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AMPK AND metformin

Davide Di Fusco, Vincenzo Dinallo, Ivan Monteleone, Federica Laudisi, Irene Marafini, Eleonora Franzè, Antonio Di Grazia, Rami Dwairi, Alfredo Colantoni, Angela Ortenzi, Carmine Stolfi, Giovanni Monteleone
Metformin, a hypoglycemic drug used for treatment of type 2 diabetes, regulates also inflammatory pathways. By using several models of intestinal inflammation, we examined whether metformin exerts anti-inflammatory effects and investigated the basic mechanism by which metformin blocks pathologic signals. Colitic mice given metformin exhibited less colonic inflammation and increased expression of active AMP-activated protein kinase, a mediator of the metabolic effects of metformin, in both epithelial and lamina propria compartments...
March 14, 2018: Clinical Science (1979-)
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
Xu Chen, Xuan Li, Wenyan Zhang, Jie He, Bo Xu, Bin Lei, Zhenhua Wang, Courtney Cates, Thomas Rousselle, Ji Li
BACKGROUND: AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-κB is an important transcription factor involved in ischemia and reperfusion injury. METHODS AND RESULTS: The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-κB signaling pathway...
March 8, 2018: Metabolism: Clinical and Experimental
Guang Ren, Agnes M Rimando, Suresh T Mathews
Pterostilbene, a bioactive component of blueberries and grapes, shows structural similarity to resveratrol, and exhibits antioxidant, anti-inflammatory, anti-cancer, hypoglycemic, and cholesterol lowering effects. Recent evidence indicates that pterostilbene is an agonist of the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-α). Since PPAR-α agonists induce peroxisomal proliferation and fatty acid oxidation, we examined gene expression of acyl CoA oxidase (ACO) and carnitine palmitoyl transferase-1 (CPT-1)...
March 7, 2018: Biochemical and Biophysical Research Communications
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
Qiongli Su, Ting Tao, Lei Tang, Jun Deng, Kwame Oteng Darko, Sichun Zhou, Mei Peng, Shanping He, Qing Zeng, Alex F Chen, Xiaoping Yang
Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels that are correlated with the sensitivity of anticancer chemotherapeutic drugs. THP is one of the major drugs used in non-muscle-invasive bladder cancer instillation chemotherapy. However, low response ratio of THP (19.7%) treatment to human genitourinary tumours using collagen gel matrix has been observed. This study aims to investigate the effect of down-regulation of PKM2 on THP efficiency. Via inhibitor or siRNA, the effects of reduced PKM2 on the efficiency of THP were determined in 2 human and 1 murine bladder cancer cell lines, using MTT, cologenic and fluorescence approaches...
March 7, 2018: Journal of Cellular and Molecular Medicine
Raja Gopoju, Sravya Panangipalli, Srigiridhar Kotamraju
Lipids are responsible for the atheromatous plaque formation during atherosclerosis by their deposition in the subendothelial intima of the aorta, leading to infarction. Sterol regulatory element-binding protein 2 (SREBP2), regulating cholesterol homeostasis, is suggested to play a pivotal role during the early incidence of atherosclerosis through dysregulation of lipid homeostasis. Here we demonstrate that oxidative stress stimulates SREBP2-mediated cholesterol uptake via low density lipoprotein receptor (LDLR), rather than cholesterol synthesis, in mouse vascular aortic smooth muscle cells (MOVAS) and THP-1 monocytes...
February 27, 2018: Free Radical Biology & Medicine
Yilin Pan, Lu Liu, Shaojun Li, Ke Wang, Rui Ke, Wenhua Shi, Jian Wang, Xin Yan, Qianqian Zhang, Qingting Wang, Limin Chai, Xinming Xie, Manxiang Li
The aims of the present study were to examine signaling mechanisms underlying transforming growth factor β1 (TGF-β1)-induced airway smooth muscle cells (ASMCs) proliferation and to determine the effect of adenosine monophosphate-activated protein kinase (AMPK) activation on TGF-β1-induced ASMCs proliferation and its potential mechanisms. TGF-β1 reduced microRNA-206 (miR-206) level by activating Smad2/3, and this in turn up-regulated histone deacetylase 4 (HDAC4) and consequently increased cyclin D1 protein leading to ASMCs proliferation...
February 26, 2018: Scientific Reports
Saverio Candido, Stephen L Abrams, Linda Steelman, Kvin Lertpiriyapong, Alberto M Martelli, Lucio Cocco, Stefano Ratti, Matilde Y Follo, Ramiro M Murata, Pedro L Rosalen, Paolo Lombardi, Giuseppe Montalto, Melchiorre Cervello, Agnieszka Gizak, Dariusz Rakus, Pann-Gill Suh, Massimo Libra, James A McCubrey
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes...
February 12, 2018: Advances in Biological Regulation
Leon Varjabedian, Mohammad Bourji, Leili Pourafkari, Nader D Nader
Metformin is a biguanide that is widely used as an insulin-sparing agent to treat diabetes. When compared with the general population, diabetics are twice as likely to die from fatal myocardial infarction and congestive heart failure (CHF). There has been a significant concern regarding the use of metformin in patients with CHF because of their higher tendency to develop lactic acidosis. However, large epidemiological trials have reported better cardiovascular prognosis with metformin compared to other glucose-lowering agents among diabetics...
February 24, 2018: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
Tianxing Chen, Dong Yan, Xiaoying Cheng, XiaoJun Ji, Wu Yin
MicroRNAs are potential therapeutic targets for metabolic diseases. Here, miR-1224-5p was highly expressed in the livers of both high fat diet (HFD)-fed mice and obese (ob/ob) mice. To examine the potential role of miR-1224-5p, we constructed liver-specific adenoviral vectors expressing either an miR-1224-5p inhibitor sequence or miR-1224-5p mimic sequences. Following tail-vein vector injection, HFD-fed mice were examined for expression of lipogenic genes. We found that miR-1224-5p inhibitors significantly attenuated hepatic lipogenesis and steatosis in HFD-fed mice, while miR-1224-5p mimics promoted lipid accumulation in the liver of chow-fed C57BL/6 mice...
February 21, 2018: Endocrinology
You Kyoung Shin, Yu Shan Hsieh, Soonho Kwon, Hui Su Lee, Geun Hee Seol
Although stress is one of the risk factors of diabetes, few studies have assessed the effects of stress on diabetic rats. This study therefore analyzed differences in cardiovascular-related factors among control, non-stressed diabetic, and stressed diabetic rats, as well as assessed the effects of linalyl acetate (LA) on stressed diabetic rats. Male Sprague-Dawley rats were subjected to immobilization stress throughout the entire experimental period, and diabetes was induced on day 15 by a single injection of streptozotocin...
February 22, 2018: Journal of Applied Physiology
Zhen Li, Qian Ding, Li-Ping Ling, Ying Wu, Dong-Xiao Meng, Xiao Li, Chun-Qing Zhang
AIM: To investigate the effect of metformin on activated hepatic stellate cells (HSCs) and the possible signaling pathways involved. METHODS: A fibrotic mouse model was generated by intraperitoneal injection of carbon tetrachloride (CCl4 ) and subsequent treatment with or without metformin. The level of fibrosis was detected by hematoxylin-eosin staining, Sirius Red staining, and immunohistochemistry. The HSC cell line LX-2 was used for in vitro studies. The effect of metformin on cell proliferation (CCK8 assay), motility (scratch test and Transwell assay), contraction (collagen gel contraction assay), extracellular matrix (ECM) secretion (Western blot), and angiogenesis (ELISA and tube formation assay) was investigated...
February 21, 2018: World Journal of Gastroenterology: WJG
S C Bridgeman, G C Ellison, P E Melton, P Newsholme, Cds Mamotte
There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly via modulating the activation of AMP-activated protein kinase (AMPK)...
February 19, 2018: Diabetes, Obesity & Metabolism
Xiaoli Yang, Yan Liu, Menghui Li, Hao Wu, Yunbing Wang, Yu You, Peizhi Li, Xiong Ding, Chang'an Liu, Jianping Gong
Metformin has been demonstrated to prevent hepatocellular carcinoma (HCC). Metformin acts mainly by phosphorylation of AMPK. However, the phosphorylation status of AMPK and its role in the prediction and prevention of HCC in cirrhotic patients remains unclear. The phosphorylation status of AMPK (Thr172) was determined by immunostaining in tissue microarrays of 426 cirrhotic liver tissues. Low expression of p-AMPK was observed in 94 (22.1%) cases. The median follow-up time was 87 months. HCC occurrence probability at 1/3/5/10 years after Hassab procedure was 3...
February 15, 2018: Cell Death & Disease
Valentina Celestini, Tugsan Tezil, Luciana Russo, Candida Fasano, Paola Sanese, Giovanna Forte, Alessia Peserico, Martina Lepore Signorile, Giovanna Longo, Domenico De Rasmo, Anna Signorile, Raffaella Maria Gadaleta, Natasha Scialpi, Mineko Terao, Enrico Garattini, Tiziana Cocco, Gaetano Villani, Antonio Moschetta, Valentina Grossi, Cristiano Simone
While aberrant cancer cell growth is frequently associated with altered biochemical metabolism, normal mitochondrial functions are usually preserved and necessary for full malignant transformation. The transcription factor FoxO3A is a key determinant of cancer cell homeostasis, playing a dual role in survival/death response to metabolic stress and cancer therapeutics. We recently described a novel mitochondrial arm of the AMPK-FoxO3A axis in normal cells upon nutrient shortage. Here, we show that in metabolically stressed cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK, which phosphorylate serine 12 and 30, respectively, on FoxO3A N-terminal domain...
February 14, 2018: Cell Death & Disease
Yuanyuan Wu, Pengfen Li, Dan Zhang, Yingpu Sun
Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance...
February 2018: Experimental and Therapeutic Medicine
Anqi Ge, Shu Wang, Bei Miao, Ming Yan
Neuropathic pain (NP) is a frustrating and burdensome problem. Current treatments for NP have unendurable side effects and/or questionable efficacy, and once these therapies are stopped, the symptoms often return. Thus, novel drugs are needed to enhance the effectiveness of treatments for NP. One novel target for pain treatments is adenosine monophosphate‑activated protein kinase (AMPK), which regulates a variety of cellular processes, including protein translation, which is considered to be affected in NP...
February 1, 2018: Molecular Medicine Reports
Jing Ding, Yue-Ting Zhu, Lie Yang, Jie Tang, Yu-Yi Wang, Ye Chen, Ke Cheng, Jia-Qi Liu, Yun-Ni Zhang, Zhi-Ke Li, Yang Du, Meng Qiu, Ji-Yan Liu
Metformin is a promising drug for cancer prevention and treatment, especially in the diabetic population. We aimed to test whether 14-3-3zeta affects the anticancer effect of metformin on colorectal carcinoma (CRC). In this study, we confirmed higher 14-3-3zeta expression was found in CRC tissues than in peri-carcinoma tissues, and in CRC tissue of patients with diabetes than in those without diabetes. A knockdown of 14-3-3zeta inhibited CRC proliferation and promoted apoptosis in vitro and in vivo. Then, we created stable cell lines with under-expressed 14-3-3zeta from SW480 and HCT15 cells after infection by a lentiviral vector carrying short hairpin RNA targeting 14-3-3zeta (named LV-sh14-3-3zeta)...
January 30, 2018: Carcinogenesis
Dannielle DeWaal, Veronique Nogueira, Alexander R Terry, Krushna C Patra, Sang-Min Jeon, Grace Guzman, Jennifer Au, Christopher P Long, Maciek R Antoniewicz, Nissim Hay
Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained...
January 31, 2018: Nature Communications
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