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Metformin AND AMPK

Amber F MacDonald, Ahmed Bettaieb, Dallas R Donohoe, Dina S Alani, Anna Han, Yi Zhao, Jay Whelan
BACKGROUND: Zyflamend, a blend of herbal extracts, effectively inhibits tumor growth using preclinical models of castrate-resistant prostate cancer mediated in part by 5'-adenosine monophosphate-activated protein kinase (AMPK), a master energy sensor of the cell. Clinically, treatment with Zyflamend and/or metformin (activators of AMPK) had benefits in castrate-resistant prostate cancer patients who no longer responded to treatment. Two predominant upstream kinases are known to activate AMPK: liver kinase B1 (LKB1), a tumor suppressor, and calcium-calmodulin kinase kinase-2 (CaMKK2), a tumor promotor over-expressed in many cancers...
June 18, 2018: BMC Complementary and Alternative Medicine
Yapeng Li, Dianhong Zhang, Lingyao Kong, Huiting Shi, Xinyu Tian, Lu Gao, Yuzhou Liu, Leiming Wu, Binbin Du, Zhen Huang, Cui Liang, Zheng Wang, Rui Yao, Yanzhou Zhang
Metabolic dysfunction is a hallmark of cardiac hypertrophy and heart failure. During cardiac failure, the metabolism of cardiomyocyte switches from fatty acid oxidation to glycolysis. However, the roles of key metabolic enzymes in cardiac hypertrophy are not understood fully. Here in the present work, we identified Aldolase A (AldoA) as a core regulator of cardiac hypertrophy. The mRNA and protein levels of AldoA were significantly up-regulated in transverse aortic constriction (TAC)- and isoproterenol (ISO)-induced hypertrophic mouse hearts...
June 11, 2018: Experimental Cell Research
Guohui Qin, Jingyao Lian, Lan Huang, Qitai Zhao, Shasha Liu, Zhen Zhang, Xinfeng Chen, Dongli Yue, Lifeng Li, Feng Li, Lidong Wang, Viktor Umansky, Bin Zhang, Shengli Yang, Yi Zhang
Purpose : Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. Experimental Design : We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured...
2018: Oncoimmunology
Ran Lu, Jin Yang, Rui Wei, Jing Ke, Qing Tian, Fei Yu, Junling Liu, Jingjing Zhang, Tianpei Hong
Either metformin or liraglutide has been reported to have anti-tumor effects on pancreatic cancer cells. However, it is not clear whether their combined treatment has additive or synergistic anti-tumor effects on pancreatic cancer cells. In this study, the human pancreatic cancer cell line MiaPaca-2 was incubated with liraglutide and/or metformin. The cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound-healing and transwell migration assays were used to detect cell viability, clonogenic survival, cell cycle and cell migration, respectively...
2018: PloS One
You-Lin Tain, Chien-Ning Hsu
Suboptimal early-life conditions affect the developing kidney, resulting in long-term programming effects, namely renal programming. Adverse renal programming increases the risk for developing hypertension and kidney disease in adulthood. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life. AMP-activated protein kinase (AMPK) plays a key role in normal renal physiology and the pathogenesis of hypertension and kidney disease. This review discusses the regulation of AMPK in the kidney and provides hypothetical mechanisms linking AMPK to renal programming...
June 12, 2018: International Journal of Molecular Sciences
Juan Zhu, Kewei Liu, Kaibin Huang, Yong Gu, Yafang Hu, Suyue Pan, Zhong Ji
BACKGROUND: Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation. METHODS AND RESULTS: Rats were subjected to 9-minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP-activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation...
June 12, 2018: Journal of the American Heart Association
Alicia J Jenkins, Paul Welsh, John R Petrie
PURPOSE OF REVIEW: We provide an overview of recent publications that extend clinically relevant knowledge relating to metformin's effects on lipids and atherosclerotic vascular disease and/or provide insights into the drug's mechanisms of action on the heart and vasculature. RECENT FINDINGS: We focus on original research in humans or in human tissues. Several recently completed randomized clinical trials have reported effects of metformin on surrogate measures of atherosclerotic vascular disease, including carotid-intima media thickness, vascular reactivity and calcification in people with Type 1 (T1D) and Type 2 (T2D) diabetes as well as nondiabetic dysglycaemia...
June 6, 2018: Current Opinion in Lipidology
Luana A Biondo, Helena A Batatinha, Camila O Souza, Alexandre A S Teixeira, Loreana S Silveira, Maria I Alonso-Vale, Lila M Oyama, Michele J Alves, Marilia Seelaender, José C R Neto
Doxorubicin (DX) is a chemotherapeutic drug that is used in clinical practice that promotes deleterious side effects in non-tumor tissues such as adipose tissue. We showed that DX leads to extensive damage in adipose tissue via a disruption in 5'-adenosine monophosphate-activated protein kinase (AMPK) and PPAR-gamma signaling. Thus, we investigated whether co-treatment with the biguanide drug metformin (MET) could prevent the side effects of DX through the activation of AMPK in adipose tissue. The goal of the present study was to verify the effects of DX and adjuvant MET treatment in subcutaneous adipose tissue (SAT) and to determine whether MET could protect against chemotherapy-induced side effects...
2018: Frontiers in Pharmacology
Peter Arner, Agné Kulyté, Kenneth Batchelor, Jurga Laurencikiene, James Livingston, Mikael Rydén
AIMS: The anti-lipolytic actions of biguanides in fat cells may contribute to their antidiabetic effects. Biguanides use membrane transporters to act intracellularly. The transporters involved in mediating the antilipolytic effect in human fat cells are unknown and were presently examined. MATERIALS AND METHODS: Gene expression of biguanide transporters was mapped in human subcutaneous adipose tissue and in adipocytes before and after differentiation. Those expressed in mature fat cells were knocked down by RNA interference and the antilipolytic effect of metformin and two novel, highly potent biguanides, NT1014 and NT1044, was examined...
June 4, 2018: Diabetes, Obesity & Metabolism
Kejia Wu, Rui Tian, Jing Huang, Yongqiang Yang, Jie Dai, Rong Jiang, Li Zhang
Inflammation requires intensive metabolic support and modulation of the metabolic pathways might become a novel strategy to limit inflammatory injury. Recent studies have revealed the anti-inflammatory effects of the anti-diabetic reagent metformin, but the underlying mechanisms remain unclear. In the present study, the potential effects of metformin on endotoxemia-induced acute lung injury (ALI) and their relationship with the representative metabolic regulator, including AMPK, sirtuin 1 and mTOR, were investigated...
May 31, 2018: Chemico-biological Interactions
Jahahreeh Finley
Learning and memory are generally considered the behavioral correlates of long-term potentiation (LTP), a form of synaptic plasticity associated with a persistent and long-lasting increase in synaptic strength. Repetitive stimulation of excitatory synapses in the hippocampal CA1 region leads to release and binding of glutamate to the glutamate receptors AMPAR and NMDAR located on pyramidal neurons. Activation of AMPARs facilitates Na+ influx, postsynaptic depolarization, NMDAR-mediated Ca2+ influx, and activation of several intracellular mechanisms that characterize LTP, including increased AMPAR synthesis, ROS production, and ER Ca2+ release...
July 2018: Medical Hypotheses
Gretchen Collins, Sam Mesiano, Analisa DiFeo
Endometrial cancer (EC) is the most common gynecologic malignancy and is the result of disruption of the balance between estrogen-stimulated growth and progesterone-induced growth modulation. Metformin has been shown to inhibit EC proliferation; however, its role in early-stage EC and its effects on steroid hormone receptors have not been adequately explored. Our aim was to examine the effects of metformin on cellular proliferation in patient-derived, low-grade EC cell lines and to determine whether it directly modulates steroid hormone receptor expression...
January 1, 2018: Reproductive Sciences
Jaroon Wandee, Auemduan Prawan, Laddawan Senggunprai, Sarinya Kongpetch, Ornanong Tusskorn, Veerapol Kukongviriyapan
AIMS: AMP-activated protein kinase (AMPK) functions as a cellular energy sensor regulating various aspects of cellular metabolism. Metformin (Met), an activator of AMPK, has been reported to reduce the cancer risk and enhance antitumor effects in certain cancers. Cholangiocarcinoma (CCA) is an aggressive malignancy which rarely responds to chemotherapeutic agents. We investigated the chemosensitizing effects of Met in CCA cells. MATERIALS AND METHODS: KKU-100 and KKU-452 cells were used in the study...
May 27, 2018: Life Sciences
Tyler Barnes, Katie M Di Sebastiano, Filip Vlavcheski, Joe Quadrilatero, Evangelia Tsiani, Marina Mourtzakis
Various in vivo studies have investigated the insulin response that is elicited when glutamate is elevated in circulation or in a given tissue; fewer studies have investigated the effects of glutamate on glucose uptake and handling. Glutamate ingestion in humans can attenuate rises in blood glucose following a carbohydrate load in absence of increases in serum insulin concentrations. However, the underlying mechanisms have yet to be investigated. To elucidate the effects of glutamate on glucose handling in skeletal muscle tissue, differentiated rat L6 myocytes were treated with glutamate and glucose uptake was assessed by the use of [3H]-2-Deoxyglucose ([3H]-2-DG)...
May 30, 2018: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
Derek T Hall, Takla Griss, Jennifer F Ma, Brenda Janice Sanchez, Jason Sadek, Anne Marie K Tremblay, Souad Mubaid, Amr Omer, Rebecca J Ford, Nathalie Bedard, Arnim Pause, Simon S Wing, Sergio Di Marco, Gregory R Steinberg, Russell G Jones, Imed-Eddine Gallouzi
Activation of AMPK has been associated with pro-atrophic signaling in muscle. However, AMPK also has anti-inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory-driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα-induced atrophy, while the mitochondrial inhibitor metformin does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin...
May 29, 2018: EMBO Molecular Medicine
Ritwika Mallik, Tahseen A Chowdhury
Metformin is a lipophilic biguanide which inhibits hepatic gluconeogenesis and improves peripheral utilization of glucose. It is the first line pharmacotherapy for glucose control in patients with Type 2 diabetes due to its safety, efficacy and tolerability. Metformin exhibits pleotropic effects, which may have beneficial effects on a variety of tissues independent of glucose control. A potential anti-tumourigenic effect of metformin may be mediated by its role in activating AMP-kinase, which in turn inhibits mammalian target of rapamycin (mTOR)...
May 26, 2018: Diabetes Research and Clinical Practice
Nanda Gamad, Salma Malik, Kapil Suchal, Swati Vasisht, Ameesha Tomar, Sudheer Arava, Dharamvir Singh Arya, Jagriti Bhatia
BACKGROUND: Metformin, a commonly used oral antidiabetic agent, is known to possess pleiotropic antioxidant, anti-inflammatory and anti-fibrotic effects. In this study, we evaluated the effect of metformin on pulmonary fibrosis and the mechanism underlying its effect. METHODS: Pulmonary fibrosis was induced experimentally with bleomycin (0.035 U/g, i.p.) given twice weekly for four weeks. Metformin (125, 250 and 500 mg/kg/day, p.o) was given seven days prior to first injection of bleomycin and continued till 28 days after starting bleomycin injection...
January 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Dian Chen, Ying Wang, Kaikai Wu, Xingya Wang
Metformin has been reported to have body weight lowering effects while treating type 2 diabetes. However, limited studies examined the effects of metformin on adipogenesis in vitro, and available data are inconclusive and contradictory. In this study, we examined the effects of a variety of concentrations of metformin on adipocyte differentiation of 3T3-L1 preadipocytes and found metformin exhibits a dual effect on adipogenesis. Metformin at lower concentrations (1.25⁻2.5 mM) significantly induced adipogenesis while at higher concentrations (5⁻10 mM) metformin significantly inhibited adipogenesis in 3T3-L1 cells...
May 23, 2018: International Journal of Molecular Sciences
Stephen L Seliger, Kaleab Z Abebe, Kenneth R Hallows, Dana C Miskulin, Ronald D Perrone, Terry Watnick, Kyongtae Tae Bae
BACKGROUND: Metformin inhibits cyclic AMP generation and activates AMP-activated protein kinase (AMPK), which inhibits the cystic fibrosis transmembrane conductance regulator and Mammalian Target of Rapamycin pathways. Together these effects may reduce cyst growth in autosomal dominant polycystic kidney disease (ADPKD). METHODS: A phase II, double-blinded randomized placebo-controlled trial of 26 months duration. Participants will include nondiabetic adults (n = 96) aged 18-60 years, with an estimated glomerular filtration rate (eGFR) ≥50 mL/min/1...
2018: American Journal of Nephrology
Vineela Chukkapalli, Leo I Gordon, Parameswaran Venugopal, Jeffrey A Borgia, Reem Karmali
Metformin exerts direct anti-tumor effects by activating AMP-activated protein kinase (AMPK), a major sensor of cellular metabolism in cancer cells. This, in turn, inhibits pro-survival mTOR signaling. Metformin has also been shown to disrupt complex 1 of the mitochondrial electron transport chain. Here, we explored the lymphoma specific anti-tumor effects of metformin using Daudi (Burkitt), SUDHL-4 (germinal center diffuse large B-cell lymphoma; GC DLBCL), Jeko-1 (Mantle-cell lymphoma; MCL) and KPUM-UH1 (double hit DLBCL) cell lines...
April 20, 2018: Oncotarget
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