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https://www.readbyqxmd.com/read/29446942/design-synthesis-and-evaluation-of-a-novel-series-of-indole-sulfonamide-peroxisome-proliferator-activated-receptors-ppar-%C3%AE-%C3%AE-%C3%AE-triple-activators-discovery-of-lanifibranor-a-new-anti-fibrotic-clinical-candidate
#1
Benaissa Boubia, Olivia Poupardin, Martine Barth, Jean Binet, Philippe Peralba, Laurent Mounier, Elise Jacquier, Emilie Gauthier, Valerie Lepais, Maryline Chatar, Stephanie Ferry, Anne Thourigny, Fabrice Guillier, Jonathan Llacer, Jerome Amaudrut, Pierre Dodey, Olivier Lacombe, Philippe Masson, Christian Montalbetti, Guillaume Wettstein, Jean Michel Luccarini, Christiane Legendre, Jean Louis Junien, Pierre Broqua
Here we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to NonAlcoholic SteatoHepatitis (NASH) pathophysiology suggesting therapeutical potential for NASH patients...
February 15, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29429540/sodium-butyrate-modulates-adipocyte-expansion-adipogenesis-and-insulin-receptor-signaling-by-upregulation-of-ppar-%C3%AE-in-obese-apo-e-knockout-mice
#2
Edenil Costa Aguilar, Josiane Fernandes da Silva, Juliana Maria Navia-Pelaez, Alda Jusceline Leonel, Lorrayne Gonçalves Lopes, Zélia Menezes-Garcia, Adaliene Versiani Matos Ferreira, Luciano Dos Santos Aggum Capettini, Lilian G Teixeira, Virginia Soares Lemos, Jacqueline I Alvarez-Leite
OBJECTIVES: Studies suggest that sodium butyrate reduces obesity-associated inflammation and insulin resistance in in vitro and in vivo models. Apo E -/- mice have high basal oxidative stress and naturally develop dyslipidemia and atherosclerosis. Because these disorders are present in obesity, the aim of this study was to determine whether Apo E -/- mice could be a more realistic model for studying obesity and insulin resistance. METHODS: We evaluated the action of orally administered sodium butyrate on adipose tissue expansion and insulin resistance using diet-induced obese Apo E -/- mice...
March 2018: Nutrition
https://www.readbyqxmd.com/read/29428530/rotenone-exerts-developmental-neurotoxicity-in-a-human-brain-spheroid-model
#3
David Pamies, Katharina Block, Pierre Lau, Laura Gribaldo, Carlos Pardo, Paula Barreras, Lena Smirnova, Daphne Wiersma, Liang Zhao, Georgina Harris, Thomas Hartung, Helena T Hogberg
Growing concern suggests that some chemicals exert (developmental) neurotoxicity (DNT and NT) and are linked to the increase in incidence of autism, attention deficit and hyperactivity disorders. The high cost of routine tests for DNT and neurotoxicity (NT) assessment make it difficult to test the high numbers of existing chemicals. Thus, more cost effective neurodevelopmental models are needed. The use of induced pluripotent stem cells (iPSC) in combination with the emerging human 3D tissue culture platforms, present a novel tool to predicting and study human toxicity...
February 8, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29422939/associations-between-fatty-acid-oxidation-hepatic-mitochondrial-function-and-plasma-acylcarnitine-levels-in-mice
#4
Bodil Bjørndal, Eva Katrine Alterås, Carine Lindquist, Asbjørn Svardal, Jon Skorve, Rolf K Berge
Background: The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels...
2018: Nutrition & Metabolism
https://www.readbyqxmd.com/read/29414995/the-peroxisome-proliferator-activated-receptor-agonist-pioglitazone-and-5-lipoxygenase-inhibitor-zileuton-have-no-effect-on-lung-inflammation-in-healthy-volunteers-by-positron-emission-tomography-in-a-single-blind-placebo-controlled-cohort-study
#5
Delphine L Chen, Howard J Huang, Derek E Byers, Adrian Shifren, Bryan Belikoff, Jacquelyn T Engle, Elizabeth Arentson, Debra Kemp, Sharon Phillips, David E Scherrer, Hideji Fujiwara, Katherine J Spayd, Frank J Brooks, Richard A Pierce, Mario Castro, Warren Isakow
BACKGROUND: Anti-inflammatory drug development efforts for lung disease have been hampered in part by the lack of noninvasive inflammation biomarkers and the limited ability of animal models to predict efficacy in humans. We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a human model of lung inflammation to assess whether pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, and zileuton, a 5-lipoxygenase inhibitor, reduce lung inflammation...
2018: PloS One
https://www.readbyqxmd.com/read/29413962/homocysteine-causes-dysfunction-of-chondrocytes-and-oxidative-stress-through-repression-of-sirt1-ampk-pathway-a-possible-link-between-hyperhomocysteinemia-and-osteoarthritis
#6
Ching-Hou Ma, Yen Chun Chiua, Chin-Hsien Wu, I-Ming Jou, Yuan-Kun Tu, Ching-Hsia Hung, Pei-Ling Hsieh, Kun-Ling Tsai
Emerging evidence has indicated that the perturbed expression of homocysteine (Hcy) may induce mitochondrial dysfunction and disturb bone metabolism. Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) are two critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in osteoarthritis (OA). This study was designed to test whether Hcy caused pro-osteoarthritic changes through modulation of SIRT1 and AMPK. Our results showed that administration of Hcy reduced the SIRT1/AMPK/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress and apoptosis...
January 31, 2018: Redox Biology
https://www.readbyqxmd.com/read/29405636/dietary-curcumin-intervention-targets-mouse-white-adipose-tissue-inflammation-and-brown-adipose-tissue-ucp1-expression
#7
Zhuolun Song, Xavier Revelo, Weijuan Shao, Lili Tian, Kejing Zeng, Helena Lei, Hong-Shuo Sun, Minna Woo, Daniel Winer, Tianru Jin
OBJECTIVE: This study aimed to determine whether dietary curcumin intervention targets both white adipose tissue (WAT) inflammation and brown adipose tissue (BAT)-mediated energy expenditure. METHODS: C57BL/6J mice were fed with a low-fat diet, high-fat diet (HFD), or HFD plus curcumin. In addition to assessing the effect of curcumin intervention on metabolic profiles, this study assessed WAT macrophage infiltration and composition and inflammatory cytokine production...
February 6, 2018: Obesity
https://www.readbyqxmd.com/read/29404484/the-selective-peroxisome-proliferator-activated-receptor-delta-agonist-seladelpar-reverses-nonalcoholic-steatohepatitis-pathology-by-abrogating-lipotoxicity-in-diabetic-obese-mice
#8
Fahrettin Haczeyni, Hans Wang, Vanessa Barn, Auvro R Mridha, Matthew M Yeh, W Geoffrey Haigh, George N Ioannou, Yun-Jung Choi, Charles A McWherter, Narcissus C-H Teoh, Geoffrey C Farrell
Lipotoxicity associated with insulin resistance is central to nonalcoholic steatohepatitis (NASH) pathogenesis. To date, only weight loss fully reverses NASH pathology, but mixed peroxisome proliferator-activated receptor-alpha/delta (PPAR-α/δ) agonists show some efficacy. Seladelpar (MBX-8025), a selective PPAR-δ agonist, improves atherogenic dyslipidemia. We therefore used this agent to test whether selective PPAR-δ activation can reverse hepatic lipotoxicity and NASH in an obese, dyslipidemic, and diabetic mouse model...
September 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29404476/the-new-generation-pan-peroxisome-proliferator-activated-receptor-agonist-iva337-protects-the-liver-from-metabolic-disorders-and-fibrosis
#9
Guillaume Wettstein, Jean-Michel Luccarini, Laurence Poekes, Patrick Faye, Francine Kupkowski, Vanessa Adarbes, Evelyne Defrêne, Céline Estivalet, Xavier Gawronski, Ingrid Jantzen, Alain Philippot, Julien Tessier, Pascale Tuyaa-Boustugue, Fiona Oakley, Derek A Mann, Isabelle Leclercq, Sven Francque, Irena Konstantinova, Pierre Broqua, Jean-Louis Junien
IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis...
August 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29402273/in-vitro-assessment-of-nutraceutical-compounds-and-novel-nutraceutical-formulations-in-a-liver-steatosis-based-model
#10
Antonietta Stellavato, Anna Virginia Adriana Pirozzi, Francesca de Novellis, Ilaria Scognamiglio, Valentina Vassallo, Andrea Maria Giori, Mario De Rosa, Chiara Schiraldi
BACKGROUND: Steatosis is a chronic liver disease that depends on the accumulation of intracellular fatty acids. Currently, no drug treatment has been licensed for steatosis; thus, only nutritional guidelines are indicated to reduce its progression. The aim of this study is to combine different nutraceutical compounds in order to evaluate their synergistic effects on a steatosis in vitro model compared to their separate use. In particular, three different formulations based on silymarin, curcumin, vitamin E, docosahexaenoic acid (DHA), choline, and phosphatidylcholine were assayed...
February 5, 2018: Lipids in Health and Disease
https://www.readbyqxmd.com/read/29400412/synthesis-docking-in-vitro-and-in-vivo-antidiabetic-activity-of-pyrazole-based-2-4-thiazolidinedione-derivatives-as-ppar-%C3%AE-modulators
#11
Mohd Javed Naim, Ozair Alam, Md Jahangir Alam, Mohammad Shaquiquzzaman, Md Mumtaz Alam, Vegi Ganga Modi Naidu
The design, synthesis, structure-activity relationship, and biological activity of 2,4-thiazolidinedione derivatives as peroxisome proliferator-activated receptor-γ (PPAR-γ) modulators for antidiabetic activity are reported. Fifteen 2,4-thiazolidinedione derivatives clubbed with pyrazole moiety were docked into the ligand binding domain of PPAR-γ by the Glide XP module of Schrodinger. Eight derivatives (5a, 5b, 5d, 5f, 5i, 5l, 5n, 5o) having Glide XP scores > -8 as compared to the standard drug, rosiglitazone (Glide XP score = -9...
February 5, 2018: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29399062/the-effect-of-hydroxy-safflower-yellow-a-on-coronary-heart-disease-through-bcl-2-bax-and-ppar-%C3%AE
#12
Dayan Zhou, Zongjie Qu, Hao Wang, Yong Su, Yazhu Wang, Weiwei Zhang, Zhe Wang, Qiang Xu
The aim of the present study was to investigate the effect of hydroxy safflower yellow A (HSYA) on coronary heart disease through assessing the expression of B-cell lymphoma 2 (Bcl-2)/Bcl-2-like protein 4 (Bax) and peroxisome proliferator-activated receptor (PPAR)-γ. Coronary heart disease was induced in male Bama miniature swines via thoracoscope to serve as an animal model. Coronary heart disease swine were lavaged with 20 or 40 mg/kg HSYA. The mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-10, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected using reverse transcription-quantitative polymerase chain reaction...
January 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29386501/emodin-a-chinese-herbal-medicine-inhibits-reoxygenation-induced-injury-in-cultured-human-aortic-endothelial-cells-by-regulating-the-peroxisome-proliferator-activated-receptor-%C3%AE-ppar-%C3%AE-and-endothelial-nitric-oxide-synthase-enos-signaling-pathway
#13
Xiaoling Shou, Rongfang Zhou, Liyue Zhu, Aihua Ren, Lei Wang, Yan Wang, Jianmei Zhou, Xinwen Liu, Bozhong Wang
BACKGROUND Ischemia-reperfusion injury is associated with vascular dysfunction. The aim of this study was to investigate the role of emodin, a Chinese herbal medicine, in hypoxia-reoxygenation injury in cultured human aortic endothelial cells (HAECs) and its effects on the expression of the peroxisome proliferator-activated receptor-γ (PPAR-γ) and endothelial nitric oxide synthase (eNOS) signaling pathway. MATERIAL AND METHODS An in vitro hypoxia-reoxygenation model used cultured human aortic endothelial cells (HAECs)...
February 1, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29383869/metformin-regulates-metabolic-and-nonmetabolic-pathways-in-skeletal-muscle-and-subcutaneous-adipose-tissues-of-older-adults
#14
Ameya S Kulkarni, Erika F Brutsaert, Valentin Anghel, Kehao Zhang, Noah Bloomgarden, Michael Pollak, Jessica C Mar, Meredith Hawkins, Jill P Crandall, Nir Barzilai
Administration of metformin increases healthspan and lifespan in model systems, and evidence from clinical trials and observational studies suggests that metformin delays a variety of age-related morbidities. Although metformin has been shown to modulate multiple biological pathways at the cellular level, these pleiotropic effects of metformin on the biology of human aging have not been studied. We studied ~70-year-old participants (n = 14) in a randomized, double-blind, placebo-controlled, crossover trial in which they were treated with 6 weeks each of metformin and placebo...
January 31, 2018: Aging Cell
https://www.readbyqxmd.com/read/29377597/a-phytol-enriched-diet-activates-ppar%C3%AE-in-the-liver-and-brown-adipose-tissue-to-ameliorate-obesity-induced-metabolic-abnormalities
#15
Ji-Yeong An, Huei-Fen Jheng, Hiroyuki Nagai, Kohei Sanada, Haruya Takahashi, Mari Iwase, Natsumi Watanabe, Young-Il Kim, Aki Teraminami, Nobuyuki Takahashi, Rieko Nakata, Hiroyasu Inoue, Shigeto Seno, Hideo Mastuda, Teruo Kawada, Tsuyoshi Goto
SCOPE: Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that regulates lipid and carbohydrate metabolism. We investigated the effects of naturally occurring PPARα agonists, phytol, and its metabolite phytanic acid, on obesity-induced metabolic disorders using a mouse model. METHODS AND RESULTS: A luciferase reporter assay showed that phytanic acid potently activated PPARα among PPAR subtypes. In high fat diet-induced severe obese mice, a phytol-enriched diet increased phytanic acid levels in the liver and adipose tissue, where PPARα is abundantly expressed...
January 27, 2018: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/29374954/stimulatory-action-of-telmisartan-an-antagonist-of-angiotensin-ii-receptor-on-voltage-gated-na%C3%A2-%C2%BA-current-experimental-and-theoretical-studies
#16
Tzu-Tung Chang, Chia-Jung Yang, Yu-Chi Lee, Sheng-Nan Wu
Telmisartan (Tel) is recognized as a non-peptide blocker of angiotensin II type-1 receptor. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel increased the peak amplitude of voltage-gated Na⁺ current (INa) accompanied by the increased time constant of INa inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of angiotensin II receptors or activation of PPAR-γ...
January 29, 2018: Chinese Journal of Physiology
https://www.readbyqxmd.com/read/29371918/long-term-administration-of-tacrolimus-and-everolimus-prevents-high-cholesterol-high-fructose-induced-steatosis-in-c57bl-6j-mice-by-inhibiting-de-novo-lipogenesis
#17
Sharma Love, Malik A Mudasir, Subhash C Bhardwaj, Gurdarshan Singh, Sheikh A Tasduq
Aim: To investigate the effects of tacrolimus (TC) and everolimus (EV) on non-alcoholic steatohepatitis (NASH) induced by high fat, high cholesterol and fructose (fast food) diet in C57BL/6J mice. Materials and Methods: C57BL/6J mice were divided into four groups (n=8). 1) Standard Chow (SC); 2) Fast food (FF) diet; 3) FF + Tacrolimus (TC, 1mg/kg) and; 4) FF + Everolimus (EV, 1mg/kg) and treated for 16 weeks. Serum and tissue samples were analyzed for evidence of inflammation, fibrosis, lipogenesis, and apoptosis...
December 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/29364492/rosuvastatin-inhibits-inflammatory-response-and-resists-fibrosis-after-myocardial-infarction
#18
J-W Bao, B Sun, P-P Ma, Y-S Gai, W-Z Sun, H-Q Yu, J Li
OBJECTIVE: To study the effect of rosuvastatin on myocardial infarction in rats and its mechanism of action. MATERIALS AND METHODS: 24 Sprague-Dawley (SD) rats were randomly divided into 3 groups: intensive statin group (n=8), myocardial infarction control group (n=8) and sham-operation group (n=8). The left anterior descending coronary artery was ligated to establish myocardial infarction models. Rats in intensive statin group were treated with gavage via rosuvastatin (1 mg × kg) and 1...
January 2018: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29359338/pi3k-akt-jnk-p38-signalling-pathway-mediated-neural-apoptosis-in-the-prefrontal-cortex-of-mice-is-involved-in-the-antidepressant-like-effect-of-pioglitazone
#19
Jie Li, Bing Xu, Zhi Chen, Chanjuan Zhou, Li Liao, Yinghua Qin, Chuangchuang Yang, Xiaodong Zhang, Zicheng Hu, Lin Sun, Dan Zhu, Peng Xie
Numerous studies have reported that inflammation is involved in the pathophysiology of depression. Pioglitazone, a PPAR-γ agonist, has potential anti-inflammatory and antidepressive effects. However, the underlying molecular mechanisms of the antidepressant-like effect of pioglitazone on an inflammation-related mouse model of depression remain to be fully elucidated. Herein, we aimed to explore the effects of pioglitazone on depressive-like behaviours of mice exposed to lipopolysaccharides (LPS), and elucidate the underlying mechanisms...
January 23, 2018: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/29355629/sulfated-laminaria-japonica-polysaccharides-inhibit-macrophage-foam-cell-formation
#20
Qiang-Ming Li, Hao Teng, Xue-Qiang Zha, Li-Hua Pan, Jian-Ping Luo
In this work, a purified Laminaria japonica polysaccharide (LJP61A) was chemically modified to obtain three sulfated polysaccharides (SLJP1, SLJP2 and SLJP3) with different degrees of sulfation using the method of chlorosulfonic acid/pyridine. The effects and underlying mechanism of SLJP1, SLJP2 and SLJP3 on the suppression of macrophage foam cell formation were further investigated using the model of oxidized low-density lipoprotein (ox-LDL)-induced foam cell formation. Results exhibited that the macrophage foam cell formation induced by ox-LDL could be significantly alleviated by these sulfated polysaccharides in a dose-dependent manner...
January 17, 2018: International Journal of Biological Macromolecules
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