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Diabetes New Target

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https://www.readbyqxmd.com/read/29050400/metformin-reverses-trap1-mutation-associated-alterations-in-mitochondrial-function-in-parkinson-s-disease
#1
Julia C Fitzgerald, Alexander Zimprich, Daniel A Carvajal Berrio, Kevin M Schindler, Brigitte Maurer, Claudia Schulte, Christine Bus, Anne-Kathrin Hauser, Manuela Kübler, Rahel Lewin, Dheeraj Reddy Bobbili, Lisa M Schwarz, Evangelia Vartholomaiou, Kathrin Brockmann, Richard Wüst, Johannes Madlung, Alfred Nordheim, Olaf Riess, L Miguel Martins, Enrico Glaab, Patrick May, Katja Schenke-Layland, Didier Picard, Manu Sharma, Thomas Gasser, Rejko Krüger
The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1...
September 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29050364/lncrnas-key-players-and-novel-insights-into-diabetes-mellitus
#2
REVIEW
Xiaoyun He, Chunlin Ou, Yanhua Xiao, Qing Han, Hao Li, Suxian Zhou
Long non-coding RNAs (LncRNAs) are a class of endogenous RNA molecules, which have a transcribing length of over 200 nt, lack a complete functional open reading frame (ORF), and rarely encode a functional short peptide. Recent studies have revealed that disruption of LncRNAs levels correlates with several human diseases, including diabetes mellitus (DM), a complex multifactorial metabolic disorder affecting more than 400 million people worldwide. LncRNAs are emerging as pivotal regulators in various biological processes, in the progression of DM and its associated complications, involving pancreatic β-cell disorder, insulin resistance, and epigenetic regulation, etc...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29043504/the-molecular-physiopathogenesis-of-islet-amyloidosis
#3
Diti Chatterjee Bhowmick, Sanghamitra Singh, Saurabh Trikha, Aleksandar M Jeremic
Human islet amyloid polypeptide or amylin (hA) is a 37-amino acid peptide hormone produced and co-secreted with insulin by pancreatic β-cells. Under physiological conditions, hA regulates a broad range of biological processes including insulin release and slowing of gastric emptying, thereby maintaining glucose homeostasis. However, under the pathological conditions associated with type 2 diabetes mellitus (T2DM), hA undergoes a conformational transition from soluble random coil monomers to alpha-helical oligomers and insoluble β-sheet amyloid fibrils or amyloid plaques...
October 18, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29042195/circular-rna-wdr77-target-fgf-2-to-regulate-vascular-smooth-muscle-cells-proliferation-and-migration-by-sponging-mir-124
#4
Junjiang Chen, Lianqun Cui, Jingliang Yuan, Yuqing Zhang, Hongjun Sang
Increasing evidences have revealed the important role of circular RNAs (circRNAs) in cardiovascular system disease. Whereas, the expression profiles and in-depth regulation of circRNAs on vascular smooth muscle cells (VSMCs) is still undetermined. In present study, our research team performed circRNAs microarray analysis to present the circRNAs expression profiles in high glucose induced VSMCs in vitro. Results showed that total of 983 circRNAs were discovered to be differentially expressed, and of these, 458 were upregulated and 525 were downregulated...
October 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29042190/hematopoietic-stem-progenitor-involvement-in-retinal-microvascular-repair-during-diabetes-implications-for-bone-marrow-rejuvenation
#5
Ashay D Bhatwadekar, Yaqian Duan, Maria Korahw, Jeffrey S Thinschmidt, Ping Hu, Sameer P Leley, Sergio Caballero, Lynn Shaw, Julia Busik, Maria B Grant
The widespread nature of diabetes affects all organ systems of an individual including the bone marrow. Long-term damage to the cellular and extracellular components of the bone marrow leads to a rapid decline in the bone marrow-hematopoietic stem/progenitor cells (HS/PCs) compartment. This review will highlight the importance of bone marrow microenvironment in maintaining bone marrow HS/PC populations and the contribution of these key populations in microvascular repair during the natural history of diabetes...
October 14, 2017: Vision Research
https://www.readbyqxmd.com/read/29041003/depression-in-the-context-of-medical-disorders-new-pharmacological-pathways-revisited
#6
Undine E Lang, Marc Walter
The depressive state has been characterised as one of elevated inflammation, changed cardiovascular parameters and a deranged metabolic situation all of which holds promise for a better understanding and handling of treatment-resistance in affective disorders as well as for future developments in treatment algorithms. In this context several biomarkers are differentially regulated by antidepressant treatment and connected to metabolic, inflammatory, cardiovascular and apoptotic components of the pathophysiology, i...
October 17, 2017: Neuro-Signals
https://www.readbyqxmd.com/read/29036789/protein-kinase-c-%C3%AE-dependent-regulation-of-ubiquitin-proteasome-system-function-in-breast-cancer
#7
Si Sun, Qi Wu, Junlong Song, Shengrong Sun
Besides the crucial role of hyperinsulinemia in the development of breast cancer with Type 2 diabetes mellitus (T2DM), it has been shown that hyperglycemia could contribute to promote cancer progression. A remarkable association within hyperglycemia, PKCδ and Ubiquitin-proteasome system (UPS) has been reported, suggesting that PKCδ may mediate high glucose-induced UPS activation in breast cancer cells. Although the independent effects of PKCδ or UPS on breast cancer and T2DM are increasingly supported by experimental evidence, the complex interactional link between PKCδ and UPS is still unclear...
September 29, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/29031711/lorcaserin-improves-glycemic-control-via-a-melanocortin-neurocircuit
#8
Luke K Burke, Emmanuel Ogunnowo-Bada, Teodora Georgescu, Claudia Cristiano, Pablo B Martinez de Morentin, Lourdes Valencia Torres, Giuseppe D'Agostino, Christine Riches, Nicholas Heeley, Yue Ruan, Marcelo Rubinstein, Malcolm J Low, Martin G Myers, Justin J Rochford, Mark L Evans, Lora K Heisler
OBJECTIVE: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved...
October 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29030662/oral-histone-deacetylase-inhibitor-synergises-with-t-cell-targeted-immunotherapy-to-preserve-beta-cell-metabolic-function-and-induce-stable-remission-of-new-onset-autoimmune-diabetes-in-nod-mice
#9
Alix Besançon, Tania Goncalves, Fabrice Valette, Mattias S Dahllöf, Thomas Mandrup-Poulsen, Lucienne Chatenoud, Sylvaine You
AIM/HYPOTHESIS: Combination therapy targeting the major actors involved in the immune-mediated destruction of pancreatic beta cells appears to be an indispensable approach to treat type 1 diabetes effectively. We hypothesised that the combination of an orally active pan-histone deacetylase inhibitor (HDACi: givinostat) with subtherapeutic doses of CD3 antibodies may provide ideal synergy to treat ongoing autoimmunity. METHODS: NOD mice transgenic for the human CD3ε (also known as CD3E) chain (NOD-huCD3ε) were treated for recent-onset diabetes with oral givinostat, subtherapeutic doses of humanised CD3 antibodies (otelixizumab, 50 μg/day, 5 days, i...
October 13, 2017: Diabetologia
https://www.readbyqxmd.com/read/29028440/intracerebroventricular-infusion-of-an-angiotensin-at2-receptor-agonist-novokinin-aggravates-some-diabetes-mellitus-induced-alterations-in-wistar-rats
#10
Daniela Pechlivanova, Kiril Petrov, Petar Grozdanov, Zlatina Nenchovska, Jana Tchekalarova, Alexander Stoynev
Cumulative data suggest the significant role of the Renin - Angiotensin System in the development of the pathological consequences of diabetes mellitus (DM). Newly synthesized AT2 receptor agonists gained importance as a target for creating new antihypertensives. The aim of the present work was to study the effects of a peptide AT2 agonist Novokinin, infused intracerebroventricularly, on the consequences of the streptozotocin-induced type 1 DM (T1 DM) in Wistar rats. Food and water consumption, body weight, urine excretion (metabolic cages), motor activity (open field test), anxiety (elevated plus maze), nociception (paw pressure analgesimeter test), spatial memory (T-maze alternation test) and plasma levels of glucose and corticosterone (ELISA) were assessed two weeks after the T1 DM induction...
October 13, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/29026101/heterozygous-rfx6-protein-truncating-variants-are-associated-with-mody-with-reduced-penetrance
#11
Kashyap A Patel, Jarno Kettunen, Markku Laakso, Alena Stančáková, Thomas W Laver, Kevin Colclough, Matthew B Johnson, Marc Abramowicz, Leif Groop, Päivi J Miettinen, Maggie H Shepherd, Sarah E Flanagan, Sian Ellard, Nobuya Inagaki, Andrew T Hattersley, Tiinamaija Tuomi, Miriam Cnop, Michael N Weedon
Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10(-4))...
October 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29025710/opposing-actions-of-akt-protein-kinase-b-isoforms-in-vascular-smooth-muscle-injury-and-therapeutic-response
#12
Yu Jin, Yi Xie, Allison C Ostriker, Xinbo Zhang, Renjing Liu, Monica Y Lee, Kristen L Leslie, Waiho Tang, Jing Du, Seung Hee Lee, Yingdi Wang, William C Sessa, John Hwa, Jun Yu, Kathleen A Martin
OBJECTIVE: Drug-eluting stent delivery of mTORC1 (mammalian target of rapamycin complex 1) inhibitors is highly effective in preventing intimal hyperplasia after coronary revascularization, but adverse effects limit their use for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell differentiation in an AKT2-dependent manner in vitro. Here, we investigate the roles of AKT (protein kinase B) isoforms in intimal hyperplasia...
October 12, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29024600/liver-x-receptor-%C3%AE-is-targeted-by-microrna-1-to-inhibit-cardiomyocyte-apoptosis-through-ros-mediated-mitochondrial-pathway
#13
Yongxia Cheng, Dawei Zhang, Min Zhu, Ying Wang, Sufen Guo, Biao Xu, Guangyu Hou, Yukuan Feng, Guibo Liu
Diabetic cardiomyopathy (DCM) is defined as ventricular dysfunction occurring independently of a recognized cause such as hypertension or coronary artery disease. Liver X receptor α (LXRα), a subtype of ligand-activated transcription factors LXRs, has been considered as a potential pharmacological target in the pathogenesis of cardiovascular and metabolic diseases. However, the potential mechanism of how LXRα is regulated in cardiomyocytes is still unclear. This study investigated the effect of activating LXRα with GW3965 on cardiomyocyte apoptosis and its upstream regulator in glucose-induced H9C2 cells...
October 12, 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/29021829/review-article-effects-of-type-2-diabetes-therapies-on-bone-metabolism
#14
REVIEW
A G D Vianna, C P Sanches, F C Barreto
Diabetes complications and osteoporotic fractures are two of the most important causes of morbidity and mortality in older patients, and they share many features, including genetic susceptibility, molecular mechanisms, and environmental factors. Type 2 diabetes mellitus (T2DM) compromises bone microarchitecture by inducing abnormal bone cell function and matrix structure with increased osteoblast apoptosis, diminished osteoblast differentiation, and enhanced osteoclast-mediated bone resorption. The linkage between these two chronic diseases creates a possibility that certain antidiabetic therapies may affect bone function...
2017: Diabetology & Metabolic Syndrome
https://www.readbyqxmd.com/read/29017535/the-leucopatch%C3%A2-system-in-the-management-of-hard-to-heal-diabetic-foot-ulcers-study-protocol-for-a-randomised-controlled-trial
#15
Frances Game, William Jeffcoate, Lise Tarnow, Florence Day, Deborah Fitzsimmons, Judith Jacobsen
BACKGROUND: Diabetic foot ulcers are a common and severe complication of diabetes mellitus. Standard treatment includes debridement, offloading, management of infection and revascularisation where appropriate, although healing times may be long. The LeucoPatch® device is used to generate an autologous platelet-rich fibrin and leucocyte wound dressing produced from the patient's own venous blood by centrifugation, but without the addition of any reagents. The final product comprises a thin, circular patch composed predominantly of fibrin together with living platelets and leucocytes...
October 10, 2017: Trials
https://www.readbyqxmd.com/read/29016751/cardiac-effects-of-sglt2-inhibitors-the-sodium-hypothesis
#16
Edoardo Bertero, Leticia Prates Roma, Pietro Ameri, Christoph Maack
The effects of intense glycaemic control on macrovascular complications in patients with type 2 diabetes are incompletely resolved, and many glucose-lowering medications negatively affect cardiovascular outcomes. Recently, the EMPA-REG OUTCOME trial revealed that empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), substantially reduced the risk of hospitalization for heart failure, death from cardiovascular causes, and all-cause mortality in patients with type 2 diabetes mellitus at high cardiovascular risk...
August 4, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28994638/dendrimers-carotenoids-and-monoclonal-antibodies
#17
Yuriy K Bashmakov, Ivan M Petyaev
Dendrimers are unimolecular architectural nano- or microparticle entities that can accommodate various nutraceuticals and pharmaceuticals between their branches (dendrons) and provide targeted delivery of biomimetics into different tissues upon addition of functionalized groups to the dendrimer's surface. Covalent binding, hydrogen bonds, and electrostatic interactions between dendrimer-composing molecules are known to form and stabilize dendrimer structure. Carotenoids have recently been shown to form dendrimer-like structures and promote targeted delivery of "cargo" molecules into organs characterized by high-carotenoid uptake (adrenal glands, prostate, liver, and brain)...
October 10, 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/28993906/antiangiogenesis-and-medical-therapy-failure-in-intracranial-atherosclerosis
#18
Nestor R Gonzalez, Raymond Liou, Florian Kurth, Hao Jiang, Jeffrey Saver
Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and the one with the worst prognosis. In this study, we assessed the hypothesis that the balance of circulating pro- and antiangiogenic factors plays a role in the evolution of the disease and can be used as a potential marker for the disease course and a target for treatment. Seventy-four patients with severe ICAD were enrolled in this prospective observational study, medically optimized, and followed for 6 months...
October 9, 2017: Angiogenesis
https://www.readbyqxmd.com/read/28993341/insights-from-molecular-characterization-of-adult-patients-of-families-with-multigenerational-diabetes-mellitus
#19
Serena Pezzilli, Ornella Ludovico, Tommaso Biagini, Luana Mercuri, Federica Alberico, Eleonora Lauricella, Hamza Dallali, Daniele Capocefalo, Massimo Carella, Elide Miccinilli, Pamela Piscitelli, Maria Giovanna Scarale, Tommaso Mazza, Vincenzo Trischitta, Sabrina Prudente
Multigenerational diabetes of the adulthood is a mostly overlooked entity, simplistically comprised in the large basin of type 2 diabetes. The general aim we are pursuing in last years is to unravel the genetic causes of such form of diabetes. Identifying among families with multigenerational diabetes those carrying mutations in known monogenic diabetes genes is the first step to then concentrate on remaining pedigrees where to unravel new diabetogenes.Targeted Next Generation Sequencing of 27 monogenic diabetes-genes has been carried out in 55 family probands and identified mutations verified among their relatives by Sanger sequencing...
October 9, 2017: Diabetes
https://www.readbyqxmd.com/read/28992340/gremlin-and-renal-diseases-ready-to-jump-the-fence-to-clinical-utility
#20
Sergio Mezzano, Alejandra Droguett, Carolina Lavoz, Paola Krall, Jesús Egido, Marta Ruiz-Ortega
The current therapeutic strategy for the treatment of chronic kidney diseases only ameliorates disease progression. During renal injury, developmental genes are re-expressed and could be potential therapeutic targets. Among those genes reactivated in the adult damaged kidney, Gremlin is of particular relevance since recent data suggest that it could be a mediator of diabetic nephropathy and other progressive renal diseases. Earlier studies have shown that Gremlin is upregulated in trans-differentiated renal proximal tubular cells and in several chronic kidney diseases associated with fibrosis...
July 8, 2017: Nephrology, Dialysis, Transplantation
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