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https://www.readbyqxmd.com/read/28646406/podocytes-and-the-quest-for-precision-medicines-for-kidney-diseases
#1
REVIEW
Peter Mundel
In this review, I describe a 30-year journey in the quest for precision medicines for patients with kidney diseases. In 1987, when I started my reseach career, most scientists studying glomerular disease biology were focused on mesangial cells. The crucial role of the podocyte in many kidney diseases characterized by proteinuria, including focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, had not yet been recognized. We were not aware of genetic causes or drivers of kidney diseases nor of molecular markers and cell culture systems for mechanistic studies of podocyte biology...
June 23, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28646072/genetic-and-environmental-interactions-modify-the-risk-of-diabetes-related-autoimmunity-by-6-years-of-age-the-teddy-study
#2
Jeffrey P Krischer, Kristian F Lynch, Åke Lernmark, William A Hagopian, Marian J Rewers, Jin-Xiong She, Jorma Toppari, Anette-G Ziegler, Beena Akolkar
OBJECTIVE: We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes. RESEARCH DESIGN AND METHODS: Infants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. SNPs came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years. RESULTS: Insulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children)...
June 23, 2017: Diabetes Care
https://www.readbyqxmd.com/read/28643424/mdm2-is-implicated-in-high-glucose-induced-podocyte-mitotic-catastrophe-via-notch1-signalling
#3
Hui Tang, Chun-Tao Lei, Chen Ye, Pan Gao, Cheng Wan, Shan Chen, Fang-Fang He, Yu-Mei Wang, Hua Su, Chun Zhang
Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in 'post-mitosis' state and unable to regenerate. Re-entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia...
June 23, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28643218/empagliflozin-improves-left-ventricular-diastolic-dysfunction-in-a-genetic-model-of-type-2-diabetes
#4
Nadjib Hammoudi, Dongtak Jeong, Rajvir Singh, Ahmed Farhat, Michel Komajda, Eric Mayoux, Roger Hajjar, Djamel Lebeche
PURPOSE: Cardiovascular (CV) diseases in type 2 diabetes (T2DM) represent an enormous burden with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a new antidiabetic class that improves glucose control, as well as body weight and blood pressure with no increased risk of hypoglycemia. The first CV outcome study terminated with empagliflozin, a specific SGLT2 inhibitor, has shown a reduction in CV mortality and in heart failure hospitalization, suggesting a beneficial impact on cardiac function which remains to be demonstrated...
June 22, 2017: Cardiovascular Drugs and Therapy
https://www.readbyqxmd.com/read/28641522/advances-on-ppar%C3%AE-research-in-the-emerging-era-of-precision-medicine
#5
Pinyi Lu, Zhongming Zhao
BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily that functions as a ligand-inducible transcription factor. It regulates glucose and lipid metabolism, immunity, and cellular growth and differentiation. Thiazolidinediones (TZDs) are potent insulin sensitizers that function by activating PPARs, with a high specificity for PPARγ. Due to their ability to preserve pancreatic beta cell function and reduce insulin resistance, TZDs have become one of the most prescribed classes of medications for type 2 diabetes (T2D) since their approval by the US Food and Drug Administration (FDA) and initial use in 1997...
June 21, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28640866/diet-induced-adipose-tissue-expansion-is-mitigated-in-mice-with-a-targeted-inactivation-of-mesoderm-specific-transcript-mest
#6
Rea P Anunciado-Koza, Justin Manuel, Randall L Mynatt, Jingying Zhang, Leslie P Kozak, Robert A Koza
Interindividual variation of white adipose tissue (WAT) expression of mesoderm specific transcript (Mest), a paternally-expressed imprinted gene belonging to the α/β-hydrolase fold protein family, becomes apparent among genetically inbred mice fed high fat diet (HFD) and is positively associated with adipose tissue expansion (ATE). To elucidate a role for MEST in ATE, mice were developed with global and adipose tissue inactivation of Mest. Mice with homozygous (MestgKO) and paternal allelic (MestpKO) inactivation of Mest were born at expected Mendelian frequencies, showed no behavioral or physical abnormalities, and did not perturb expression of the Mest locus-derived microRNA miR-335...
2017: PloS One
https://www.readbyqxmd.com/read/28640243/in-depth-investigations-of-adolescents-and-adults-with-holoprosencephaly-identify-unique-characteristics
#7
Karin Weiss, Paul Kruszka, Maria J Guillen Sacoto, Yonit A Addissie, Donald W Hadley, Casey K Hadsall, Bethany Stokes, Ping Hu, Erich Roessler, Beth Solomon, Edythe Wiggs, Audrey Thurm, Robert B Hufnagel, Wadih M Zein, Jin S Hahn, Elaine Stashinko, Eric Levey, Debbie Baldwin, Nancy J Clegg, Mauricio R Delgado, Maximilian Muenke
PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios...
June 22, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28639538/metabolic-syndrome-pathophysiology-management-and-modulation-by-natural-compounds
#8
Yogita Rochlani, Naga Venkata Pothineni, Swathi Kovelamudi, Jawahar L Mehta
Metabolic syndrome (MetS) represents a cluster of metabolic abnormalities that include hypertension, central obesity, insulin resistance, and atherogenic dyslipidemia, and is strongly associated with an increased risk for developing diabetes and atherosclerotic and nonatherosclerotic cardiovascular disease (CVD). The pathogenesis of MetS involves both genetic and acquired factors that contribute to the final pathway of inflammation that leads to CVD. MetS has gained significant importance recently due to the exponential increase in obesity worldwide...
June 1, 2017: Therapeutic Advances in Cardiovascular Disease
https://www.readbyqxmd.com/read/28639375/challenges-in-regenerating-the-diabetic-heart-a-comprehensive-review
#9
REVIEW
Venkata R Satthenapalli, Regis R Lamberts, Rajesh Katare
Stem cell therapy is one of the promising regenerative strategies developed to improve cardiac function in patients with ischemic heart diseases (IHD). However, this approach is limited in IHD patients with diabetes due to a progressive decline in the regenerative capacity of stem cells. This decline is mainly attributed to the metabolic memory incurred by diabetes on stem cell niche and their systemic cues. Understanding the molecular pathways involved in the diabetes-induced deterioration of stem cell function will be critical for developing new cardiac regeneration therapies...
June 22, 2017: Stem Cells
https://www.readbyqxmd.com/read/28638342/warfarin-anticoagulation-therapy-in-caribbean-hispanics-of-puerto-rico-a-candidate-gene-association-study
#10
Karla Claudio-Campos, Aurora Labastida, Alga Ramos, Andrea Gaedigk, Jessicca Renta-Torres, Dariana Padilla, Giselle Rivera-Miranda, Stuart A Scott, Gualberto Ruaño, Carmen L Cadilla, Jorge Duconge-Soler
Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28637897/heritability-of-resting-heart-rate-and-association-with-mortality-in-middle-aged-and-elderly-twins
#11
Magnus T Jensen, Mette Wod, Søren Galatius, Jacob B Hjelmborg, Gorm B Jensen, Kaare Christensen
OBJECTIVE: Resting heart rate (RHR) possibly has a hereditary component and is associated with longevity. We used the classical biometric twin study design to investigate the heritability of RHR in a population of middle-aged and elderly twins and, furthermore, studied the association between RHR and mortality. METHODS: In total, 4282 twins without cardiovascular disease were included from the Danish Twin Registry, hereof 1233 twin pairs and 1816 'single twins' (twins with a non-participating co-twin); mean age 61...
June 21, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28637406/socioeconomic-status-the-missing-link-between-obesity-and-diabetes-mellitus
#12
Alexei Volaco, Ana Maria Cavalcanti, Roberto Pecoits Filho, Dalton Bertolim Précoma
BACKGROUND: Currently, there is an epidemic expansion of the obesity rates worldwide. The increasing number of obese individuals associated with the aging of population leads to increasing number of individuals with type 2 diabetes mellitus (T2DM) at the same rate. The traditional factors that link obesity to T2DM are related to genetics, hypercaloric diet, sedentary lifestyle, and stress. Individuals from lower socioeconomic status (SES) have restricted autonomy and opportunities that could lead to more stress and consequently increase in stress hormones, such as cortisol, catecholamines, glucagon, and growth hormone, which might ultimately change fat deposition, increasing visceral fat and increasing the risk of T2DM mellitus development...
June 21, 2017: Current Diabetes Reviews
https://www.readbyqxmd.com/read/28636934/the-tmao-producing-enzyme-flavin-containing-monooxygenase-3-regulates-obesity-and-the-beiging-of-white-adipose-tissue
#13
Rebecca C Schugar, Diana M Shih, Manya Warrier, Robert N Helsley, Amy Burrows, Daniel Ferguson, Amanda L Brown, Anthony D Gromovsky, Markus Heine, Arunachal Chatterjee, Lin Li, Xinmin S Li, Zeneng Wang, Belinda Willard, YongHong Meng, Hanjun Kim, Nam Che, Calvin Pan, Richard G Lee, Rosanne M Crooke, Mark J Graham, Richard E Morton, Carl D Langefeld, Swapan K Das, Lawrence L Rudel, Nizar Zein, Arthur J McCullough, Srinivasan Dasarathy, W H Wilson Tang, Bernadette O Erokwu, Chris A Flask, Markku Laakso, Mete Civelek, Sathyamangla V Naga Prasad, Joerg Heeren, Aldons J Lusis, Stanley L Hazen, J Mark Brown
Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here, we demonstrate that the gut microbiota-initiated trimethylamine N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism. In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes. In addition, circulating TMAO levels were associated with obesity traits in the different inbred strains represented in the Hybrid Mouse Diversity Panel...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28636232/a-genetic-stochastic-process-model-for-genome-wide-joint-analysis-of-biomarker-dynamics-and-disease-susceptibility-with-longitudinal-data
#14
Liang He, Ilya Zhbannikov, Konstantin G Arbeev, Anatoliy I Yashin, Alexander M Kulminski
Unraveling the underlying biological mechanisms or pathways behind the effects of genetic variations on complex diseases remains one of the major challenges in the post-GWAS (where GWAS is genome-wide association study) era. To further explore the relationship between genetic variations, biomarkers, and diseases for elucidating underlying pathological mechanism, a huge effort has been placed on examining pleiotropic and gene-environmental interaction effects. We propose a novel genetic stochastic process model (GSPM) that can be applied to GWAS and jointly investigate the genetic effects on longitudinally measured biomarkers and risks of diseases...
June 21, 2017: Genetic Epidemiology
https://www.readbyqxmd.com/read/28635624/effects-of-type-1-diabetes-risk-alleles-on-immune-cell-gene-expression
#15
REVIEW
Ramesh Ram, Grant Morahan
Genetic studies have identified 61 variants associated with the risk of developing Type 1 Diabetes (T1D). The functions of most of the non-HLA (Human Leukocyte Antigen) genetic variants remain unknown. We found that only 16 of these risk variants could potentially be linked to a protein-coding change. Therefore, we investigated whether these variants affected susceptibility by regulating changes in gene expression. To do so, we examined whole transcriptome profiles of 600 samples from the Type 1 Diabetes Genetics Consortium (T1DGC)...
June 21, 2017: Genes
https://www.readbyqxmd.com/read/28632874/screening-for-obesity-in-children-and-adolescents-us-preventive-services-task-force-recommendation-statement
#16
David C Grossman, Kirsten Bibbins-Domingo, Susan J Curry, Michael J Barry, Karina W Davidson, Chyke A Doubeni, John W Epling, Alex R Kemper, Alex H Krist, Ann E Kurth, C Seth Landefeld, Carol M Mangione, Maureen G Phipps, Michael Silverstein, Melissa A Simon, Chien-Wen Tseng
Importance: Based on year 2000 Centers for Disease Control and Prevention growth charts, approximately 17% of children and adolescents aged 2 to 19 years in the United States have obesity, and almost 32% of children and adolescents are overweight or have obesity. Obesity in children and adolescents is associated with morbidity such as mental health and psychological issues, asthma, obstructive sleep apnea, orthopedic problems, and adverse cardiovascular and metabolic outcomes (eg, high blood pressure, abnormal lipid levels, and insulin resistance)...
June 20, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28632820/the-nexus-of-stem-cell-derived-beta-cells-and-genome-engineering
#17
Sara D Sackett, Aida Rodriguez, Jon S Odorico
Diabetes, type 1 and type 2 (T1D and T2D), are diseases of epidemic proportions, which are complicated and defined by genetics, epigenetics, environment, and lifestyle choices. Current therapies consist of whole pancreas or islet transplantation. However, these approaches require life-time immunosuppression, and are compounded by the paucity of available donors. Pluripotent stem cells have advanced research in the fields of stem cell biology, drug development, disease modeling, and regenerative medicine, and importantly allows for the interrogation of therapeutic interventions...
2017: Review of Diabetic Studies: RDS
https://www.readbyqxmd.com/read/28632336/serious-life-events-and-the-risk-of-latent-autoimmune-diabetes-in-adults-lada-and-type-2-diabetes
#18
B Rasouli, T Andersson, P-O Carlsson, R Hjort, J E Löfvenborg, M Martinell, L Groop, T Tuomi, S Carlsson
AIM: It has been suggested that experiencing serious life events may promote Type 1 diabetes in children. Studies in adults are lacking, as are studies on the interaction of life events with genetic factors. We aimed to investigate life events and the risk of latent autoimmune diabetes in adults (LADA) and Type 2 diabetes while taking into account HLA genotype. METHODS: Analysis was based on 425 incident cases of LADA, 1417 incident cases of Type 2 diabetes and 1702 population-based controls recruited in Sweden between 2010 and 2016...
June 20, 2017: Diabetic Medicine: a Journal of the British Diabetic Association
https://www.readbyqxmd.com/read/28632032/plasminogen-activator-inhibitor-type-1-tag-single-nucleotide-polymorphisms-in-patients-with-diabetes-mellitus-type-2-and-diabetic-retinopathy
#19
Vasileios Siokas, Efthimios Dardiotis, Thomas Sokolakis, Maria Kotoula, Sophia V Tachmitzi, Dimitrios Z Chatzoulis, Pavlina Almpanidou, Ioannis Stefanidis, Georgios M Hadjigeorgiou, Evangelia E Tsironi
BACKGROUND: There is accumulating evidence for genetic susceptibility to the development of diabetic retinopathy (DR). The role of plasminogen activator inhibitor-1 (PAI-1) in DR risk remains controversial. OBJECTIVE: The present study was designed to investigate possible influence of PAI-1 gene region polymorphisms on the risk of DR and on the risk of developing DR early vs late in the course of type 2 diabetes mellitus (T2DM). METHODS: A total of 138 patients with DR, 107 patients with T2DM without DR, and 315 healthy controls were recruited...
February 28, 2017: Current Eye Research
https://www.readbyqxmd.com/read/28629388/the-albumin-exendin-4-recombinant-protein-e2hsa-improves-glycemic-control-and-%C3%AE-cell-function-in-spontaneous-diabetic-kkay-mice
#20
Caina Li, Shaocong Hou, Shuainan Liu, Yi Huan, Sujuan Sun, Quan Liu, Zhufang Shen
BACKGROUND: E2HSA is a genetic fusion protein that consists of two tandem exendin-4 molecules that are covalently bonded to recombinant human serum albumin via a peptide linker. Previous studies have demonstrated that E2HSA significantly decreased blood glucose levels, improved β-cell function and promoted β-cell proliferation in diabetic db/dB mice. This study aimed to evaluate the benefits of E2HSA on glucose and lipid metabolism in a spontaneous diabetes animal model, KKAy mice. METHODS: E2HSA was acutely administered at doses of 1, 3 and 9 mg/kg by subcutaneous injection in diabetic KKAy mice with exendin-4 (2 μg/kg) as a positive reference, and then the non-fasting blood glucose and food intake levels were dynamically monitored...
June 19, 2017: BMC Pharmacology & Toxicology
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