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https://www.readbyqxmd.com/read/28202347/in-silico-design-chemical-synthesis-and-toxicological-evaluation-of-1-3-thiazolidine-2-4-dione-derivatives-as-ppar%C3%AE-agonists
#1
D Alemán-González-Duhart, F Tamay-Cach, J Correa-Basurto, Padilla-Martínez, S Álvarez-Almazán, J E Mendieta-Wejebe
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the metabolism of lipids and carbohydrates. The exogenous ligands of these receptors are thiazolidinediones (TZDs), which are used to treat type 2 diabetes mellitus (DM2). However, drugs from this group produce adverse effects such as hepatic steatosis. Hence, the aim of this work was to design a set of small molecules that can activate the γ isoform of PPARs while minimizing the adverse effects. The derivatives were designed containing the polar head of TZD and an aromatic body, serving simultaneously as the body and tail...
February 12, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28195389/no-increased-risk-of-cardiovascular-events-in-older-adults-initiating-dipeptidyl-peptidase-4-inhibitors-versus-therapeutic-alternatives
#2
Mugdha Gokhale, John B Buse, Michele Jonsson Funk, Jennifer Lund, Virginia Pate, Ross J Simpson, Til Stürmer
OBJECTIVE: Randomized placebo-controlled trials have examined the cardiovascular (CV) effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), but data on incidence relative to therapeutic alternatives are limited in the older US Medicare population. We compared the CV risk with DPP-4i relative to sulfonylureas (SU) and thiazolidinediones (TZD). METHODS: During 2007-2013, using Medicare beneficiaries >65 years we identified two new-user cohorts without the use of drugs being compared in the 6 months before initiation: DPP-4i versus SU and DPP-4i versus TZD...
February 14, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28193552/rational-design-and-synthesis-of-some-ppar-%C3%AE-agonists-substituted-benzylideneamino-benzylidene-thiazolidine-2-4-diones
#3
Santosh S Chhajed, Shital Chaskar, Sanjay K Kshirsagar, G M Animeshchandra Haldar, Debarshi Kar Mahapatra
The peroxisome proliferator activator receptor-γ (PPAR-γ) remained the most successful target for management of diabetes mellitus. The present work endeavors rational designing of some novel PPAR-γ agonists bearing benzylideneamino-benzylidene-thiazolidine-2,4-dione scaffold. The research involved virtual screening of 37 different molecules by molecular docking studies performed by Molecular Design Suite (MDS) into the ligand binding domain of PPAR-γ receptor to explore the binding affinity and conformations of the molecules...
February 7, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28165718/modification-of-the-orthosteric-ppar%C3%AE-covalent-antagonist-scaffold-yields-an-improved-dual-site-allosteric-inhibitor
#4
Richard Brust, Hua Lin, Jakob Fuhrmann, Alice Asteian, Theodore M Kamenecka, Douglas J Kojetin
GW9662 and T0070907 are widely used commercially available irreversible antagonists of peroxisome proliferator-activated receptor gamma (PPARγ). These antagonists covalently modify Cys285 located in an orthosteric ligand-binding pocket embedded in the PPARγ ligand-binding domain and are used to block binding of other ligands. However, we recently identified an alternate/allosteric ligand-binding site in the PPARγ LBD to which ligand binding is not inhibited by these orthosteric covalent antagonists. Here, we developed a series of analogs based on the orthosteric covalent antagonist scaffold with the goal of inhibiting both orthosteric and allosteric cellular activation of PPARγ by MRL20, an orthosteric agonist that also binds to an allosteric site...
February 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28128331/identification-of-a-novel-selective-ppar%C3%AE-ligand-with-a-unique-binding-mode-and-improved-therapeutic-profile-in-vitro
#5
Wei Yi, Jingjing Shi, Guanguan Zhao, X Edward Zhou, Kelly Suino-Powell, Karsten Melcher, H Eric Xu
Thiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), but their therapeutic benefits are compromised by severe side effects. To address this concern, here we developed a potent "hit" compound, VSP-51, which is a novel selective PPARγ-modulating ligand with improved therapeutic profiles in vitro compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPARγ with improved insulin sensitivity due to its ability to bind PPARγ with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28028073/thiazolidinediones-are-associated-with-a-decreased-risk-of-atrial-fibrillation-compared-with-other-antidiabetic-treatment-a-nationwide-cohort-study
#6
Jannik Langtved Pallisgaard, Tommi Bo Lindhardt, Laila Staerk, Jonas Bjerring Olesen, Christian Torp-Pedersen, Morten Lock Hansen, Gunnar Hilmar Gislason
AIM: The aim of this study was to investigate the association between thiazolidinediones (TZDs) vs. other antidiabetic drugs and risk of atrial fibrillation (AF) in diabetic patients. METHOD AND RESULTS: Diabetes mellitus (diabetes) increases the risk of AF by approximately 34%. TZD is an insulin sensitizer that also has anti-inflammatory effects, which might decrease the risk of AF compared with other antidiabetic drugs. We used data from the Danish nationwide registries to study 108 624 patients with diabetes and without prior AF who were treated with metformin or sulfonylurea as first-line drugs...
November 8, 2016: European Heart Journal. Cardiovascular Pharmacotherapy
https://www.readbyqxmd.com/read/27997588/protective-effects-of-vildagliptin-against-pioglitazone-induced-bone-loss-in-type-2-diabetic-rats
#7
Young Sil Eom, A-Ryeong Gwon, Kyung Min Kwak, Ju-Young Kim, Seung Hee Yu, Sihoon Lee, Yeun Sun Kim, Ie Byung Park, Kwang-Won Kim, Kiyoung Lee, Byung-Joon Kim
Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model...
2016: PloS One
https://www.readbyqxmd.com/read/27995594/liraglutide-versus-sglt-2-inhibitors-in-people-with-type-2-diabetes-a-network-meta-analysis
#8
Maria Lorenzi, Uffe Jon Ploug, Jakob Langer, Rasmus Skovgaard, Michael Zoratti, Jeroen Jansen
INTRODUCTION: For people with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs (OADs), evidence from both randomized controlled trials (RCTs) and real-world studies has demonstrated that treatment intensification with liraglutide offers effective glycemic control, weight reduction, and a lower risk of hypoglycemia compared to treatment intensification with insulin or additional OADs. Sodium glucose cotransporter 2 (SGLT-2) inhibitors are a new class of OADs that have also been shown to be effective in T2DM patients inadequately controlled with OADs...
February 2017: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
https://www.readbyqxmd.com/read/27903228/synthesis-and-evaluation-of-the-hypoglycemic-and-hypolipidemic-activity-of-novel-sulfonamide-benzothiazole-derivatives-of-benzylidene-2-4-thiazolidnedione
#9
Abbas Ahmadi, Mohsen Khalili, Lida Sohrabi, Nazanin Delzendeh, Babak Nahri-Niknafs, Fariba Ansari
Thiazolidinediones (TZDs) and sulfonamides are important and highly consumption class of antidiabetic drugs having insulin sensitizing and stimulating properties in patients with type 2 diabetes, respectively. In this paper, some novel benzothiazole derivatives of TZD-sulfonamides were synthesized (I-IV) and evaluated for anti-hyperglycemic and anti-hyperlipidemic activities in the STZ-induced diabetic rat model. Results indicated that all new conjugated drugs showed significant hypoglycemic activities compared to the control animals that were better for I and IV than others...
November 29, 2016: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/27867269/platyphylloside-isolated-from-betula-platyphylla-inhibit-adipocyte-differentiation-and-induce-lipolysis-via-regulating-adipokines-including-ppar%C3%AE-in-3t3-l1-cells
#10
Mina Lee, Sang Hyun Sung
BACKGROUND: Obesity causes or aggravates many health problems, both independently and in association with several pathological disorders, including Type II diabetes, hypertension, atherosclerosis, and cancer. Therefore, we screened small compounds isolated from natural products for the development of anti-obesity drugs. OBJECTIVE: The purpose of this study was to investigate the anti-adipogenic activities of platyphylloside, diarylheptanoid isolated from Betula platyphylla, which was selected based on the screening using 3T3-L1 cells...
October 2016: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/27865894/activation-of-peroxisome-proliferator-activated-receptor-gamma-in-mammary-epithelial-cells-upregulates-the-expression-of-tumor-suppressor-cyld-to-mediate-growth-inhibition-and-anti-inflammatory-effects
#11
Athanasios Pseftogas, Christos Gonidas, George Mosialos
Several studies have implicated the downregulation of the tumor suppressor Cyld expression in breast cancer development. However, the mechanisms that regulate Cyld expression in mammary epithelial cells are largely unknown. In order to investigate them, a bioinformatic analysis of the promoter region of Cyld was performed and identified putative nuclear hormone receptor response elements that included peroxisome proliferator-activated receptor gamma (PPAR-γ)-responsive elements. In the present study, we showed that upon activation of the nuclear hormone receptor PPAR-γ by the agonist troglitazone (TZD), there was a significant increase in Cyld mRNA in human mammary epithelial cell lines...
January 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27759627/thiazolidinediones-for-nonalcoholic-steatohepatitis-a-meta-analysis-of-randomized-clinical-trials
#12
REVIEW
Lingling He, Xiaoli Liu, Lijia Wang, Zhiyun Yang
The findings regarding the effects of thiazolidinediones (TZDs) in nonalcoholic steatohepatitis (NASH) patients have been inconsistent, and the assessment of different clinical variables for evaluating the effects of TZDs confound a direct comparison of the results of different randomized clinical trials (RCTs), especially with regard to lifestyle changes. In this paper, we performed a meta-analysis of randomized controlled trials to clarify the effects of TZD treatment with and without lifestyle changes on histological markers of NASH and clinical variables related to insulin resistance (IR), hyperlipidemia, and obesity...
October 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27708617/increased-circulating-adiponectin-in-response-to-thiazolidinediones-investigating-the-role-of-bone-marrow-adipose-tissue
#13
Richard J Sulston, Brian S Learman, Bofeng Zhang, Erica L Scheller, Sebastian D Parlee, Becky R Simon, Hiroyuki Mori, Adam J Bree, Robert J Wallace, Venkatesh Krishnan, Ormond A MacDougald, William P Cawthorn
BACKGROUND: Bone marrow adipose tissue (MAT) contributes to increased circulating adiponectin, an insulin-sensitizing hormone, during caloric restriction (CR), but whether this occurs in other contexts remains unknown. The antidiabetic thiazolidinediones (TZDs) also promote MAT expansion and hyperadiponectinemia, even without increasing adiponectin expression in white adipose tissue (WAT). OBJECTIVES: To test the hypothesis that MAT expansion contributes to TZD-associated hyperadiponectinemia, we investigated the effects of rosiglitazone, a prototypical TZD, in wild-type (WT) or Ocn-Wnt10b mice...
2016: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/27703271/pioglitazone-ameliorates-smooth-muscle-cell-proliferation-in-cuff-induced-neointimal-formation-by-both-adiponectin-dependent-and-independent-pathways
#14
Tetsuya Kubota, Naoto Kubota, Hiroyuki Sato, Mariko Inoue, Hiroki Kumagai, Tomokatsu Iwamura, Iseki Takamoto, Tsuneo Kobayashi, Masao Moroi, Yasuo Terauchi, Kazuyuki Tobe, Kohjiro Ueki, Takashi Kadowaki
The aim of this study is to elucidate to what degree adiponectin is involved in TZD-mediated amelioration of neointimal formation. We investigated the effect of 3- or 8-weeks' pioglitazone on cuff-induced neointimal formation in adiponectin-deficient (APN-KO) and wild-type (WT) mice. Pioglitazone for 3 weeks reduced neointimal formation in the WT mice with upregulation of the plasma adiponectin levels, but failed to reduce neointimal formation in the APN-KO mice, suggesting that pioglitazone suppressed neointimal formation by adiponectin-dependent mechanisms...
October 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27693798/chronic-lpsf-gq-02-treatment-attenuates-inflammation-and-atherosclerosis-development-in-ldlr-mice
#15
Amanda Karolina Soares E Silva, Fabiana Oliveira Dos Santos Gomes, Bruna Dos Santos Silva, Edlene Lima Ribeiro, Amanda Costa Oliveira, Shyrlene Meyre da Rocha Araújo, Ingrid Tavares de Lima, Anne Gabrielle Vasconcelos Oliveira, Martina Rudnicki, Dulcineia S P Abdalla, Maria do Carmo Alves de Lima, Ivan da Rocha Pitta, Christina Alves Peixoto
BACKGROUND: Atherosclerosis is a complex disorder with a multifactorial pathogenesis. We previously indicated that the new TZD LPSF/GQ-02 inhibits hepatic steatosis and inflammation, which are reported as risk factors for atherosclerosis development. Here, we explored the effects of LPSF/GQ-02 on atherosclerosis in LDLr-/- mice comparing two treatment periods. METHODS AND RESULTS: LDLr(-/-) mice were fed a high-fat diet for 10 and 12 weeks and received oral treatment with LPSF/GQ-02 (30mg/kg/day) or pioglitazone (20mg/kg/day) for 15 and 30 days, respectively...
November 15, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27692066/macrophage-ppar%C3%AE-inhibits-gpr132-to-mediate-the-anti-tumor-effects-of-rosiglitazone
#16
Wing Yin Cheng, HoangDinh Huynh, Peiwen Chen, Samuel Peña-Llopis, Yihong Wan
Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPARγ loss-of-function mutations, but inhibited by PPARγ agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARγ tumor-suppressive functions. Here we report that macrophage PPARγ deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARγ target in macrophage whose expression is enhanced by PPARγ loss but repressed by PPARγ activation...
October 3, 2016: ELife
https://www.readbyqxmd.com/read/27687671/identification-of-small-molecules-that-bind-to-the-mitochondrial-protein-mitoneet
#17
Werner J Geldenhuys, Heather M Yonutas, Daniel L Morris, Patrick G Sullivan, Altaf S Darvesh, Thomas C Leeper
MitoNEET (CISD1) is a 2Fe-2S iron-sulfur cluster protein belonging to the zinc-finger protein family. Recently mitoNEET has been shown to be a major role player in the mitochondrial function associated with metabolic type diseases such as obesity and cancers. The anti-diabetic drug pioglitazone and rosiglitazone were the first identified ligands to mitoNEET. Since little is known about structural requirements for ligand binding to mitoNEET, we screened a small set of compounds to gain insight into these requirements...
November 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27622746/structure-activity-relationship-studies-of-non-carboxylic-acid-peroxisome-proliferator-activated-receptor-%C3%AE-%C3%AE-ppar%C3%AE-%C3%AE-dual-agonists
#18
Shogo Okazaki, Ryuta Shioi, Tomomi Noguchi-Yachide, Minoru Ishikawa, Makoto Makishima, Yuichi Hashimoto, Takao Yamaguchi
The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that contribute to the regulation of lipid, glucose and cholesterol homeostases. They are considered as therapeutic targets for metabolic diseases such as dyslipidemia and type 2 diabetes mellitus. Various PPAR agonists have been developed, but most of them contain a carboxylic acid (CA) or thiazolidinedione (TZD) moiety, which is essential for the activity. However, we recently discovered non-CA/non-TZD class PPARα/δ dual agonists having an acetamide structure...
November 1, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27602497/modulation-of-glycogen-synthase-kinase-3%C3%AE-following-trail-combinatorial-treatment-in-cancer-cells
#19
Sreevidya Santha, Gantulga Davaakhuu, Aninda Basu, Rong Ke, Subhasis Das, Ajay Rana, Basabi Rana
Glycogen Synthase Kinase-3β (GSK3β) is a serine/threonine kinase, known to regulate various cellular processes including proliferation, differentiation, survival, apoptosis as well as TRAIL-resistance. Thus pathways that can modulate GSK3β axis are important targets for cancer drug development. Our earlier studies have shown that combinatorial treatment with Troglitazone (TZD) and TRAIL can induce apoptosis in TRAIL-resistant cancer cells. The current studies were undertaken to investigate whether GSK3β pathway was modulated during this apoptosis...
October 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27598860/does-thiazolidinedione-therapy-exacerbate-fluid-retention-in-congestive-heart-failure
#20
REVIEW
Ilia Goltsman, Emad E Khoury, Joseph Winaver, Zaid Abassi
The ever-growing global burden of congestive heart failure (CHF) and type 2 diabetes mellitus (T2DM) as well as their co-existence necessitate that anti-diabetic pharmacotherapy will modulate the cardiovascular risk inherent to T2DM while complying with the accompanying restrictions imposed by CHF. The thiazolidinedione (TZD) family of peroxisome proliferator-activated receptor γ (PPARγ) agonists initially provided a promising therapeutic option in T2DM owing to anti-diabetic efficacy combined with pleiotropic beneficial cardiovascular effects...
December 2016: Pharmacology & Therapeutics
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