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Metformin AND AMPK

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https://www.readbyqxmd.com/read/29032153/metformin-overcomes-high-glucose-induced-insulin-resistance-of-podocytes-by-pleiotropic-effects-on-sirt1-and-ampk
#1
Dorota Rogacka, Irena Audzeyenka, Michał Rychłowski, Patrycja Rachubik, Maria Szrejder, Stefan Angielski, Agnieszka Piwkowska
Podocyte insulin sensitivity is critical for glomerular function, and the loss of appropriate insulin signaling leads to alterations and disorders featuring diabetic nephropathy. Energy-sensing pathways, such as AMP-dependent protein kinase (AMPK) and protein deacetylase SIRT1, have been shown to play an important role in insulin resistance. The absence of a stimulating effect of insulin on glucose uptake into podocytes after exposure to hyperglycemic conditions has been demonstrated to be related to a decreased level and activity of SIRT1 protein, leading to reduced AMPK phosphorylation...
October 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29027899/metformin-extends-c-elegans-lifespan-through-lysosomal-pathway
#2
Jie Chen, Yuhui Ou, Yi Li, Shumei Hu, Li-Wa Shao, Ying Liu
Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin...
October 13, 2017: ELife
https://www.readbyqxmd.com/read/29025968/activation-of-ampk-mtorc1-mediated-autophagy-by-metformin-reverses-clk1-deficiency-sensitized-dopaminergic-neuronal-death
#3
Qiuting Yan, Chaojun Han, Guanghui Wang, John L Waddington, Longtai Zheng, Xuechu Zhen
The autophagy-lysosome pathway (ALP) plays a critical role in the pathology of Parkinson's disease (PD). Clk1 (coq7) is a mitochondrial hydroxylase that is essential for Coenzyme Q (ubiquinone) biosynthesis. We have reported previously that Clk1 regulates microglia activation via modulating microglia metabolic reprogramming, which contributes to dopaminergic neuronal survival. This study explored the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrated that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in SNc of Clk+/- mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects...
October 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29025860/negative-regulation-of-trpa1-by-amp-activated-protein-kinase-in-primary-sensory-neurons-as-a-potential-mechanism-of-painful-diabetic-neuropathy
#4
Shenglan Wang, Kimiko Kobayashi, Yoko Kogure, Hiroki Yamanaka, Satoshi Yamamoto, Hideshi Yagi, Koichi Noguchi, Yi Dai
AMP activated protein kinase (AMPK) is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure. Transient receptor potential ankyrin 1 (TRPA1) channel is a widely recognized chemical and thermal sensor that plays vital roles in pain transduction. Here, we discovered a functional link between AMPK and TRPA1 in dorsal root ganglion (DRG) neurons, in which AMPK activation rapidly resulted in downregulation of membrane-associated TRPA1 and its channel activity within minutes...
October 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28993280/antidiabetic-activities-of-entagenic-acid-in-type-2-diabetic-db-db-mice-and-l6-myotubes-via-ampk-glut4-pathway
#5
Hui Xiong, Shengnan Zhang, Zhongqiu Zhao, Ping Zhao, Lvyi Chen, Zhinan Mei
ETHNOPHARMACOLOGICAL RELEVANCE: Entada phaseoloides (L.) Merr., a traditional Chinese folk medicine, has been used in treating diabetes and other inflammatory disorders. Our previous study revealed that the triterpene saponins in E.Phaseoloides possessed an antidiabetic effect in type 2 diabetic rats by activating AMP-activated protein kinase (AMPK). Entagenic acid, the principal aglycon, isolated from the seed kernels of E. phaseoloides, has been proposed to possess a significant role in the antidiabetic effect, however, its actual effect and pertinent mechanisms are still unknown...
October 7, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28991159/rosmarinic-acid-a-rosemary-extract-polyphenol-increases-skeletal-muscle-cell-glucose-uptake-and-activates-ampk
#6
Filip Vlavcheski, Madina Naimi, Brennan Murphy, Tomas Hudlicky, Evangelia Tsiani
Skeletal muscle is a major insulin-target tissue and plays an important role in glucose homeostasis. Impaired insulin action in muscles leads to insulin resistance and type 2 diabetes mellitus. 5' AMP-activated kinase (AMPK) is an energy sensor, its activation increases glucose uptake in skeletal muscle and AMPK activators have been viewed as a targeted approach in combating insulin resistance. We previously reported AMPK activation and increased muscle glucose uptake by rosemary extract (RE). In the present study, we examined the effects and the mechanism of action of rosmarinic acid (RA), a major RE constituent, in L6 rat muscle cells...
October 7, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28978947/ampk-is-not-required-for-the-effect-of-metformin-on-the-inhibition-of-bmp6-induced-hepcidin-gene-expression-in-hepatocytes
#7
Jean-Christophe Deschemin, Marc Foretz, Benoit Viollet, Sophie Vaulont
The biguanide metformin is used for its antidiabetic effect for many years but how metformin acts remains poorly understood and controversial. AMP-activated protein kinase (AMPK), a protein kinase that plays a key role in maintaining energy homeostasis, is assumed to be one of the prime targets of metformin. However, since our demonstration that AMPK is not required for the beneficial effects of metformin on the control of glycemia, the list of AMPK-independent actions of metformin is rapidly increasing. Given the conflicting results on the effects of metformin we sought, using our genetic mouse models deficient in the catalytic subunits of AMPK, to determine whether this kinase is involved in the effects of metformin on the expression of the iron-regulatory hormone hepcidin, as recently proposed...
October 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28977822/blocking-epithelial-to-mesenchymal-transition-in-glioblastoma-with-a-sextet-of-repurposed-drugs-the-eis-regimen
#8
Richard E Kast, Nicolas Skuli, Georg Karpel-Massler, Guido Frosina, Timothy Ryken, Marc-Eric Halatsch
This paper outlines a treatment protocol to run alongside of standard current treatment of glioblastoma- resection, temozolomide and radiation. The epithelial to mesenchymal transition (EMT) inhibiting sextet, EIS Regimen, uses the ancillary attributes of six older medicines to impede EMT during glioblastoma. EMT is an actively motile, therapy-resisting, low proliferation, transient state that is an integral feature of cancers' lethality generally and of glioblastoma specifically. It is believed to be during the EMT state that glioblastoma's centrifugal migration occurs...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28975042/5-aminoimidazole-4-carboxamide-ribonucleoside-induced-autophagy-flux-during-differentiation-of-monocytic-leukemia-cells
#9
Vilma Dembitz, Hrvoje Lalic, Dora Visnjic
Pharmacological modulators of AMP-dependent kinase (AMPK) have been suggested in treatment of cancer. The biguanide metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) have been reported to inhibit proliferation of solid tumors and hematological malignancies, but their role in differentiation is less explored. Our previous study demonstrated that AICAR alone induced AMPK-independent expression of differentiation markers in monocytic U937 leukemia cells, and no such effects were observed in response to metformin...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28966224/interaction-between-bone-and-glucose-metabolism-review
#10
Ippei Kanazawa
Accumulating evidence has shown that bone and glucose metabolism are closely associated with each other. Since the risk of osteoporotic fractures is increased in patients with diabetes mellitus (DM), osteoporosis is recently recognized as one of diabetic complications, called DM-induced bone fragility. Previous studies showed that collagen cross-links of advanced glycation end products (AGEs) and dysfunctions of osteoblast and osteocyte are involved in DM-induced bone fragility. Circulating levels of AGEs and homocysteine are increased in patients with DM, and they directly impair the functions of osteoblast and osteocyte, resulting in decreased bone formation and bone remodeling...
September 30, 2017: Endocrine Journal
https://www.readbyqxmd.com/read/28964970/metformin-triggers-apoptosis-in-pel-cells-and-alters-bortezomib-induced-unfolded-protein-response-increasing-its-cytotoxicity-and-inhibiting-kshv-lytic-cycle-activation
#11
Marisa Granato, Maria Saveria Gilardini Montani, Maria Anele Romeo, Roberta Santarelli, Roberta Gonnella, Gabriella D'Orazi, Alberto Faggioni, Mara Cirone
Metformin, the most used drug for the treatment of diabetes type 2 patients, has been shown to have anti-cancer properties. In this study, we found that metformin induced apoptosis in Primary Effusion Lymphoma (PEL) cells, an aggressive B cell lymphoma associated with KSHV against which the conventional therapies usually fail. The cytotoxic effect of metformin correlated with intracellular reactive oxygen species reduction, activation of AMPK, the inhibition of pro-survival pathways such as mTOR and STAT3 and the down-regulation of v-FLIP, a latent viral antigen that also plays a pivotal role in PEL cell survival...
September 28, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28964787/negative-regulation-of-sirtuin-1-by-amp-activated-protein-kinase-promotes-metformin-induced-senescence-in-hepatocellular-carcinoma-xenografts
#12
Xinke Zhou, Jitao Chen, Liangcai Chen, Xiao Feng, Zhaoyu Liu, La Hu, Zicheng Zeng, Xiaoting Jia, Min Liang, Boyun Shi, Gao Yi, Jifang Liu
Increasing evidence suggests that therapy-induced senescence (TIS), a novel therapeutic approach in which low doses of therapeutic drugs or radiation are used to induce senescence, suppresses tumor development. Our previous in vitro studies have demonstrated that a low dose of metformin promoted hepatoma cell senescence instead of apoptosis via activation of AMP-activated protein kinase (AMPK) and inactivation of Sirtuin 1 (SIRT1) deacetylase activity. However, the intricate relationship between AMPK and SIRT1, and how they cooperate to induce senescence remains elusive...
September 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28962892/effects-of-metformin-on-cell-growth-and-ampk-activity-in-pituitary-adenoma-cell-cultures-focusing-on-the-interaction-with-adenylyl-cyclase-activating-signals
#13
Lara Faggi, Andrea Giustina, Giovanni Tulipano
For a few years we have been investigating AMP-activated protein kinase (AMPK) as a target for drug therapy of GH-secreting pituitary adenomas. Aim of this study was to investigate the direct effects of metformin, which causes AMPK activation in different cell types, on rat pituitary adenoma cell growth and on related cell signalling pathways. Our results suggest that metformin can exert a growth-inhibitory activity in rat pituitary tumor cells mediated by AMPK activation, although multiple mechanisms are most likely involved...
September 27, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28962017/treatment-with-aicar-inhibits-blastocyst-development-trophectoderm-differentiation-and-tight-junction-formation-and-function-in-mice
#14
Michele D Calder, Nicole A Edwards, Dean H Betts, Andrew J Watson
STUDY QUESTION: What is the impact of adenosine monophosphate-activated protein kinase (AMPK) activation on blastocyst formation, gene expression, and tight junction formation and function? SUMMARY ANSWER: AMPK activity must be tightly controlled for normal preimplantation development and blastocyst formation to occur. WHAT IS KNOWN ALREADY: AMPK isoforms are detectable in oocytes, cumulus cells and preimplantation embryos. Cultured embryos are subject to many stresses that can activate AMPK...
September 13, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28954268/glibenclamide-mimics-metabolic-effects-of-metformin-in-h9c2-cells
#15
Barbara Salani, Silvia Ravera, Patrizia Fabbi, Silvano Garibaldi, Mario Passalacqua, Claudio Brunelli, Davide Maggi, Renzo Cordera, Pietro Ameri
BACKGROUND: Sulfonylureas, such as glibenclamide, are antidiabetic drugs that stimulate beta-cell insulin secretion by binding to the sulfonylureas receptors (SURs) of adenosine triphosphate-sensitive potassium channels (KATP). Glibenclamide may be also cardiotoxic, this effect being ascribed to interference with the protective function of cardiac KATP channels for which glibenclamide has high affinity. Prompted by recent evidence that glibenclamide impairs energy metabolism of renal cells, we investigated whether this drug also affects the metabolism of cardiac cells...
September 28, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28947430/sirt2-acts-as-a-cardioprotective-deacetylase-in-pathological-cardiac-hypertrophy
#16
Xiaoqiang Tang, Xiao-Feng Chen, Nan-Yu Wang, Xiao-Man Wang, Shu-Ting Liang, Wei Zheng, Yun-Biao Lu, Xiang Zhao, De-Long Hao, Zhu-Qin Zhang, Ming-Hui Zou, De-Pei Liu, Hou-Zao Chen
Background -Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)-induced pathological cardiac hypertrophy. Methods -Male C57BL/6J wild-type (WT) and Sirt2 knockout (Sirt2-KO) mice were subjected to the investigation of aging-related cardiac hypertrophy...
September 25, 2017: Circulation
https://www.readbyqxmd.com/read/28945024/-pathogenesis-and-treatment-of-insulin-resistance-in-chronic-kidney-disease-and-interventional-effects-of-chinese-herbal-medicine
#17
REVIEW
Wei Wu, Jing-Jing Yang, Yi-Gang Wan, Yue Tu, Ge Shi, Wen-Bei Han, Bu-Hui Liu, Jian Yao
The kidney is the target organ of insulin with abundant insulin receptors. Thereinto,the renal intrinsic cells including glomerular podocytes,endothelial cells,mesangial cells,renal tubular epitheliums and collecting duct epithelial cells are all highly sensitive to insulin as the effector cells. Furthermore,the structural and functional abnormalities of these cells are closely related to insulin and its receptors activity. It is reported that the chronic kidney disease(CKD)patients have systemic or renal insulin resistance(IR)...
January 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/28937612/houttuynia-cordata-facilitates-metformin-on-ameliorating-insulin-resistance-associated-with-gut-microbiota-alteration-in-oletf-rats
#18
Jing-Hua Wang, Shambhunath Bose, Soo-Kyoung Lim, AbuZar Ansari, Young-Won Chin, Han Seok Choi, Hojun Kim
Metformin and Houttuynia cordata are representative anti-diabetic therapeutics in western and oriental medicine, respectively. The current study examined the synergistic anti-diabetic effect of Houttuynia cordata extraction (HCE) and metformin combination in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Fecal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE) and real-time PCR. Combining HCE + metformin resulted in significantly ameliorated glucose tolerance (oral glucose tolerance test (OGTT))-the same as metformin alone...
September 22, 2017: Genes
https://www.readbyqxmd.com/read/28935544/metformin-improves-obesity-associated-inflammation-by-altering-macrophages-polarization
#19
Yuanyuan Jing, Fan Wu, Dai Li, Lei Yang, Qi Li, Rong Li
Obesity is reported to be a chronic low-grade inflammatory state. Adipose tissue macrophages play a key role in obesity-related inflammation. Metformin, the most widely used anti-diabetic drug, has recently been reported to have an effect on inflammation, but the mechanism is poorly understood. This study aims to investigate how metformin works on chronic low-grade inflammation in obesity and whether the mechanism underlying it is associated with macrophage polarization. Metformin was administered for 7 weeks to high fat-fed C57/6J male mice in vivo...
September 18, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28933290/nutraceuticals-and-repurposed-drugs-of-phytochemical-origin-in-prevention-and-interception-of-chronic-degenerative-disease-and-cancer
#20
Adriana Albini, Barbara Bassani, Denisa Baci, Katiuscia Dallaglio, Matteo Gallazzi, Paola Corradino, Antonino Bruno, Douglas M Noonan
Chronic, degenerative diseases are often characterized by inflammation and aberrant angiogenesis. For many of these pathologies, including rheumatoid arthritis, cardiovascular and autoimmune diseases, cancer, diabetes, and obesity, current therapies have limited efficacy, thus the validation of novel (chemo)preventive and interceptive approaches, of new or repurposed agents, alone or in combination with registered drugs, are urgently required. Phytochemicals (triterpenoids, flavonoids, retinoids) and their derivatives, non-steroidal anti-inflammatory drugs (aspirin) as well as biguanides (metformin and phenformin) originally developed from phytochemical backbones, are multi-target agents showing anti-angiogenic and anti-anti-inflammatory proprieties...
September 20, 2017: Current Medicinal Chemistry
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