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mechanism metformin

Xiong Yang, Hao Ding, Zhenbang Qin, Changwen Zhang, Shiyong Qi, Hongtuan Zhang, Tong Yang, Zhen He, Kuo Yang, E Du, Chunyu Liu, Yong Xu, Zhihong Zhang
Oxidative stress is a causal factor and key promoter of urolithiasis associated with renal tubular epithelium cell injury. The present study was designed to investigate the preventive effects of metformin on renal tubular cell injury induced by oxalate and stone formation in a hyperoxaluric rat model. MTT assays were carried out to determine the protection of metformin from oxalate-induced cytotoxicity. The intracellular superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels were measured in vitro...
2016: Oxidative Medicine and Cellular Longevity
Wei Zhao, Xiaohui Zhang, Jia Liu, Bei Sun, Hua Tang, Hong Zhang
Metformin was demonstrated to have effects on breast cancer, and microRNA-27a (miR-27a) is a prognostic marker for breast cancer progression and patient survival. AMPKα2 was found to be a suppressor in breast cancer MCF-7 cells. Therefore, the present study aimed to explain this phenomenon in regards to the relationship between microRNAs (miRNAs) and their target genes and to predict how AMPKα2 may be a downstream target gene of miR-27a, thus exploring the new mechanism of metformin in the treatment of breast cancer regarding miRNAs...
October 24, 2016: Oncology Reports
Hua-Qiang Zhu, Jin-Ben Ma, Xie Song, Heng-Jun Gao, Chao-Qun Ma, Hong Chang, Hong-Guang Li, Fang-Feng Liu, Jun Lu, Xu Zhou
Metformin, an oral biguanide drug used to treat type 2 diabetes, has displayed anticancer activities in several types of cancer cells. The combination of gemcitabine and cisplatin is the standard chemotherapy regimen for cholangiocarcinoma, but its benefit is limited. The present study aimed to investigate whether metformin could enhance the activities of gemcitabine and cisplatin against cholangiocarcinoma, and the underlying mechanisms. Metformin inhibited the proliferation of human cholangiocarcinoma RBE and HCCC-9810 cells and induced cell cycle arrest at the G0/G1 phase by increasing the activation of AMP-activated protein kinase (AMPK) pathways...
October 20, 2016: Oncology Reports
Mark M Smits, Lennart Tonneijck, Marcel H A Muskiet, Trynke Hoekstra, Mhh Kramer, Michaela Diamant, Daniël H van Raalte
OBJECTIVE: To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients. DESIGN: Acute and 12-week randomised placebo-controlled, double-blind, single-centre parallel-group trial. METHODS: 57 type 2 diabetes patients (mean±SD age 62.8±6.9 years; BMI 31.8±4.1 kg/m2; HbA1c 7.3±0.6%), treated with metformin and/or sulfonylureas, were included between July 2013 and August 2015...
October 24, 2016: European Journal of Endocrinology
T Zhong, Y Men, L Lu, T Geng, J Zhou, A Mitsuhashi, M Shozu, N J Maihle, G G Carmichael, H S Taylor, Y Huang
The molecular mechanisms underlying the antineoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. Here we report that metformin induces genome-wide alterations in DNA methylation by modulating the activity of S-adenosylhomocysteine hydrolase (SAHH). Exposing cancer cells to metformin leads to hypermethylation of tumor-promoting pathway genes and concomitant inhibition of cell proliferation. Metformin acts by upregulating microRNA let-7 through AMPK activation, leading to degradation of H19 long noncoding RNA, which normally binds to and inactivates SAHH...
October 24, 2016: Oncogene
Xiaofeng Qi, Wengguang Xu, Junqi Xie, Yufeng Wang, Shengwei Han, Zheng Wei, Yanhong Ni, Yingchun Dong, Wei Han
Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms...
October 20, 2016: Scientific Reports
Ning Xia, Huige Li
Under physiological conditions, perivascular adipose tissue (PVAT) attenuates agonist-induced vasoconstriction by releasing vasoactive molecules including hydrogen peroxide, angiotensin 1-7, adiponectin, methyl palmitate, hydrogen sulfide, nitric oxide (NO) and leptin. This anticontractile function of PVAT is lost under conditions of obesity. The central mechanism underlying PVAT dysfunction in obesity is likely to be an "obesity triad" (consisting of PVAT hypoxia, inflammation and oxidative stress) that leads to dysregulation of PVAT-derived vasoregulators...
October 20, 2016: British Journal of Pharmacology
FangFang, Hongyan Li, Tingting Qin, Min Li, Shiping Ma
The impaired insulin signaling has been recognized as a common pathogenetic mechanism between diabetes and Alzheimer's disease (AD). In the progression of AD, brain is characterized by defective insulin receptor substrate-1 (IRS-1) and increased oxidative stress. Thymol, a monoterpene phenol isolated from medicinal herbs, has exhibited robust neuroprotective effects. The present study was designed to investigate the protective effect of thymol on HFD-induced cognitive deficits, and explore the possible mechanisms...
October 20, 2016: Metabolic Brain Disease
Zhong'e Zhou, Yong Tang, Xian Jin, Chengjun Chen, Yi Lu, Liang Liu, Chengxing Shen
Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) mRNA expression, RAGE expression, and NFκB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects...
2016: Journal of Diabetes Research
Connie M Rhee, Csaba P Kovesdy, Kamyar Kalantar-Zadeh
Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction...
October 20, 2016: Nephron
Himalee S Sabnis, Heath L Bradley, Shweta Tripathi, Wen-Mei Yu, William Tse, Cheng-Kui Qu, Kevin D Bunting
Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism...
October 5, 2016: Leukemia Research
Qing-Shuo Zhang, Weiliang Tang, Matthew Deater, Ngoc Phan, Andrea N Marcogliese, Hui Li, Muhsen Al-Dhalimy, Angela Major, Susan Olson, Raymond J Monnat, Markus Grompe
Fanconi anemia is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2(-/-) mice. Metformin is the first compound reported to improve both of these Fanconi anemia phenotypes...
October 18, 2016: Blood
Kalina Biernacka, Raj A Persad, Amit Bahl, David Gillatt, Jeff M P Holly, Claire M Perks
The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes via targeting this pathway...
October 17, 2016: Endocrine-related Cancer
Myung-Shik Lee
Low-grade systemic inflammation in adipose tissues or liver, is an important etiologic factor in insulin resistance. LPS is an important element causing such metabolic inflammation, and intestinal flora is considered a major source of systemic LPS. We studied changes of intestinal microbiota associated with high-fat diet (HFD) that causes insulin resistance and metabolic stress. 16S rRNA gene sequencing showed that HFD significantly decreased the abundance of a mucin-degrading bacterium Akkermansia muciniphila compared to control diet...
September 2016: Journal of Hypertension
Mohamed Alalem, Alpana Ray, Bimal K Ray
Activation of mTOR is implicated in the development and progression of breast cancer. mTOR inhibition exhibited promising antitumor effects in breast cancer; however, its effect is compromised by several feedback mechanisms. One of such mechanisms is the upregulation of mTOR pathway in breast cancer cells. Despite the established role of mTOR activation in breast cancer, the status of total mTOR protein and its impact on the tumor behavior and response to treatment are poorly understood. Besides, the mechanisms underlying mTOR protein degradation in normal and cancer breast cells are still largely unknown...
October 17, 2016: Cancer Medicine
S Gibiino, A Trappoli, B Balzarro, A R Atti, D De Ronchi
A 71-year-old man developed coma with severe respiratory failure, hypotension, and tachycardia induced by the intentional ingestion of quetiapine fumarate extended release (XR) 20 g. At the time, he had been treated for bipolar depression with venlafaxine 75 mg/day, lamotrigine 100 mg/day, pregabalin 75 mg/day, and quetiapine XR 400 mg/day for approximately 1 year. Comorbidities were hypertension treated with metoprolol, diabetes mellitus type 2 treated with metformin, and benign prostatic hyperplasia treated with silodosin...
December 2015: Drug Saf Case Rep
Yu-Shen Huang, Yi-Chieh Li, Pei-Yun Tsai, Chia-En Lin, Chien-Ming Chen, Shih-Ming Chen, Jen-Ai Lee
Lead (Pb) is an environmental pollutant associated with several diseases, such as nephrotoxicity. Methylglyoxal (MG) is a reactive dicarbonyl compound formed during glycolysis and reported to increase in kidney damage. Metformin is used as a MG scavenger in the clinic. In this study, we investigated the mechanism of Pb-induced renal injury and the effect of metformin on Pb-induced nephrotoxicity. Eighteen Wistar rats were randomly divided into three groups: control, Pb, and Pb + metformin groups. Pb (250 ppm) was administered in drinking water, and 50 mg/Kg of metformin was co-administered orally...
October 14, 2016: Biomedical Chromatography: BMC
Rong Qiu, Dainius Balis, George Capuano, John Xie, Gary Meininger
: Metformin is typically the first pharmacologic treatment recommended for type 2 diabetes mellitus (T2DM), but many patients do not achieve glycemic control with metformin alone and eventually require combination therapy with other agents. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was assessed in a comprehensive Phase 3 clinical development program consisting of ~10,000 participants, of which ~80% were on background therapy that consisted of metformin alone or in combination with other antihyperglycemic agents (AHAs; e...
October 12, 2016: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Nathaniel B Bone, Zhongyu Liu, Jean-Francois Pittet, Jaroslaw W Zmijewski
Catecholamines, including β-adrenergic and dopaminergic neurotransmitters, have an essential role in regulating the "fight or flight" reflex and also affects immune cell proinflammatory action. However, little is known about whether catecholamines prevent dysfunction of metabolic pathways associated with inflammatory organ injury, including development of acute lung injury (ALI). We hypothesize that selected catecholamines may reduce metabolic alterations in LPS-stimulated macrophages and in the lungs of mice subjected to endotoxin-induced ALI, a situation characterized by diminished activity of AMP-activated protein kinase (AMPK)...
October 12, 2016: Journal of Leukocyte Biology
Quan-Yong Yi, Gang Deng, Nan Chen, Zhi-Sha Bai, Jian-Shu Yuan, Guo-Hai Wu, Yu-Wen Wang, Shan-Jun Wu
Previous studies have shown that metformin, an AMP-activated protein kinase activator widely prescribed for type 2 diabetes, is especially beneficial in cases of diabetic retinopathy (DR) with undetermined mechanisms. Here, we used a streptozotocin-induced diabetes model in mice to study the effects of metformin on the development of DR. We found that 10 weeks after STZ treatment, DR was induced in STZ-treated mice, regardless treatment of metformin. However, metformin alleviated the DR, seemingly through attenuating the retina neovascularization...
2016: American Journal of Translational Research
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