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the target of metformin

Faisal E Al Jofi, Tao Ma, Dong Guo, Monica P Schneider, Yan Shu, Hockin H K Xu, Abraham Schneider
BACKGROUND: Compelling evidence indicates that metformin, a low-cost and safe orally administered biguanide prescribed to millions of type 2 diabetics worldwide, induces the osteoblastic differentiation of mesenchymal stromal cells (MSCs) through the 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway. As a highly hydrophilic cationic compound, metformin uptake is facilitated by cell membrane organic cation transporters (OCTs) of the solute carrier 22A gene family...
March 16, 2018: Cytotherapy
Yan Wang, Wenbin Xu, Zixun Yan, Weili Zhao, Jianqing Mi, Junmin Li, Hua Yan
BACKGROUND: Metformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-tumor effects in many cancers, including multiple myeloma (MM); however, the underlying molecular mechanisms have not been clearly elucidated. METHODS: The anti-myeloma effects of metformin were evaluated using human MM cell lines (RPMI8226 and U266) in vitro and in vivo NOD-SCID murine xenograft MM model. Cell viability was assessed with CCK8 and cell proliferation was measured by EdU incorporation assay...
March 20, 2018: Journal of Experimental & Clinical Cancer Research: CR
Rowena M Briones, Ajit K Sarmah
Detection of metformin, an antidiabetic drug and its transformation product guanylurea in various environmental matrices such as surface water and groundwater, coupled with their effects on aquatic organisms warrant an understanding of the compounds fate and behaviour in the environment. Batch studies were conducted with the aim of evaluating the sorption of these two emerging contaminants in six New Zealand agricultural soils of contrasting physico-chemical properties. Kinetic studies revealed that metformin and guanylurea sorption in Te Kowhai soil was very rapid initially achieving 90% sorption within the first 4 and 13h, respectively...
March 2, 2018: Science of the Total Environment
Zhaodi Zheng, Wenzhen Zhu, Bingwu Yang, Rongfei Chai, Tingting Liu, Fenglin Li, Guanghui Ren, Shuhua Ji, Shan Liu, Guorong Li
Metformin, a widely used antidiabetic drug, exhibits anticancer effects which are mediated by the phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT) signaling pathway. However, its use in anticancer therapy combined with other natural products remains unclear. Flavone as the core structure of flavonoids has been demonstrated to induce cell apoptosis without causing serious side effect. Murine double minute X (MDMX) inhibits tumor suppressor gene p53 whose function is associated with the PI3K/AKT pathway...
April 2018: Oncology Letters
Corina T Madreiter-Sokolowski, Armin A Sokolowski, Markus Waldeck-Weiermair, Roland Malli, Wolfgang F Graier
Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca2+ sequestration, fine-tuning mitochondrial activity appropriately, is a tightrope walk during aging. For instance, the mitochondrial oxidative phosphorylation (OXPHOS) ensures a supply of adenosine triphosphate (ATP), but is also the main source of potentially harmful levels of reactive oxygen species (ROS)...
March 16, 2018: Genes
Stephen Safe, James L Abbruzzese, Maen Abdelrahim, Erik Hedrick
Specificity protein (Sp) transcription factors (TFs) such as Sp1 are critical for early development but their expression decreases with age and there is evidence that transformation of normal cells to cancer cells is associated with upregulation of Sp1, Sp3 and Sp4 which are highly expressed in cancer cells and tumors. Sp1 is a negative prognostic factor for pancreatic, colon, glioma, gastric, breast, prostate, and lung cancer patients. Functional studies also demonstrate that Sp TFs regulate genes responsible for cancer cell growth, survival, migration/invasion, inflammation and drug resistance, and Sp1, Sp3 and Sp4 are also non-oncogene addiction (NOA) genes and important drug targets...
March 15, 2018: Cancer Prevention Research
Sen Xu, Zong-Yuan Yang, Ping Jin, Xin Yang, Xiaoting Li, Xiao Wei, Ya Wang, Sixiang Long, Taoran Zhang, Gang Chen, Chaoyang Sun, Ding Ma, Qinglei Gao
Ovarian cancer (OC) is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in OC. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the OC tumor cells...
March 15, 2018: Molecular Cancer Therapeutics
Liisa Ailanen, Natalia N Bezborodkina, Laura Virtanen, Suvi T Ruohonen, Anastasia V Malova, Sergey V Okovityi, Elizaveta Y Chistyakova, Eriika Savontaus
Hepatic insulin resistance and increased gluconeogenesis are known therapeutic targets of metformin, but the role of hepatic glycogen in the pathogenesis of diabetes is less clear. Mouse model of neuropeptide Y (NPY) overexpression in noradrenergic neurons (OE-NPYD βH ) with a phenotype of late onset obesity, hepatosteatosis, and prediabetes was used to study early changes in glycogen structure and metabolism preceding prediabetes. Furthermore, the effect of the anti-hyperglycemic agent, metformin (300 mg/kg/day/4 weeks in drinking water), was assessed on changes in glycogen metabolism, body weight, fat mass, and glucose tolerance...
April 2018: Pharmacology Research & Perspectives
Eunyoung Bang, Boyoung Lee, Joon-Oh Park, Yooncheol Jang, Aekyong Kim, Sungwuk Kim, Hee-Sup Shin
In recent years, as the aging population grows, aging-induced cognitive impairments including dementia and Alzheimer's disease (AD) have become the biggest challenges for global public health and social care. Therefore, the development of potential therapeutic drugs for aging-associated cognitive impairment is essential. Metabolic dysregulation has been considered to be a key factor that affects aging and dementia. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a primary sensor of cellular energy states and regulates cellular energy metabolism...
February 2018: Experimental Neurobiology
Min Hu, Yuehui Zhang, Jiaxing Feng, Xue Xu, Jiao Zhang, Wei Zhao, Xiaozhu Guo, Juan Li, Edvin Vestin, Peng Cui, Xin Li, Xiaoke Wu, Mats Brannstrom, Linus R Shao, Hakan Billig
Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance...
March 13, 2018: Journal of Endocrinology
Frank Matthes, Moritz M Hettich, Judith Schilling, Diana Flores-Dominguez, Nelli Blank, Thomas Wiglenda, Alexander Buntru, Hanna Wolf, Stephanie Weber, Ina Vorberg, Alina Dagane, Gunnar Dittmar, Erich Wanker, Dan Ehninger, Sybille Krauss
Alzheimer's disease (AD) is characterized by two neuropathological hallmarks: senile plaques, which are composed of amyloid-β (Aβ) peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated tau protein. Aβ peptides are derived from sequential proteolytic cleavage of the amyloid precursor protein (APP). In this study, we identified a so far unknown mode of regulation of APP protein synthesis involving the MID1 protein complex: MID1 binds to and regulates the translation of APP mRNA...
December 2018: Cell Death Discovery
Ke Li, Ting-Ting Zhang, Feng Wang, Bing Cui, Chen-Xi Zhao, Jiao-Jiao Yu, Xiao-Xi Lv, Xiao-Wei Zhang, Zhao-Na Yang, Bo Huang, Xia Li, Fang Hua, Zhuo-Wei Hu
Metformin has beneficial effects of preventing and treating cancers on type 2 diabetic patients. However, the role of metformin in non-diabetic cancer patients and the precise molecular mechanisms against cancer have not yet been sufficiently elucidated. We recently reported that the pseudokinase protein TRIB3 acts as a stress sensor linking metabolic stressors to cancer promotion by inhibiting autophagy and ubiquitin-proteasomal degradation systems; genetically abrogating of TRIB3 expression reduces tumourigenesis and cancer progression...
March 9, 2018: Oncogene
A H Heald, A A Fryer, S G Anderson, M Livingston, M Lunt, M Davies, Gyc Moreno, R Gadsby, R J Young, M Stedman
AIMS: Despite increasing spend on new Type 2 diabetes mellitus (T2DM) therapies, the proportion of people with T2DM achieving target glycaemia outcomes is declining. Our aim was to determine, using published General Practice level data, how differences in T2DM prescribing patterns relate to glycaemic target achievement levels. METHODS: Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of class of medication in 2015/16 and changes to 2014/15 in medication to proportions achieving target glycaemic control (TGC; glycated haemoglobin A1c (HbA1c) ≤7...
March 8, 2018: Diabetes, Obesity & Metabolism
Haoran Wang, Chen Zhu, Ying Ying, Lingyu Luo, Deqiang Huang, Zhijun Luo
Metformin has been used as a glucose lowering drug for several centuries and is now a first-line drug for type 2 diabetes mellitus (T2DM). Since the discovery that it activates AMP-activated protein kinase (AMPK) and reduces risk of cancer, metformin has drawn great attentions. Another drug, berberine, extracted from berberis vulgaris L. (root), was an ancient herbal medicine in treating diarrhea. Ongoing experimental and clinical studies have illuminated great potential of berberine in regulation of glucose and lipid homeostasis, cancer growth and inflammation...
February 9, 2018: Oncotarget
Lucía Trilla-Fuertes, Angelo Gámez-Pozo, Jorge M Arevalillo, Mariana Díaz-Almirón, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Hilario Navarro, Rosa Aras-López, Irene Dapía, Rocío López-Vacas, Paolo Nanni, Sara Llorente-Armijo, Pedro Arias, Alberto M Borobia, Paloma Maín, Jaime Feliú, Enrique Espinosa, Juan Ángel Fresno Vara
Metabolic reprogramming is a hallmark of cancer. It has been described that breast cancer subtypes present metabolism differences and this fact enables the possibility of using metabolic inhibitors as targeted drugs in specific scenarios. In this study, breast cancer cell lines were treated with metformin and rapamycin, showing a heterogeneous response to treatment and leading to cell cycle disruption. The genetic causes and molecular effects of this differential response were characterized by means of SNP genotyping and mass spectrometry-based proteomics...
February 9, 2018: Oncotarget
Yitao Chen, Yangsheng Wu, Yuanxiao Yang, Zhiwei Xu, Junfeng Tong, Zheming Li, Xiaojie Zhou, Changyu Li
The main actions of metformin are as follows: To reduce hyperglycemia via the suppression of gluconeogenesis, improve glucose uptake and insulin sensitivity, and stimulate activation of adenosine monophosphate‑activated protein kinase during the treatment of diabetes mellitus. It is well known that metformin acts via complex mechanisms, including multitarget and multipathway mechanisms; however, the multitargeted antidiabetic genes of metformin remain obscure. The present study aimed to perform transcriptomic and proteomic analysis of potential therapeutic target genes in the liver of metformin‑treated Sprague‑Dawley rats with type 2 diabetes mellitus...
March 6, 2018: International Journal of Molecular Medicine
Bahendeka Silver, Kaushik Ramaiya, Swai Babu Andrew, Otieno Fredrick, Sarita Bajaj, Sanjay Kalra, Bavuma M Charlotte, Karigire Claudine, Anthony Makhoba
A diagnosis of diabetes or hyperglycemia should be confirmed prior to ordering, dispensing, or administering insulin (A). Insulin is the primary treatment in all patients with type 1 diabetes mellitus (T1DM) (A). Typically, patients with T1DM will require initiation with multiple daily injections at the time of diagnosis. This is usually short-acting insulin or rapid-acting insulin analogue given 0 to 15 min before meals together with one or more daily separate injections of intermediate or long-acting insulin...
March 5, 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Antonio Cuadrado, Gina Manda, Ahmed Hassan, María José Alcaraz, Coral Barbas, Andreas Daiber, Pietro Ghezzi, Rafael León, Manuela G López, Baldo Oliva, Marta Pajares, Ana I Rojo, Natalia Robledinos-Antón, Angela M Valverde, Emre Guney, Harald H H W Schmidt
Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome)...
April 2018: Pharmacological Reviews
Cinzia Antognelli, Rodolfo Cecchetti, Francesca Riuzzi, Matthew J Peirce, Vincenzo N Talesa
Metastasis is the primary cause of death in prostate cancer (PCa) patients. Effective therapeutic intervention in metastatic PCa is undermined by our poor understanding of its molecular aetiology. Defining the mechanisms underlying PCa metastasis may lead to insights into how to decrease morbidity and mortality in this disease. Glyoxalase 1 (Glo1) is the detoxification enzyme of methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs). Hydroimidazolone (MG-H1) and argpyrimidine (AP) are AGEs originating from MG-mediated post-translational modification of proteins at arginine residues...
March 5, 2018: Journal of Cellular and Molecular Medicine
Wen-Jing Liang, Sheng-Nan Zhou, Mei-Rong Shan, Xue-Qin Wang, Miao Zhang, Yuan Chen, Yun Zhang, Shuang-Xi Wang, Tao Guo
Diabetes mellitus is one of risk factors of cardiovascular diseases including atherosclerosis. Whether and how diabetes promotes the formation of unstable atherosclerotic plaque is not fully understood. Here, we show that streptozotocin-induced type 1 diabetes reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout (Apoe-/- ) mice. These detrimental effects of hyperglycemia on plaque stability were reversed by metformin in vivo without altering the levels of blood glucose and lipids...
March 3, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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