Ueki, Hyoh Kim, Jinpeng Li, Satoru Takeda, Keizo Kanasaki, Daisuke Koya
2-methoxyestradiol (2-ME), an estrogen metabolite generated via catechol-o-methyltransferase (COMT), is multifunctional methoxy-catechol. Here, we report that COMT deficiency leads to glucose intolerance and 2-ME rescues COMT-deficient-associated metabolic defects. Liver COMT protein was suppressed in high fat diet (HFD)-fed or in pregnant mice. COMT suppression, by Ro41-0960 or siRNA, in HFD fed mice or in pregnant mice exacerbated glucose intolerance; 2-ME intervention ameliorated these defects. 2-ME effects on glucose tolerance were associated with AMPK phosphorylation in the liver and in islet cells...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28791738/metformin-promotes-neuronal-differentiation-and-neurite-outgrowth-through-ampk-activation-in-human-bone-marrow-mesenchymal-stem-cells
#13
Min-Ji Ahn, Goang-Won Cho
Metformin is an AMP-activated kinase (AMPK) activator that plays a role in glucose energy metabolism and cell protection. It is widely used to treat several diseases, including type 2 diabetes, cardiovascular diseases, cancer, and metabolic diseases. In this study, we investigated whether AMPK activation upon treatment with metformin may promote neurite outgrowth during the progression of neuronal differentiation in human bone marrow-mesenchymal stem cells (hBM-MSCs). Differentiation of metformin-treated MSCs (Met-MSCs to Met-diMSCs) in the neuronal induction media resulted in an increase in the number of differentiated cells in a metformin concentration dependent manner...
August 9, 2017: Biotechnology and Applied Biochemistry
https://www.readbyqxmd.com/read/28791487/metformin-attenuates-the-tlr4-inflammatory-pathway-in-skeletal-muscle-of-diabetic-rats
#14
Leonardo Gomes Peixoto, Renata Roland Teixeira, Danielle Diniz Vilela, Lara Naves Barbosa, Douglas Carvalho Caixeta, Simone Ramos Deconte, Fernanda de Assis de Araújo, Robinson Sabino-Silva, Foued Salmen Espindola
AIMS: Inflammation induced by hyperglycemia triggers the toll-like receptor (TLR) pathway into cells. Our hypothesis was that metformin treatment attenuates the TLR signaling pathways triggered by inflammation in skeletal muscle of hypoinsulinemic/hyperglycemic STZ-induced rats. Thus, we examined TLR signaling under hypoinsulinemia and hyperglycemia conditions and its correlation with insulin resistance in muscle of diabetic rats treated with metformin. METHODS: Ten-day diabetic rats were submitted to 7 days of saline (D group) or metformin (500 mg/kg once per day) (D + M group)...
August 9, 2017: Acta Diabetologica
https://www.readbyqxmd.com/read/28791376/macc1-induces-autophagy-to-regulate-proliferation-apoptosis-migration-and-invasion-of-squamous-cell-carcinoma
#15
Jian Wu, Dawei Zhang, Jun Li, Xin Deng, Guannan Liang, Yang Long, Xuemei He, Tianyang Dai, Delian Ren
Metastasis-associated colon cancer-1 (MACC1) plays an important role in cancer development, but the role and mechansim of MACC1 in squamous cell carcinoma (ESCC) remain unclear. In this study, we found that MACC1 expression was increased in ESCC, and correlated with lymph node metastasis. MACC1 knockdown suppresed ESCC cell proliferation, metastasis and enchanced cell apoptosis. Moreover, MACC1 knockdown inhibited ESCC cell autophagy, and 3-methyladenine was able to rescue MACC1-induced malignant phenotype of ESCC cells...
August 8, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28776086/the-mechanisms-of-action-of-metformin
#16
REVIEW
Graham Rena, D Grahame Hardie, Ewan R Pearson
Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration...
August 3, 2017: Diabetologia
https://www.readbyqxmd.com/read/28769124/metformin-inhibits-cyst-formation-in-a-zebrafish-model-of-polycystin-2-deficiency
#17
Ming-Yang Chang, Tsu-Lin Ma, Cheng-Chieh Hung, Ya-Chung Tian, Yung-Chang Chen, Chih-Wei Yang, Yi-Chuan Cheng
Autosomal dominant polycystic kidney disease (ADPKD) is a common kidney disease caused by mutations in PKD1 or PKD2. Metformin reduces cyst growth in mouse models of PKD1. However, metformin has not been studied in animal models of PKD2, and the cellular mechanism underlying its effectiveness is not entirely clear. This study investigated the effects of metformin on cyst formation in a zebrafish model of polycystin-2 deficiency resulting from morpholino knockdown of pkd2. We added metformin (2.5 to 20 mM) to the embryo media between 4 and 48 hours post fertilisation and observed pronephric cyst formation by using the wt1b promoter-driven GFP signal in Tg(wt1b:GFP) pkd2 morphants...
August 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28767685/histone-deacetylase-inhibition-prevents-cell-death-induced-by-loss-of-tricellular-tight-junction-proteins-in-temperature-sensitive-mouse-cochlear-cells
#18
Kenichi Takano, Takuya Kakuki, Yakuto Kaneko, Takayuki Kohno, Shin Kikuchi, Tetsuo Himi, Takashi Kojima
Tricellular tight junctions (tTJs) are specialized structures that occur where the corners of three cells meet to seal adjacent intercellular space. The molecular components of tTJs include tricellulin (TRIC) and lipolysis-stimulated lipoprotein receptor (LSR) which recruits TRIC, are required for normal hearing. Although loss of TRIC causes hearing loss with degeneration of cochlear cells, the detailed mechanisms remains unclear. In the present study, by using temperature-sensitive mouse cochlear cells, US/VOT-E36 cell line, we investigated the changes of TRIC and LSR during cochlear cell differentiation and the effects of histone deacetylase (HDAC) inhibitors against cell degeneration induced by loss of TRIC and LSR...
2017: PloS One
https://www.readbyqxmd.com/read/28766983/lkb1-ampk-modulates-nutrient-induced-changes-in-the-mode-of-division-of-intestinal-epithelial-crypt-cells-in-mice
#19
Katherine Blackmore, Weinan Zhou, Megan J Dailey
Nutrient availability influences intestinal epithelial stem cell proliferation and tissue growth. Increases in food result in a greater number of epithelial cells, villi height and crypt depth. We investigated whether this nutrient-driven expansion of the tissue is the result of a change in the mode of intestinal epithelial stem cell division and if LKB1-AMPK signaling plays a role. We utilized in vivo and in vitro experiments to test this hypothesis. C57BL/6J mice were separated into four groups and fed varying amounts of chow for 18 h: (1) ad libitum, (2) 50% of their average daily intake (3) fasted or (4) fasted for 12 h and refed...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28755883/metformin-insights-into-its-anticancer-potential-with-special-reference-to-ampk-dependent-and-independent-pathways
#20
REVIEW
Shoeb Ikhlas, Masood Ahmad
Metformin has been known for its antidiabetic effects for decades and is used as a first line therapy in type 2 diabetes. But recently its anticancer potential has also been discovered. Metformin targets many pathways that play an important role in cancer cell proliferation and angiogenesis, mTORC1 signaling is a crucial pathway among them. Metformin inhibits mTORC1 via AMPK dependent and AMPK independent pathways, thereby inhibiting cancer cell growth and development. Encouraged by positive results of numerous preclinical studies on various types of cancer, many clinical trials are underway to study metformin's effect in chemoprevention and treatment of cancers in humans...
July 26, 2017: Life Sciences
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