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Metformin AND Sirt1

Qi Chen, Xiaoying Yang, Huabing Zhang, Xingxing Kong, Lu Yao, Xiaona Cui, Yongkang Zou, Fude Fang, Jichun Yang, Yongsheng Chang
Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport...
January 2017: Biochimica et Biophysica Acta
Kalathookunnel Antony Antu, Mariam Philip Riya, Anupama Nair, Arvind Mishra, Arvind K Srivastava, Kozhiparambil Gopalan Raghu
ETHNOPHARMACOLOGICAL RELEVANCE: This plant has been utilized in Indian system of medicine for treatment of diabetes. This is clearly evident from the composition of Ayurvedic preparation for diabetes 'Nisakathakadi Kashayam' where this is one of the main ingredients of this preparation AIM OF THE STUDY: The study aims in elucidating the molecular mechanisms underlying the insulin sensitizing effects of Symplocos cochinchinensis ethanol extract (SCE) using a high fructose and saturated fat (HFS) fed insulin resistant rat model...
December 4, 2016: Journal of Ethnopharmacology
Adan Rios, Sigmund H Hsu, Angel Blanco, Jamie Buryanek, Arthur L Day, Mary F McGuire, Robert E Brown
UNLABELLED: Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site...
2016: Oncoscience
Jheelam Banerjee, Antje Bruckbauer, Michael B Zemel
BACKGROUND: We have previously shown leucine (Leu) to activate Sirt1 by lowering its KM for NAD(+), thereby amplifying the effects of other sirtuin activators and improving insulin sensitivity. Metformin (Met) converges on this pathway both indirectly (via AMPK) and by direct activation of Sirt1, and we recently found Leu to synergize with Met to improve insulin sensitivity and glycemic control while achieving ~80% dose-reduction in diet-induced obese mice. Accordingly, we sought here to define the mechanism of this interaction...
November 2016: Metabolism: Clinical and Experimental
Xiaole Li, Jia Li, Lulu Wang, Aiyun Li, Zhixia Qiu, Lian-Wen Qi, Junping Kou, Kang Liu, Baolin Liu, Fang Huang
BACKGROUND AND PURPOSE: Hypoxic activation of hypoxia-inducible factor 1α (HIF-1α) and fibrosis in adipose tissue contribute to adipose dysfunction. This study was designed to investigate the effects of metformin and resveratrol on the regulation of HIF-1α and fibrosis in hypoxic adipose tissue. EXPERIMENTAL APPROACH: Mice were fed a high-fat diet to induce hypoxia and fibrosis in adipose tissue; adipose tissue incubated in vitro in 1% O2 showed a similar change...
June 2016: British Journal of Pharmacology
Hye Suk Kang, Ho-Chan Cho, Jae-Ho Lee, Goo Taeg Oh, Seung-Hoi Koo, Byung-Hyun Park, In-Kyu Lee, Hueng-Sik Choi, Dae-Kyu Song, Seung-Soon Im
The anti-diabetic drug, metformin, exerts its action through AMP-activated protein kinase (AMPK), and Sirtuin (Sirt1) signaling. Insulin-like growth factor (IGF)-binding protein 2 (IGFBP-2) prevents IGF-1 binding to its receptors, thereby contributing to modulate insulin sensitivity. In this study, we demonstrate that metformin upregulates Igfbp-2 expression through the AMPK-Sirt1-PPARα cascade pathway. In the liver of high fat diet, ob/ob, and db/db mice, Igfbp-2 expression was significantly decreased compared to the expression levels in the wild-type mice (p < 0...
March 24, 2016: Scientific Reports
Fenqing Shang, Jiao Zhang, Zhao Li, Jin Zhang, Yanjun Yin, Yaqiong Wang, Traci L Marin, Brendan Gongol, Han Xiao, You-Yi Zhang, Zhen Chen, John Y-J Shyy, Ting Lei
Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity...
2016: PloS One
Long Chen, Nihal Ahmad, Xiaoqi Liu
Since altered energy metabolism is a hallmark of cancer, many drugs targeting metabolic pathways are in active clinical trials. The tumor suppressor p53 is often inactivated in cancer, either through downregulation of protein or loss-of-function mutations. As such, stabilization of p53 is considered as one promising approach to treat those cancers carrying wild type (WT) p53. Herein, SIRT1 inhibitor Tenovin-1 and polo-like kinase 1 (Plk1) inhibitor BI2536 were used to stabilize p53. We found that both Tennovin-1 and BI2536 increased the anti-neoplastic activity of metformin, an inhibitor of oxidative phosphorylation, in a p53 dependent manner...
2016: Cell Cycle
Xiaojuan Han, Haoran Tai, Xiaobo Wang, Zhe Wang, Jiao Zhou, Xiawei Wei, Yi Ding, Hui Gong, Chunfen Mo, Jie Zhang, Jianqiong Qin, Yuanji Ma, Ning Huang, Rong Xiang, Hengyi Xiao
AMPK activation is beneficial for cellular homeostasis and senescence prevention. However, the molecular events involved in AMPK activation are not well defined. In this study, we addressed the mechanism underlying the protective effect of AMPK on oxidative stress-induced senescence. The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated...
June 2016: Aging Cell
Ching-Hsia Hung, Shih-Hung Chan, Pei-Ming Chu, Huei-Chen Lin, Kun-Ling Tsai
It is suggested that oxLDL is decisive in the initiation and development of atherosclerotic injuries. The up-regulation of oxidative stress and the generation of ROS act as key modulators in developing pro-atherosclerotic and anti-atherosclerotic processes in the human endothelial wall. In this present study, we confirmed that metformin enhanced SIRT1 and AMPK expression in human umbilical vein endothelial cells (HUVECs). Metformin also inhibited oxLDL-increased LOX-1 expression and oxLDL-collapsed AKT/eNOS levels...
March 8, 2016: Oncotarget
Young Mi Song, Woo Kyung Lee, Yong-Ho Lee, Eun Seok Kang, Bong-Soo Cha, Byung-Wan Lee
Metformin is known to alleviate hepatosteatosis by inducing 5' adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the suppressed Parkin-mediated mitophagy. To this end, our ob/ob mice were divided into three groups: (1) ad libitum feeding of a standard chow diet; (2) intraperitoneal injections of metformin 300 mg/kg; and (3) 3 g/day caloric restriction (CR)...
January 16, 2016: International Journal of Molecular Sciences
Hongxia Sun, Mary F McGuire, Songlin Zhang, Robert E Brown
NUT midline carcinoma is a rare entity arising primarily in the midline of teenagers and young adults. Genomically, it is associated with a translocation involving a nuclear protein in testis (NUT) gene with other genes, most commonly, the BRD4 gene. The resultant is a partial or near total block in differentiation of tumor cells into mature squamous elements. Such tumors are resistant to conventional therapy with a reported mean survival at less than 1 year. In this study, we investigated two cases with genomic confirmation as NUT midline carcinoma by morphoproteomic analysis using immunohistochemical antibodies...
2015: Annals of Clinical and Laboratory Science
Erli Zhang, Qianyun Guo, Haiyang Gao, Ruixia Xu, Siyong Teng, Yongjian Wu
Endothelial senescence plays crucial roles in diabetic vascular complication. Recent evidence indicated that transient hyperglycaemia could potentiate persistent diabetic vascular complications, a phenomenon known as "metabolic memory." Although SIRT1 has been demonstrated to mediate high glucose-induced endothelial senescence, whether and how "metabolic memory" would affect endothelial senescence through SIRT1 signaling remains largely unknown. In this study, we investigated the involvement of SIRT1 axis as well as the protective effects of resveratrol (RSV) and metformin (MET), two potent SIRT1 activators, during the occurrence of "metabolic memory" of cellular senescence (senescent "memory")...
2015: PloS One
Gnanapragasam Arunachalam, Arun Prasath Lakshmanan, Samson Mathews Samuel, Chris R Triggle, Hong Ding
Impaired angiogenesis is a prominent risk factor that contributes to the development of diabetes-associated cardiovascular disease. MicroRNAs (miRNAs), small noncoding RNAs, are implicated as important regulators of vascular function, including endothelial cell differentiation, proliferation, and angiogenesis. In silico analysis and in vitro studies indicate that silent information regulator 1 (SIRT1) is a potential target for endothelial cell-specific miRNAs. In this study, we investigated the molecular crosstalk between miR-34a, the protein product of SIRT1 (sirtuin1), and the antidiabetic drug, metformin, in hyperglycemia-mediated impaired angiogenesis in mouse microvascular endothelial cells (MMECs)...
February 2016: Journal of Pharmacology and Experimental Therapeutics
Suparna Ghosh, Arun P Lakshmanan, Mu Ji Hwang, Haidar Kubba, Ahmed Mushannen, Chris R Triggle, Hong Ding
The cellular mechanisms whereby metformin, the first line drug for type 2 diabetes (T2DM), mediates its antidiabetic effects remain elusive, particularly as to whether metformin has a direct protective action on the vasculature. This study was designed to determine if a brief 3-h exposure to metformin protects endothelial function against the effects of hyperglycaemia. We investigated the protective effects of metformin on endothelial-dependent vasodilatation (EDV) in thoracic aortae from T2DM db/db mice and on high glucose (HG, 40 mM) induced changes in endothelial nitric oxide synthase (eNOS) signaling in mouse microvascular endothelial cells (MMECs) in culture...
December 1, 2015: Biochemical Pharmacology
Xin Tao, Xiao Zhang, Shu-Qi Ge, Er-Hong Zhang, Bin Zhang
AIM: To investigate the expression of silent information regulator 1 (SIRT1) in rats with polycystic ovary syndrome (PCOS) and its alteration after exenatide treatment. METHODS: PCOS rat model was established by dehydroepiandrosterone induction. The animals were randomly divided into exenatide treatment group (EX group, n = 10), metformin treatment group (MF group, n = 10), PCOS group (PCOS group, n = 9) and normal control group (NC group, n = 10). Histological changes of the ovarian tissues were examined by HE staining...
2015: International Journal of Clinical and Experimental Pathology
Mark F McCarty, James J DiNicolantonio, James H O'Keefe
Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxia-inducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Moreover, there is reason to suspect that ketones can activate Sirt1 in neurons, in part by increasing cytoplasmic and nuclear levels of Sirt1's obligate cofactor NAD(+). Another recent study has observed reduced activity of mTORC1 in the hippocampus of rats fed a ketogenic diet - an effect plausibly attributable to Sirt1 activation...
November 2015: Medical Hypotheses
Lizhi Fu, Antje Bruckbauer, Fenfen Li, Qiang Cao, Xin Cui, Rui Wu, Hang Shi, Michael B Zemel, Bingzhong Xue
BACKGROUND: Leucine stimulates Sirt1 and AMPK signaling in vitro and in vivo. Since metformin converges on the same pathway, we have tested the ability of leucine to amplify the effects of metformin on AMPK-mediated hepatic lipid metabolism in diet-induced-obese insulin-resistant mice. METHODS: Mice were fed high leucine (24 g/kg diet) with or without sub-therapeutic levels of metformin (0.05-0.50 g/kg diet) or therapeutic levels of metformin (1.5 g/kg diet; ~300 mg/kg body weight)...
November 2015: Metabolism: Clinical and Experimental
Paradesi Naidu Gollavilli, Anantha Koteswararao Kanugula, Rajeswari Koyyada, Santosh Karnewar, Praveen Kumar Neeli, Srigiridhar Kotamraju
Recent studies have highlighted the involvement of metadherin (MTDH), an oncogenic protein, in promoting cancer progression, metastasis and chemoresistance in many cancers including mammary carcinomas. However, the molecular regulation of MTDH is still not completely understood. In this study we document that AMP activated protein kinase (AMPK) activation-induced anti-proliferative effects are, in part, mediated by inhibiting MTDH expression in MDA-MB-231 and BT-549 triple negative breast cancer (TNBC) cells...
October 2015: FEBS Journal
Wei Xu, Yang-Yang Deng, Lin Yang, Sijia Zhao, Junhui Liu, Zhao Zhao, Lijun Wang, Prabindra Maharjan, Shanshan Gao, Yuling Tian, Xiaozhen Zhuo, Yan Zhao, Juan Zhou, Zuyi Yuan, Yue Wu
Metformin is a widely used classic antidiabetic drug. However, its clinical pharmacologic mechanism remains poorly understood. In the present study, we investigated the anti-inflammatory effects of metformin on circulating peripheral blood mononuclear cells (MNCs) of patients with carotid artery atherosclerosis (AS). A total of 42 patients with carotid artery AS were randomly assigned to metformin (500 mg twice a day; Met; n = 21) or placebo control (Con; n = 21) groups. After 12 weeks of treatment, plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) significantly decreased in the Met group compared with the Con group...
November 2015: Translational Research: the Journal of Laboratory and Clinical Medicine
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