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Diabetes New Target

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https://www.readbyqxmd.com/read/29454281/probing-the-%C3%AE-pocket-of-the-active-site-of-human-liver-glycogen-phosphorylase-with-3-c-%C3%AE-d-glucopyranosyl-5-4-substituted-phenyl-1-2-4-triazole-inhibitors
#1
Efthimios Kyriakis, Theodora G A Solovou, Sándor Kun, Katalin Czifrák, Béla Szőcs, László Juhász, Éva Bokor, George A Stravodimos, Anastassia L Kantsadi, Demetra S M Chatzileontiadou, Vassiliki T Skamnaki, László Somsák, Demetres D Leonidas
Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a β-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the β-pocket. Recently, C-β-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP...
February 12, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29453020/2018-consensus-of-the-taiwan-society-of-cardiology-and-the-diabetes-association-of-republic-of-china-taiwan-on-the-pharmacological-management-of-patients-with-type-2-diabetes-and-cardiovascular-diseases
#2
Chern-En Chiang, Shih-Yi Lin, Tsung-Hsien Lin, Tzung-Dau Wang, Hung-I Yeh, Jung-Fu Chen, Chia-Ti Tsai, Yi-Jen Hung, Yi-Heng Li, Ping-Yen Liu, Kuan-Cheng Chang, Kang-Ling Wang, Ting-Hsing Chao, Kou-Gi Shyu, Wei-Shiung Yang, Kwo-Chang Ueng, Pao-Hsien Chu, Wei-Hsian Yin, Yen-Wen Wu, Hao-Min Cheng, Shyi-Jang Shin, Chien-Ning Huang, Lee-Ming Chuang, Shing-Jong Lin, San-Jou Yeh, Wayne Huey-Herng Sheu, Jiunn-Lee Lin
The global incidence and prevalence of type 2 diabetes have been escalating in recent decades. Patients with type 2 diabetes have an increased risk of atherosclerotic cardiovascular disease (ASCVD). About two-thirds of death in type 2 diabetes are due to ASCVD, including 40% from coronary heart disease (CHD), 15% from heart failure (HF), and 10% from stroke. The association between hyperglycemia and elevated CV risk has been demonstrated in multiple cohort studies. However, clinical trials of intensive glucose reduction did not significantly reduce macrovascular outcomes...
February 13, 2018: Journal of the Chinese Medical Association: JCMA
https://www.readbyqxmd.com/read/29451523/-towards-new-therapeutic-paradigms-beyond-symptom-control-in-the-management-of-inflammatory-bowel-diseases
#3
Stefano Festa, Giulia Zerboni, Annalisa Aratari, Riccardo Ballanti, Claudio Papi
Inflammatory bowel diseases, Crohn's disease and ulcerative colitis are chronic relapsing conditions that may result in progressive bowel damage, high risk of complications, surgery and permanent disability. The conventional therapeutic approach for inflammatory bowel diseases is based mainly on symptom control. Unfortunately, a symptom-based therapeutic approach has little impact on major long-term disease outcomes. In other chronic disabling conditions such as diabetes, hypertension and rheumatoid arthritis, the development of new therapeutic approaches has led to better outcomes...
January 2018: Recenti Progressi in Medicina
https://www.readbyqxmd.com/read/29449830/screening-for-ppar-non-agonist-ligands-followed-by-characterization-of-a-hit-am-879-with-additional-no-adipogenic-and-cdk5-mediated-phosphorylation-inhibition-properties
#4
Helder Veras Ribeiro Filho, Natália Bernardi Videira, Aline Villanova Bridi, Thais Helena Tittanegro, Fernanda Aparecida Helena Batista, José Geraldo de Carvalho Pereira, Paulo Sérgio Lopes de Oliveira, Marcio Chaim Bajgelman, Albane Le Maire, Ana Carolina Migliorini Figueira
Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor, playing key roles in maintenance of adipose tissue and in regulation of glucose and lipid homeostasis. This receptor is the target of thiazolidinediones, a class of antidiabetic drugs, which improve insulin sensitization and regulate glycemia in type 2 diabetes. Despite the beneficial effects of drugs, such as rosiglitazone and pioglitazone, their use is associated with several side effects, including weight gain, heart failure, and liver disease, since these drugs induce full activation of the receptor...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29448118/calcium-channel-blockers-as-drug-repurposing-candidates-for-gestational-diabetes-mining-large-scale-genomic-and-electronic-health-records-data-to-repurpose-medications
#5
Jeffery A Goldstein, Lisa A Bastarache, Joshua C Denny, Dan M Roden, Jill M Pulley, David M Aronoff
New therapeutic approaches are needed for gestational diabetes mellitus (GDM), but must show safety and efficacy in a historically understudied population. We studied associations between electronic medical record (EMR) phenotypes and genetic variants to uncover drugs currently considered safe in pregnancy that could treat or prevent GDM. We identified 129 systemically active drugs considered safe in pregnancy targeting the proteins produced from 196 genes. We tested for associations between GDM and/or type 2 diabetes (DM2) and 306 SNPs in 130 genes represented on the Illumina Infinium Human Exome Bead Chip (DM2 was included due to shared pathophysiological features with GDM)...
February 12, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29447091/obesity-in-pregnancy-a-comparison-of-four-national-guidelines
#6
Dana Vitner, Kristin Harris, Cynthia Maxwell, M D Farine
BACKGROUND: Obesity in pregnancy has become one of the most important challenges in obstetrical care given its prevalence and potential adverse impact on both mother and fetus. The primary objective of this descriptive review is to identify common themes and distinctions within the current recommendations for maternal obesity in the most updated version of four published national guidelines. METHODS: We reviewed the following guidelines for obesity in pregnancy: American College of Obstetricians and Gynecologists (ACOG) 2015, Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG) 2013, Royal College of Obstetrics and Gynecology (RCOG) 2010, and Society of Obstetrics and Gynecologists of Canada (SOGC) 2010...
February 15, 2018: Journal of Maternal-fetal & Neonatal Medicine
https://www.readbyqxmd.com/read/29446769/vascular-cognitive-impairment
#7
REVIEW
Wiesje M van der Flier, Ingmar Skoog, Julie A Schneider, Leonardo Pantoni, Vincent Mok, Christopher L H Chen, Philip Scheltens
The term vascular cognitive impairment (VCI) was introduced around the start of the new millennium and refers to the contribution of vascular pathology to any severity of cognitive impairment, ranging from subjective cognitive decline and mild cognitive impairment to dementia. Although vascular pathology is common in elderly individuals with cognitive decline, pure vascular dementia (that is, dementia caused solely by vascular pathology) is uncommon. Indeed, most patients with vascular dementia also have other types of pathology, the most common of which is Alzheimer disease (specifically, the diffuse accumulation of amyloid-β plaques and neurofibrillary tangles composed of tau)...
February 15, 2018: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/29446740/role-of-immune-cells-in-diabetic-kidney-disease
#8
Xiaoqian Yang, Shan Mou
Diabetic kidney disease (DKD) is one of the major complications of diabetes mellitus (DM) and is currently the most common cause of end-stage renal disease (ESRD) worldwide. Traditionally, DKD is considered a disease which has nothing to do with the immune system, and the pathogenesis is mainly characterized to be metabolic disturbance. Recent growing evidence indicates immunologic and inflammatory mechanisms in the development and progression of DKD. This overview of macrophages, dendritic cells, T lymphocytes, B lymphocytes, neutrophils and mast cells is closely involved in the pathologic process of DKD, with more emphasis on the leucocyte accumulation and related molecular mechanisms...
February 13, 2018: Current Gene Therapy
https://www.readbyqxmd.com/read/29446615/leveraging-engineering-of-cells-for-drug-delivery
#9
Zhaowei Chen, Quanyin Hu, Zhen Gu
Cell therapy has become a momentum-gathering treatment strategy for a variety of diseases, including cancer, diabetes, hemophilia, and cardiomyopathy. However, clinical applications of conventional cell therapies have often been compromised by rapid decline in viability and function of the transplanted cells due to host recognition and subsequent foreign body rejection. Along this line, cell engineering technologies such as cell encapsulation within microcapsules and immobilization in porous scaffolds have been implemented to address the immunosuppression concerns...
February 15, 2018: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29445837/alkaline-phosphatases-in-the-complex-chronic-kidney-disease-mineral-and-bone-disorders
#10
Jordi Bover, Pablo Ureña, Armando Aguilar, Sandro Mazzaferro, Silvia Benito, Víctor López-Báez, Alejandra Ramos, Iara daSilva, Mario Cozzolino
Alkaline phosphatases (APs) remove the phosphate (dephosphorylation) needed in multiple metabolic processes (from many molecules such as proteins, nucleotides, or pyrophosphate). Therefore, APs are important for bone mineralization but paradoxically they can also be deleterious for other processes, such as vascular calcification and the increasingly known cross-talk between bone and vessels. A proper balance between beneficial and harmful activities is further complicated in the context of chronic kidney disease (CKD)...
February 14, 2018: Calcified Tissue International
https://www.readbyqxmd.com/read/29445185/iron-overload-accelerates-the-progression-of-diabetic-retinopathy-in-association-with-increased-retinal-renin-expression
#11
Kapil Chaudhary, Wanwisa Promsote, Sudha Ananth, Rajalakshmi Veeranan-Karmegam, Amany Tawfik, Pachiappan Arjunan, Pamela Martin, Sylvia B Smith, Muthusamy Thangaraju, Oleg Kisselev, Vadivel Ganapathy, Jaya P Gnana-Prakasam
Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Increased iron accumulation is associated with several degenerative diseases. However, there are no reports on the status of retinal iron or its implications in the pathogenesis of DR. In the present study, we found that retinas of type-1 and type-2 mouse models of diabetes have increased iron accumulation compared to non-diabetic retinas. We found similar iron accumulation in postmortem retinal samples from human diabetic patients...
February 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29444767/patient-reported-measures-for-person-centered-coordinated-care-a-comparative-domain-map-and-web-based-compendium-for-supporting-policy-development-and-implementation
#12
Helen Lloyd, Hannah Wheat, Jane Horrell, Thavapriya Sugavanam, Benjamin Fosh, Jose M Valderas, James Close
BACKGROUND: Patient-reported measure (PRM) questionnaires were originally used in research to measure outcomes of intervention studies. They have now evolved into a diverse family of tools measuring a range of constructs including quality of life and experiences of care. Current health and social care policy increasingly advocates their use for embedding the patient voice into service redesign through new models of care such as person-centered coordinated care (P3C). If chosen carefully and used efficiently, these tools can help improve care delivery through a variety of novel ways, including system-level feedback for health care management and commissioning...
February 14, 2018: Journal of Medical Internet Research
https://www.readbyqxmd.com/read/29439250/hoxa5-promotes-adipose-differentiation-via-increasing-dna-methylation-level-and-inhibiting-pka-hsl-signal-pathway-in-mice
#13
Weina Cao, Yatao Xu, Dan Luo, Muhammad Saeed, Chao Sun
BACKGROUND/AIMS: Impaired adipogenesis may be the underlying cause in the development of obesity and type II diabetes. Mechanistically, the family of Homeobox transcription factors is implicated in the regulation of adipocyte fate. Hoxa5 is highly expressed in adipocytes, and its mRNA expression is decreased during differentiation. However, the function of Hoxa5 in adipose tissue has been poorly understood. The aim of this study is to unveil the role of Hoxa5 on adipocyte differentiation and its underlying mechanisms...
February 7, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29437698/islet-interleukin-1%C3%AE-immunoreactivity-is-an-early-feature-of-cystic-fibrosis-that-may-contribute-to-%C3%AE-cell-failure
#14
Rebecca L Hull, Ronald L Gibson, Sharon McNamara, Gail H Deutsch, Corinne L Fligner, Charles W Frevert, Bonnie W Ramsey, Srinath Sanda
OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), increasing patient morbidity and mortality. Poor understanding of CFRD pathogenesis limits the development of targeted therapies to treat and/or prevent the disease. The aim of this study was to evaluate islet pathology, specifically, inflammation, amyloid deposition, and endocrine cell composition in subjects with CF with diabetes and with CF without diabetes. RESEARCH DESIGN AND METHODS: A retrospective analysis of archived pancreas tissue collected at autopsy was conducted using pancreas tissue from subjects with CF and diabetes (CFRD) ( n = 18) and CF without diabetes (CF-no DM) ( n = 17)...
February 1, 2018: Diabetes Care
https://www.readbyqxmd.com/read/29436254/therapeutic-targets-for-altering-mitochondrial-dysfunction-associated-with-diabetic-retinopathy
#15
Renu A Kowluru, Manish Mishra
Retinopathy remains as one of the most feared blinding complications of diabetes, and with the prevalence of this life-long disease escalating at an alarming rate, the incidence of retinopathy is also climbing. Although the cutting edge research has identified many molecular mechanisms associated with its development, the exact mechanism how diabetes damages the retina remains obscure, limiting therapeutic options for this devastating disease. Areas covered: This review focuses on the central role of mitochondrial dysfunction/damage in the pathogenesis of diabetic retinopathy, and how damaged mitochondria initiates a self-perpetuating vicious cycles of free radicals...
February 13, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29434588/gata3-hdac6-and-bcl6-regulate-foxp3-treg-plasticity-and-determine-treg-conversion-into-either-novel-antigen-presenting-cell-like-treg-or-th1-treg
#16
Keman Xu, William Y Yang, Gayani Kanchana Nanayakkara, Ying Shao, Fan Yang, Wenhui Hu, Eric T Choi, Hong Wang, Xiaofeng Yang
We conducted an experimental database analysis to determine the expression of 61 CD4+ Th subset regulators in human and murine tissues, cells, and in T-regulatory cells (Treg) in physiological and pathological conditions. We made the following significant findings: (1) adipose tissues of diabetic patients with insulin resistance upregulated various Th effector subset regulators; (2) in skin biopsy from patients with psoriasis, and in blood cells from patients with lupus, effector Th subset regulators were more upregulated than downregulated; (3) in rosiglitazone induced failing hearts in ApoE-deficient (KO) mice, various Th subset regulators were upregulated rather than downregulated; (4) aortic endothelial cells activated by proatherogenic stimuli secrete several Th subset-promoting cytokines; (5) in Treg from follicular Th (Tfh)-transcription factor (TF) Bcl6 KO mice, various Th subset regulators were upregulated; whereas in Treg from Th2-TF GATA3 KO mice and HDAC6 KO mice, various Th subset regulators were downregulated, suggesting that Bcl6 inhibits, GATA3 and HDAC6 promote, Treg plasticity; and (6) GATA3 KO, and Bcl6 KO Treg upregulated MHC II molecules and T cell co-stimulation receptors, suggesting that GATA3 and BCL6 inhibit Treg from becoming novel APC-Treg...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29433327/redox-signaling-from-and-to-peroxisomes-progress-challenges-and-prospects
#17
Marc Fransen, Celien Lismont
<b><i>Significance:</i></b> Peroxisomes are organelles that are best known for their role in cellular lipid and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) metabolism. Emerging evidence suggests that these organelles serve as guardians and modulators of cellular redox balance, and that alterations in their redox metabolism may contribute to aging and the development of chronic diseases such as neurodegeneration, diabetes, and cancer. <b><i>Recent Advances:</i></b> H<sub>2</sub>O<sub>2</sub> is an important signaling messenger that controls many cellular processes by modulating protein activity through cysteine oxidation...
February 13, 2018: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/29432738/humanin-promotes-mitochondrial-biogenesis-in-pancreatic-min6-%C3%AE-cells
#18
Qingqing Qin, Jieqiong Jin, Fang He, Yongqin Zheng, Tingting Li, Yun Zhang, Jundong He
Mitochondrial dysfunction is associated with β-cell failure and insulin resistance in diabetes. Humanin is an endogenous cytoprotective peptide. In the current study, we aimed to define the effects of Humanin on mitochondrial biogenesis in pancreatic β-cells. Our findings demonstrated that Humanin treatment significantly increased the expression of PGC-1α and its downstream target genes NRF1 and TFAM in MIN6 β-cells. Notably, Humanin treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial mass, elevating mtDNA/nDNA ratio, and stimulating the expression of cytochrome B, which were suppressed by the specific AMPK inhibitor compound C...
February 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29428595/galanin-enhances-systemic-glucose-metabolism-through-enteric-nitric-oxide-synthase-expressed-neurons
#19
Anne Abot, Alexandre Lucas, Tereza Bautzova, Arnaud Bessac, Audren Fournel, Sophie Le-Gonidec, Philippe Valet, Cédric Moro, Patrice D Cani, Claude Knauf
OBJECTIVE: Decreasing duodenal contraction is now considered as a major focus for the treatment of type 2 diabetes. Therefore, identifying bioactive molecules able to target the enteric nervous system, which controls the motility of intestinal smooth muscle cells, represents a new therapeutic avenue. For this reason, we chose to study the impact of oral galanin on this system in diabetic mice. METHODS: Enteric neurotransmission, duodenal contraction, glucose absorption, modification of gut-brain axis, and glucose metabolism (glucose tolerance, insulinemia, glucose entry in tissue, hepatic glucose metabolism) were assessed...
January 31, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29428410/fragment-growing-guided-design-of-keap1-nrf2-protein-protein-interaction-inhibitors-for-targeting-myocarditis
#20
Ning Meng, Hua Tang, Hao Zhang, Chengshi Jiang, Li Su, Xiao Min, Wannian Zhang, Hua Zhang, Zhenyuan Miao, Wen Zhang, Chunlin Zhuang
Small-molecule inhibitors that block the Keap1-Nrf2 protein-protein interactions are being intensely pursued as a new therapeutic strategy for oxidative stress-related diseases, such as cancer, diabetes, Alzheimer's disease, arteriosclerosis, inflammation and myocarditis. However, there are not enough studies on antioxidant treatments using small molecules in myocarditis. We herein provided a series of novel hydronaphthoquinones as the Keap1-Nrf2 interaction inhibitors targeting LPS-induced myocarditis both in vitro and in vivo...
February 8, 2018: Free Radical Biology & Medicine
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