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Metformin AND Sirt1

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https://www.readbyqxmd.com/read/29110598/sirt1-as-a-therapeutic-target-in-diabetic-complications
#1
Justyna Strycharz, Żaneta Rygielska, Ewa Świderska, Józef Drzewoski, Janusz Szemraj, Leszek Szmigiero, Agnieszka Śliwińska
Background SIRT1 is an epigenetic enzyme involved in histone and non-histone protein deacetylation. It acts primarily as a metabolic sensor, which responses to changing energy status by deacetylating crucial transcription factors and cofactors. In this way, SIRT1 regulates mitochondrial function and biogenesis, oxidative stress, inflammation, apoptosis and cellular senescence. Disturbance of all of these phenomena promotes the pathogenesis of diabetic complications. These disorders are inseparably connected with chronic hyperglycemia, which possesses a strong epigenetic determinant...
November 6, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29032153/metformin-overcomes-high-glucose-induced-insulin-resistance-of-podocytes-by-pleiotropic-effects-on-sirt1-and-ampk
#2
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 13, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28964787/negative-regulation-of-sirtuin-1-by-amp-activated-protein-kinase-promotes-metformin-induced-senescence-in-hepatocellular-carcinoma-xenografts
#3
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/28870631/the-sirtuin-family-members-sirt1-sirt3-and-sirt6-their-role-in-vascular-biology-and-atherogenesis
#4
REVIEW
Bożena Sosnowska, Mohsen Mazidi, Peter Penson, Anna Gluba-Brzózka, Jacek Rysz, Maciej Banach
The sirtuins, silent mating-type information regulation 2 (SIRTs), are a family of nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylases with important roles in regulating energy metabolism and senescence. Activation of SIRTs appears to have beneficial effects on lipid metabolism and antioxidants, prompting investigation of the roles of these proteins in atherogenesis. Although clinical data are currently limited, the availability and safety of SIRT activators such as metformin and resveratrol provide an excellent opportunity to conduct research to better understand the role of SIRTs in human atherosclerosis...
August 26, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28751004/polyphenols-activate-energy-sensing-network-in-insulin-resistant-models
#5
Radika Mutlur Krishnamoorthy, Anuradha Carani Venkatraman
Unhealthy diet deficient in fruits and vegetables but rich in calories is considered to be one factor responsible for the increased prevalence of insulin resistance and type 2 diabetes (T2D). The consumption of fast foods and soft drinks increases fructose consumption per se and this is of major concern since prolonged fructose intake induces insulin resistance and thereby T2D. The energy homeostasis is regulated by a network consisting of "fuel gauze" called AMP-activated protein kinase (AMPK), the NAD(+) dependent type III deacetylase (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) which is disrupted in T2D...
September 25, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28681917/concentration-dependent-metabolic-effects-of-metformin-in-healthy-and-fanconi-anemia-lymphoblast-cells
#6
Silvia Ravera, Vanessa Cossu, Barbara Tappino, Elena Nicchia, Carlo Dufour, Simona Cavani, Andrea Sciutto, Claudia Bolognesi, Marta Columbaro, Paolo Degan, Enrico Cappelli
Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10-100-fold higher than the plasmatic concentration measured in patients. Here, we evaluated the biochemical, metabolic, and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines...
July 6, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28505155/oxidative-stress-and-expression-of-insulin-signaling-proteins-in-the-brain-of-diabetic-rats-role-of-nigella-sativa-oil-and-antidiabetic-drugs
#7
Mahmoud Balbaa, Shaymaa A Abdulmalek, Sofia Khalil
BACKGROUND AND OBJECTIVES: Insulin resistance of the brain is a specific form of type2-diabetes mellitus (T2DM) and the active insulin-signaling pathway plays a neuroprotective role against damaging conditions and Alzheimer's progression. The present study identifies the mediated emerging effects of the Nigella sativa oil (NSO) on the memory enhancing process, its anti-oxidative, acetylcholinestrase (AChE) inhibition, anti-brain insulin resistance and anti-amyloidogenic activities. In addition, the possible role of some anti-diabetic drugs in the neuro-protection processes and their effect in combination with NSO and/or the insulin receptor inhibitor IOMe-AG538 were investigated...
2017: PloS One
https://www.readbyqxmd.com/read/28445726/sirtuin-1-activation-controls-tumor-growth-by-impeding-th17-differentiation-via-stat3-deacetylation
#8
Emeric Limagne, Marion Thibaudin, Romain Euvrard, Hélène Berger, Pauline Chalons, Frédérique Végan, Etienne Humblin, Romain Boidot, Cédric Rébé, Valentin Derangère, Sylvain Ladoire, Lionel Apetoh, Dominique Delmas, François Ghiringhelli
Sirtuin-1 deacetylates proteins and has emerged as a critical regulator of different cellular processes, particularly inflammation. Basal SIRT1 activity was previously found to limit Th9 and enhance Th17 differentiation in mice, but the effect of pharmacological SIRT1 activation on T cell differentiation and antitumor responses remains unclear. Here, we find that SIRT1 pharmacological agonists selectively impede mouse and human Th17 cell differentiation. SIRT1 activation induces STAT3 deacetylation, thus reducing its ability to translocate into the nucleus, bind to Rorc promoter, and induce its transcription...
April 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28298952/insights-for-oxidative-stress-and-mtor-signaling-in-myocardial-ischemia-reperfusion-injury-under-diabetes
#9
REVIEW
Dajun Zhao, Jian Yang, Lifang Yang
Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28250276/atractylenolide-iii-enhances-energy-metabolism-by-increasing-the-sirt-1-and-pgc1%C3%AE-expression-with-ampk-phosphorylation-in-c2c12-mouse-skeletal-muscle-cells
#10
Mi Young Song, Hyo Won Jung, Seok Yong Kang, Yong-Ki Park
Targeting energy expenditure provides a potential alternative strategy for achieving energy balance to combat obesity and the development of type 2 diabetes mellitus (T2DM). In the present study, we investigated whether atractylenolide III (AIII) regulates energy metabolism in skeletal muscle cells. Differentiated C2C12 myotubes were treated with AIII (10, 20, or 50 µM) or metformin (2.5 mM) for indicated times. The levels of glucose uptake, the expressions of key mitochondrial biogenesis-related factors and their target genes were measured in C2C12 myotubes...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28249909/morphoproteomics-identifies-sirt1-and-ezh2-pathways-as-commonalities-in-b-cell-acute-lymphoblastic-leukemia-pathogenetic-implications-and-opportunities-for-therapeutic-intervention
#11
Robert E Brown, Kristine E Konopka, Priya Weerasinghe, Vanya Jaitly, Amitava Dasgupta, Mary F McGuire, Nghia D Nguyen
B-cell acute lymphoblastic leukemia (ALL) represents a malignant process in which bone marrow-derived lymphoblasts retain their undifferentiated state. Genetic testing has revealed either no identifiable cytogenetic and genomic abnormalities in such patients or a wide range of aberrations that may or may not contribute to the block in differentiation and the associated proliferation of the malignant lymphoblasts in cases of B-cell ALL. In this study, we applied morphoproteomics to a representative spectrum of cases of newly diagnosed B-cell ALL in order to identify pathways that are known to be associated with the maintenance of the undifferentiated state while promoting proliferation...
January 2017: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/27816442/metformin-impairs-systemic-bile-acid-homeostasis-through-regulating-sirt1-protein-levels
#12
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
https://www.readbyqxmd.com/read/27686268/symplocos-cochinchinensis-enhances-insulin-sensitivity-via-the-down-regulation-of-lipogenesis-and-insulin-resistance-in-high-energy-diet-rat-model
#13
COMPARATIVE STUDY
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
https://www.readbyqxmd.com/read/27489862/durable-response-of-glioblastoma-to-adjuvant-therapy-consisting-of-temozolomide-and-a-weekly-dose-of-amd3100-plerixafor-a-cxcr4-inhibitor-together-with-lapatinib-metformin-and-niacinamide
#14
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
https://www.readbyqxmd.com/read/27456392/activation-of-the-ampk-sirt1-pathway-by-a-leucine-metformin-combination-increases-insulin-sensitivity-in-skeletal-muscle-and-stimulates-glucose-and-lipid-metabolism-and-increases-life-span-in-caenorhabditis-elegans
#15
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
https://www.readbyqxmd.com/read/27059094/the-role-of-metformin-and-resveratrol-in-the-prevention-of-hypoxia-inducible-factor-1%C3%AE-accumulation-and-fibrosis-in-hypoxic-adipose-tissue
#16
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
https://www.readbyqxmd.com/read/27009398/metformin-stimulates-igfbp-2-gene-expression-through-pparalpha-in-diabetic-states
#17
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
https://www.readbyqxmd.com/read/26986624/cardiovascular-protective-effect-of-metformin-and-telmisartan-reduction-of-parp1-activity-via-the-ampk-parp1-cascade
#18
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
https://www.readbyqxmd.com/read/26900800/combining-p53-stabilizers-with-metformin-induces-synergistic-apoptosis-through-regulation-of-energy-metabolism-in-castration-resistant-prostate-cancer
#19
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
https://www.readbyqxmd.com/read/26890602/ampk-activation-protects-cells-from-oxidative-stress-induced-senescence-via-autophagic-flux-restoration-and-intracellular-nad-elevation
#20
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
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