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https://www.readbyqxmd.com/read/28922161/comorbidity-analysis-between-alzheimer-s-disease-and-type-2-diabetes-mellitus-t2dm-based-on-shared-pathways-and-the-role-of-t2dm-drugs
#1
Reagon Karki, Alpha Tom Kodamullil, Martin Hofmann-Apitius
BACKGROUND: Various studies suggest a comorbid association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms. OBJECTIVE: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM. METHOD: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources...
September 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28919040/heme-binding-biguanides-target-cytochrome-p450-dependent-cancer-cell-mitochondria
#2
Zhijun Guo, Irina F Sevrioukova, Ilia G Denisov, Xia Zhang, Ting-Lan Chiu, Dafydd G Thomas, Eric A Hanse, Rebecca A D Cuellar, Yelena V Grinkova, Vanessa Wankhede Langenfeld, Daniel S Swedien, Justin D Stamschror, Juan Alvarez, Fernando Luna, Adela Galván, Young Kyung Bae, Julia D Wulfkuhle, Rosa I Gallagher, Emanuel F Petricoin, Beverly Norris, Craig M Flory, Robert J Schumacher, M Gerard O'Sullivan, Qing Cao, Haitao Chu, John D Lipscomb, William M Atkins, Kalpna Gupta, Ameeta Kelekar, Ian A Blair, Jorge H Capdevila, John R Falck, Stephen G Sligar, Thomas L Poulos, Gunda I Georg, Elizabeth Ambrose, David A Potter
The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs...
August 29, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28918830/metformin-has-positive-therapeutic-effects-in-colon-cancer-and-lung-cancer
#3
DeAnna Henderson, Danielle Frieson, Jeffrey Zuber, Solomon S Solomon
BACKGROUND: Metformin (MF), a diabetic drug, has antineoplastic activity as adjuvant therapy for breast cancer and prostate cancer. MF is thought to work via inhibition of mammalian target of rapamycin and activation of p53 and liver kinase B1 via adenosine 5'-monophosphate-activated protein kinase. We investigated survival, recurrences and metastasis in patients with type 2 diabetes mellitus (DM2) along with colorectal cancer (CC) or lung cancer (LC) taking MF using the electronic medical record in Memphis Veterans Affairs Medical Center (colon, n = 202; lung, n = 180)...
September 2017: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/28915843/protective-effects-of-gaba-against-metabolic-and-reproductive-disturbances-in-letrozole-induced-polycystic-ovarian-syndrome-in-rats
#4
Asad Ullah, Sarwat Jahan, Suhail Razak, Madeeha Pirzada, Hizb Ullah, Ali Almajwal, Naveed Rauf, Tayyaba Afsar
BACKGROUND: PCOs is a heterogeneous disorder with anovulation/oligo ovulation usually taken as oligo menorrhoea or amenorrhoea, hyperandrogenemia, hirsutism, acne, androgen alopecia and polycystic ovaries as the key diagnostic feathers. The study was undertaken to investigate the possible protective and ameliorating effects of GABA in Letrozole induced PCOS model in rats by targeting insulin resistance. METHODS: PCOs in Adult female rat was induced by the daily gastric administration of letrozole (1 mg/kg/day) in CMC (0...
September 15, 2017: Journal of Ovarian Research
https://www.readbyqxmd.com/read/28915708/targeting-metabolism-and-amp-activated-kinase-with-metformin-to-sensitize-non-small-cell-lung-cancer-nsclc-to-cytotoxic-therapy-translational-biology-and-rationale-for-current-clinical-trials
#5
REVIEW
Michael Troncone, Stephanie M Cargnelli, Linda A Villani, Naghmeh Isfahanian, Lindsay A Broadfield, Laura Zychla, Jim Wright, Gregory Pond, Gregory R Steinberg, Theodoros Tsakiridis
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28887562/metformin-improves-endothelial-function-and-reduces-blood-pressure-in-diabetic-spontaneously-hypertensive-rats-independent-from-glycemia-control-comparison-to-vildagliptin
#6
Mahdi Hamidi Shishavan, Robert H Henning, Azuwerus van Buiten, Maaike Goris, Leo E Deelman, Hendrik Buikema
Metformin confers vascular benefits beyond glycemia control, possibly via pleiotropic effects on endothelial function. In type-1-diabetes-mellitus (T1DM-)patients metformin improved flow-mediated dilation but also increased prostaglandin(PG)-F2α, a known endothelial-contracting factor. To explain this paradoxical finding we hypothesized that metformin increased endothelial-vasodilator mediators (e.g. NO and EDHF) to an even larger extent. Spontaneously-hypertensive-rats (SHR) display impaired endothelium-dependent relaxation (EDR) involving contractile PGs...
September 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28881582/metformin-requires-4e-bps-to-induce-apoptosis-and-repress-translation-of-mcl-1-in-hepatocellular-carcinoma-cells
#7
Mamatha Bhat, Akiko Yanagiya, Tyson Graber, Nataliya Razumilava, Steve Bronk, Domenick Zammit, Yunhao Zhao, Chadi Zakaria, Peter Metrakos, Michael Pollak, Nahum Sonenberg, Gregory Gores, Maritza Jaramillo, Masahiro Morita, Tommy Alain
Metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which is frequently upregulated in hepatocellular carcinoma (HCC). Metformin has also been shown to induce apoptosis in this cancer. Here, we investigate whether metformin-induced apoptosis in HCC is mediated by the downstream mTORC1 effectors eukaryotic initiation factor 4E and (eIF4E)-binding proteins (4E-BPs). Further, we ask whether changes in 4E-BPs activity during metformin treatment negatively regulate translation of the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) mRNA...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28875433/crucial-micrornas-and-genes-in-metformin-s-anti-pancreatic-cancer-effect-explored-by-microrna-mrna-integrated-analysis
#8
Yilong Li, Le Li, Guangquan Zhang, Yongwei Wang, Hua Chen, Rui Kong, Shangha Pan, Bei Sun
Despite great improvements in surgical procedures and chemotherapy, pancreatic cancer remains one of the most aggressive and fatal human malignancies, with a low 5-year survival rate. Therefore, novel therapeutic strategies for the prevention and treatment of pancreatic cancer are urgently needed. The present study aimed to investigate the mechanisms by which metformin exerts its anticancer effects on the microRNA-mRNA interactions in human pancreatic cancer. Microarray and systematic analyses revealed that the anti-pancreatic cancer effects of metformin were correlated with 3 up-regulated microRNAs and 4 of their target mRNAs...
September 5, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28874953/pleiotropic-effects-of-biguanides-on-mitochondrial-reactive-oxygen-species-production
#9
Alena Pecinova, Zdenek Drahota, Jana Kovalcikova, Nikola Kovarova, Petr Pecina, Lukas Alan, Michal Zima, Josef Houstek, Tomas Mracek
Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28870034/-the-efficacy-and-safety-of-insulin-degludec-versus-insulin-glargine-in-insulin-naive-subjects-with-type-2-diabetes-results-of-a-chinese-cohort-from-a-multinational-randomized-controlled-trial
#10
Y M Mu, L X Guo, L Li, Y M Li, X J Xu, Q M Li, M T Xu, L Y Zhu, G Y Yuan, Y Liu, C Xu, Z J Wang, F X Shen, Y Luo, J Y Liu, Q F Li, W H Wang, X Y Lai, H F Xu, C Y Pan
Objective: To compare the safety and efficacy of insulin degludec (IDeg) with those of insulin glargine (IGlar) in insulin-naive subjects with type 2 diabetes (T2DM). Methods: This was a 26-week, randomized, open-label, parallel-group, treat-to-target trial in 560 Chinese subjects with T2DM (men/women: 274/263, mean age 56 years, mean diabetes duration 7 years) inadequately controlled on oral antidiabetic drugs (OADs). Subjects were randomized 2∶1 to once-daily IDeg (373 subjects) or IGlar(187 subjects), both in combination with metformin...
September 1, 2017: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
https://www.readbyqxmd.com/read/28866649/weight-loss-for-overweight-and-obese-individuals-with-gout-a-systematic-review-of-longitudinal-studies
#11
Sabrina M Nielsen, Else M Bartels, Marius Henriksen, Eva E Wæhrens, Henrik Gudbergsen, Henning Bliddal, Arne Astrup, Filip K Knop, Loreto Carmona, William J Taylor, Jasvinder A Singh, Fernando Perez-Ruiz, Lars E Kristensen, Robin Christensen
OBJECTIVES: Weight loss is commonly recommended for gout, but the magnitude of the effect has not been evaluated in a systematic review. The aim of this systematic review was to determine benefits and harms associated with weight loss in overweight and obese patients with gout. METHODS: We searched six databases for longitudinal studies, reporting the effect of weight loss in overweight/obese gout patients. Risk of bias was assessed using the tool Risk of Bias in Non-Randomised Studies of Interventions...
September 2, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28864965/pharmacological-management-of-gestational-diabetes-mellitus
#12
Geetha Mukerji, Denice S Feig
Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes in the setting of poor glycemic control. The initial management for GDM includes intensive lifestyle modification, which often requires behavioral and nutritional changes to optimize glycemic control. Pharmacotherapy for GDM is initiated when glycemic targets are not met. The rapid-acting bolus analogues aspart and lispro achieve postprandial targets with less hypoglycemia compared to regular insulin, with similar fetal outcomes...
September 2, 2017: Drugs
https://www.readbyqxmd.com/read/28859673/multiple-therapeutic-effect-of-endothelial-progenitor-cell-regulated-by-drugs-in-diabetes-and-diabetes-related-disorder
#13
REVIEW
Rashmi K Ambasta, Harleen Kohli, Pravir Kumar
BACKGROUND: Reduced levels of endothelial progenitor cells (EPCs) counts have been reported in diabetic mellitus (DM) patients and other diabetes-related disorder. EPCs are a circulating, bone marrow-derived cell population that appears to participate in vasculogenesis, angiogenesis and damage repair. These EPC may revert the damage caused in diabetic condition. We aim to identify several existing drugs and signaling molecule, which could alleviate or improve the diabetes condition via mobilizing and increasing EPC number as well as function...
August 31, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28858080/comparative-assessment-of-the-efficacy-and-safety-of-acarbose-and-metformin-combined-with-premixed-insulin-in-patients-with-type-2-diabetes-mellitus
#14
RANDOMIZED CONTROLLED TRIAL
Honghua Wu, Jie Liu, Qingqing Lou, Jing Liu, Li Shen, Mingxia Zhang, Xiaofeng Lv, Mingjun Gu, Xiaohui Guo
This study, a subgroup analysis of the data from the Organization Program of DiabEtes INsulIN ManaGement study, aimed to compare the efficacy and safety profiles of acarbose and metformin used in combination with premixed insulin.This analysis included 80 and 192 patients taking only 1 oral antidiabetic drug, classified into acarbose (treated with acarbose + insulin) and metformin groups (treated with metformin + insulin), respectively. The efficacy and safety data were analyzed for within- and between-group differences...
September 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28842630/results-from-11-c-metformin-pet-scans-tissue-analysis-and-cellular-drug-sensitivity-assays-questions-the-view-that-biguanides-affects-tumor-respiration-directly
#15
Ane B Iversen, Michael R Horsman, Steen Jakobsen, Jonas B Jensen, Christian Garm, Niels Jessen, Peter Breining, Jørgen Frøkiær, Morten Busk
The anti-diabetic biguanide drugs metformin (METF) and phenformin (PHEN) may have anti-cancer effects. Biguanides suppress plasma growth factors, but nonetheless, the view that these mitochondrial inhibitors accumulate in tumor tissue to an extent that leads to severe energetic stress or alleviation of hypoxia-induced radioresistance is gaining ground. Our cell studies confirm that biguanides inhibits cell proliferation by targeting respiration, but only at highly suprapharmacological concentrations due to low drug retention...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28837141/metformin-reverses-prostate-cancer-resistance-to-enzalutamide-by-targeting-tgf-%C3%AE-1-stat3-axis-regulated-emt
#16
Qiuli Liu, Dali Tong, Gaolei Liu, Jing Xu, Khang Do, Kyla Geary, Dianzheng Zhang, Jun Zhang, Yao Zhang, Yaoming Li, Gang Bi, Weihua Lan, Jun Jiang
Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide...
August 24, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28834135/the-pharmacogenetics-of-metformin-in-women-with-pcos-a-randomized-trial
#17
Andreas J T Pedersen, Tore Bjerregaard Stage, Dorte Glintborg, Marianne Andersen, Mette Marie Hougaard Christensen
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin transporters, their transcriptional regulators or in metformin target genes on metformin response in women with PCOS is unclear. Associations between pharmacodynamic responses to metformin (changes in weight, lipid profile, insulin sensitivity evaluated by oral glucose tolerance testing) and polymorphisms in OCT1 (rs12208357 and rs72552763), HNF1A (rs1169288 and rs2464196), MATE1 (rs2289669 and rs2252281), MATE2-K (rs12943590) and ATM (rs11212617) were studied in 40 women with PCOS randomized to 12 months of treatment with metformin 1000 mg twice daily ± oral contraceptive pills (150 mg desogestrel + 30 μg ethinylestradiol)...
August 21, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28827783/ccdc3-a-new-p63-target-involved-in-regulation-of-liver-lipid-metabolism
#18
Wenjuan Liao, Hongbing Liu, Yiwei Zhang, Ji Hoon Jung, Jiaxiang Chen, Xiaohua Su, Yeong C Kim, Elsa R Flores, San Ming Wang, Malwina Czarny-Ratajczak, Wen Li, Shelya X Zeng, Hua Lu
TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28822889/metformin-targets-gastric-cancer-stem-cells
#19
Sarah Courtois, Raúl V Durán, Julie Giraud, Elodie Sifré, Julien Izotte, Francis Mégraud, Philippe Lehours, Christine Varon, Emilie Bessède
Gastric cancer is the third leading cause of cancer-related deaths worldwide and has still a poor prognosis. Therefore, new therapeutic strategies are needed: among them, targeting cancer stem cells (CSCs) could offer new opportunities. The aim of our study was to evaluate the anti-tumoural effect of metformin on gastric cancer in vitro and in vivo and especially, to determine whether this molecule could target the gastric CSCs. Metformin effects were evaluated on the proliferation and tumourigenic properties of the gastric CSCs from patient-derived primary tumour xenografts (PDXs) and cancer cell lines (MKN45, AGS and MKN74) in vitro in conventional 2 dimensional (2D) and in 3 dimensional (3D) culture systems, in which only CSCs are able to form tumourspheres and in mouse xenograft models in vivo...
August 17, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28821163/metformin-maintains-mucosal-integrity-in-experimental-model-of-colitis-by-inhibiting-oxidative-stress-and-pro-inflammatory-signaling
#20
Abhimanu Pandey, Sneh Verma, Vijay L Kumar
Metformin, an antidiabetic drug, is well known for its multifarious properties and its ability to modulate inflammatory cascade. Ulcerative colitis (UC) is an inflammatory condition of the colon where drugs exhibiting anti-inflammatory property have been shown to induce and maintain remission. The objective of the present study was to evaluate the efficacy of metformin against acetic-acid induced colitis in rat. The study included five groups of rats namely normal control, experimental control, drug treated groups (50 and 500mg/kg of metformin, MET50, MET500 and 300mg/kg of mesalazine, MSZ300)...
August 14, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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