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https://www.readbyqxmd.com/read/29222092/targeted-disruption-of-the-kcnj5-gene-in-the-female-mouse-lowers-aldosterone-levels
#1
Iris Hardege, Lu Long, Raya Al Maskari, Nicola Figg, Kevin M O'Shaughnessy
Aldosterone is released from adrenal zona glomerulosa cells and plays an important role in Na and K homeostasis. Mutations in the human KCNJ5 gene encoding the GIRK4 potassium channel cause abnormal aldosterone secretion and hypertension. To better understand the role of wild-type (WT) GIRK4 in regulating aldosterone release we have looked at aldosterone secretion in a Kcnj5 knock-out (KO) mouse.  We found that female, but not male, KO mice have reduced aldosterone levels compared to WT female controls, but higher levels of aldosterone after Ang-II stimulation...
December 8, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/29207101/diosgenin-prevents-high-fat-diet-induced-rat-non-alcoholic-fatty-liver-disease-through-the-ampk-and-lxr-signaling-pathways
#2
Silu Cheng, Shufang Liang, Qun Liu, Zhengting Deng, Yuanhui Zhang, Juan Du, Ya'ni Zhang, Shu Li, Binbin Cheng, Changquan Ling
Non-alcoholic fatty liver disease (NAFLD) is a major public health concern worldwide. The aim of the present study was to observe the effect of diosgenin on NAFLD and investigate the underlying mechanisms. Diosgenin treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in HepG2 cells. Diosgenin significantly inhibited high glucose (HG)-induced triglyceride (TG) accumulation and sterol regulatory element‑binding protein-1c (SREBP-1c) mRNA increase in HepG2 cells, which were partially abolished by the AMPK inhibitor compound C...
November 28, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29203092/efficacy-and-safety-of-pemafibrate-k-877-a%C3%A2-selective-peroxisome-proliferator-activated-receptor-%C3%AE-modulator-in-patients-with-dyslipidemia-results-from-a-24-week-randomized-double-blind-active-controlled-phase-3-trial
#3
Shun Ishibashi, Hidenori Arai, Koutaro Yokote, Eiichi Araki, Hideki Suganami, Shizuya Yamashita
BACKGROUND: To overcome the concerns associated with the use of fibrates, pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor modulator, was developed. In a previous phase 2 trial, we showed excellent efficacy and safety of pemafibrate in patients with dyslipidemia. OBJECTIVE: The objective of the study was to evaluate the efficacy and safety of pemafibrate over 24 weeks in adults with dyslipidemia in comparison with fenofibrate. METHODS: In this multicenter, 24-week, double-blind, clinical study, 225 patients with high triglyceride (TG; ≥150 mg/dL [1...
October 28, 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/29182629/effects-of-peroxisome-proliferator-activated-receptors-ppar-%C3%AE-and-%C3%AE-agonists-on-cochlear-protection-from-oxidative-stress
#4
Marijana Sekulic-Jablanovic, Vesna Petkovic, Matthew B Wright, Krystsina Kucharava, Nathan Huerzeler, Soledad Levano, Yves Brand, Katharina Leitmeyer, Andrea Glutz, Alexander Bausch, Daniel Bodmer
Various insults cause ototoxicity in mammals by increasing oxidative stress leading to apoptosis of auditory hair cells (HCs). The thiazolidinediones (TZDs; e.g., pioglitazone) and fibrate (e.g., fenofibrate) drugs are used for the treatment of diabetes and dyslipidemia. These agents target the peroxisome proliferator-activated receptors, PPARγ and PPARα, which are transcription factors that influence glucose and lipid metabolism, inflammation, and organ protection. In this study, we explored the effects of pioglitazone and other PPAR agonists to prevent gentamicin-induced oxidative stress and apoptosis in mouse organ of Corti (OC) explants...
2017: PloS One
https://www.readbyqxmd.com/read/29170115/incorporation-of-surface-modified-dry-micronized-poorly-water-soluble-drug-powders-into-polymer-strip-films
#5
Lu Zhang, Yidong Li, Manal Abed, Rajesh N Davé
Recent work has established polymer strip films as a robust platform for delivery of poorly water-soluble drugs via slurry casting, in particular using stable drug nanosuspensions. Here, a simpler, robust method to directly incorporate dry micronized poorly water-soluble drug, fenofibrate (FNB), is introduced. As a major novelty, simultaneous surface modification using hydrophilic silica along with micronization was done using fluid energy mill (FEM) in order to reduce FNB hydrophobicity and powder agglomeration...
November 20, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/29164955/micellar-solubilization-of-poorly-water-soluble-drugs-effect-of-surfactant-and-solubilizate-molecular-structure
#6
Zahari Vinarov, V Katev, D Radeva, S Tcholakova, N D Denkov
OBJECTIVE: The current study aims to clarify the role of surfactant and drug molecular structures on drug solubility in micellar surfactant solutions. SIGNIFICANCE: (1) Rationale for surfactant selection is provided; (2) The large data set can be used for validation of the drug solubility parameters used in oral absorption models. METHODS: Equilibrium solubility of 2 hydrophobic drugs and one model hydrophobic steroid in micellar solutions of 19 surfactants was measured by HPLC...
November 22, 2017: Drug Development and Industrial Pharmacy
https://www.readbyqxmd.com/read/29164820/dual-ppar%C3%AE-%C3%AE-agonist-saroglitazar-improves-liver-histopathology-and-biochemistry-in-experimental-nash-models
#7
Mukul R Jain, Suresh R Giri, Bibhuti Bhoi, Chitrang Trivedi, Akshyaya Rath, Rohan Rathod, Ramchandra Ranvir, Shekhar Kadam, Hiren Patel, Prabodha Swain, Sib Sankar Roy, Nabanita Das, Eshani Karmakar, Walter Wahli, Pankaj R Patel
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH. METHODS & RESULTS: HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα,IL1β and IL6)...
November 21, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29163755/uncoupling-protein-2-a-key-player-and-a-potential-therapeutic-target-in-vascular-diseases
#8
REVIEW
Giorgia Pierelli, Rosita Stanzione, Maurizio Forte, Serena Migliarino, Marika Perelli, Massimo Volpe, Speranza Rubattu
Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane protein that belongs to the uncoupling protein family and plays an important role in lowering mitochondrial membrane potential and dissipating metabolic energy with prevention of oxidative stress accumulation. In the present article, we will review the evidence that UCP2, as a consequence of its roles within the mitochondria, represents a critical player in the predisposition to vascular disease development in both animal models and in humans, particularly in relation to obesity, diabetes, and hypertension...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29137181/structure-and-functional-analysis-of-promoters-from-two-liver-isoforms-of-cpt-i-in-grass-carp-ctenopharyngodon-idella
#9
Yi-Huan Xu, Zhi Luo, Kun Wu, Yao-Fang Fan, Wen-Jing You, Li-Han Zhang
Carnitine palmitoyltransferase I (CPT I) is a key enzyme involved in the regulation of lipid metabolism and fatty acid β-oxidation. To understand the transcriptional mechanism of CPT Iα1b and CPT Iα2a genes, we cloned the 2695-bp and 2631-bp regions of CPT Iα1b and CPT Iα2a promoters of grass carp (Ctenopharyngodon idella), respectively, and explored the structure and functional characteristics of these promoters. CPT Iα1b had two transcription start sites (TSSs), while CPT Iα2a had only one TSS. DNase I foot printing showed that the CPT Iα1b promoter was AT-rich and TATA-less, and mediated basal transcription through an initiator (INR)-independent mechanism...
November 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29134746/fenofibrate-induced-ppar-alpha-expression-was-attenuated-by-oestrogen-receptor-alpha-overexpression-in-hep3b-cells
#10
Long-Bin Jeng, Bharath Kumar Velmurugan, Hsi-Hsien Hsu, Su-Ying Wen, Chia-Yao Shen, Chih-Hao Lin, Yueh-Min Lin, Ray-Jade Chen, Wei-Wen Kuo, Chih-Yang Huang
The physiological regulation of Oestrogen receptor α (ERα) and peroxisome proliferator-activated receptor alpha (PPARα) in Hepatocellular carcinoma (HCC) remains unknown. The present study we first treat the cells with fenofibrate and further investigated the possible mechanisms of 17β-estradiol (E2 ) and/or ERα on regulating PPARα expression. We also found higher PPARα expression in the tumor area than adjacent areas and subsequently compared PPARα expression in four different hepatic cancer cell lines...
November 14, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/29132235/a-cell-based-assay-to-investigate-hypolipidemic-effects-of-nonalcoholic-fatty-liver-disease-therapeutics
#11
Tapan Dave, Arno William Tilles, Muralikrishna Vemula
In the recent past, there has been a growing interest in developing nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) therapeutics. As a result, a need for in vitro cell models of human hepatic steatosis and high-throughput assays to measure intracellular lipid levels has arisen. To address this growing need, we optimized the conditions based on the current literature to fatten HepG2 hepatocytes by adding a mixture of saturated and unsaturated fatty acids (oleate/palmitate, 2:1 molar ratio) without inducing any overt cytotoxicity...
November 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29129665/intravasation-of-sw620-colon-cancer-cell-spheroids-through-the-blood-endothelial-barrier-is-inhibited-by-clinical-drugs-and-flavonoids-in-vitro
#12
Silvio Holzner, Stefan Brenner, Atanas Georgiev Atanasov, Daniel Senfter, Serena Stadler, Chi Huu Nguyen, Adryan Fristiohady, Daniela Milovanovic, Nicole Huttary, Sigurd Krieger, Zsuzsanna Bago-Horvath, Oliver de Wever, Ioannis Tentes, Ali Özmen, Walter Jäger, Helmut Dolznig, Verena Maria Dirsch, Robert Michael Mader, Liselotte Krenn, Georg Krupitza
Mechanisms how colorectal cancer (CRC) cells penetrate blood micro-vessel endothelia and metastasise is poorly understood. To study blood endothelial cell (BEC) barrier breaching by CRC emboli, an in vitro assay measuring BEC-free areas underneath SW620 cell spheroids, so called "circular chemorepellent induced defects" (CCIDs, appearing in consequence of endothelial retraction), was adapted and supported by Western blotting, EIA-, EROD- and luciferase reporter assays. Inhibition of ALOX12 or NF-κB in SW620 cells or BECs, respectively, caused attenuation of CCIDs...
November 10, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29127736/liver-x-receptor-activation-inhibits-sglt2-mediated-glucose-transport-in-human-renal-proximal-tubular-cells
#13
Pattira Chonlaket, Teerasak Wongwan, Sunhapas Soodvilai
Liver X receptors (LXRs) are members of a nuclear receptor family consisting of two isoforms, LXR-α and LXR-β. They play a major role in energy metabolism including lipid and glucose metabolism. Recent studies reported LXRs regulate plasma glucose although the mechanism is still uncertain. The present study investigated whether LXR activation regulates sodium glucose cotransporter2 (SGLT2) in human renal proximal tubular cells. LXR agonists, T0901317 and GW3965, inhibited SGLT2-mediated glucose uptake in concentration-dependent manners...
November 11, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/29127234/ppar%C3%AE-agonists-acutely-inhibit-calcium-independent-pla2-to-reduce-h2o2-induced-contractions-in-aortae-of-spontaneously-hypertensive-rats
#14
Hui Chen, Ricky Y K Man, Susan W S Leung
Hypertension is associated with endothelial dysfunction, which favors the release of endothelium-derived contracting factors, including vasoconstrictor prostanoids and reactive oxygen species. Peroxisome proliferator-activated receptor α (PPARα) agonists, clinically used as lipid lowering drugs, possess antioxidant properties and exert beneficial effects in the vascular system. The present study aimed to identify the mechanism(s) underlying the acute effects of the PPARα agonists, Wy14643 and fenofibate, on endothelium-dependent contractions, in particular, those related to oxidative stress, in the aorta of the spontaneously hypertensive rat (SHR)...
November 10, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29119413/identification-and-characterization-of-fenofibrate-induced-liver-injury
#15
Jawad Ahmad, Joseph A Odin, Paul H Hayashi, Naga Chalasani, Robert J Fontana, Huiman Barnhart, Elizabeth T Cirulli, David E Kleiner, Jay H Hoofnagle
BACKGROUND: Fenofibrate is a commonly used hypolipidemic associated with rare instances of hepatotoxicity, and routine liver biochemistry monitoring is recommended. AIMS: The aim of this study is to describe the presenting clinical features, liver histopathology, and outcomes of 7 cases of acute liver injury associated with fenofibrate. METHODS: All cases of definite, very likely, and probable drug-induced liver injury (DILI) attributed to fenofibrate enrolled in the DILI Network study between 2004 and 2015 were reviewed...
December 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29117614/the-effect-of-hypolipidemic-agents-on-thyroid-autoimmunity-in-women-with-hashimoto-s-thyroiditis-treated-with-levothyroxine-and-selenomethionine
#16
Robert Krysiak, Witold Szkróbka, Bogusław Okopień
Background Levothyroxine and selenomethionine were found to reduce thyroid antibody titers in patients with Hashimoto's thyroiditis. The same effect was produced by intensive statin therapy. The aim of the present study was to assess whether hypolipidemic agents modulate the impact of thyroid hormone supplementation and selenomethionine on thyroid autoimmunity. Methods The study included 62 women with Hashimoto's thyroiditis treated for at least 6 months with levothyroxine and selenomethionine. On the basis of plasma lipids, women were divided into three groups: women with isolated hypercholesterolemia (group A; n=20), women with isolated hypertriglyceridemia (group B; n=17), and women with normal plasma lipids (group C; n=25)...
November 8, 2017: Experimental and Clinical Endocrinology & Diabetes
https://www.readbyqxmd.com/read/29111751/extraordinary-long-term-stability-in-kinetically-stabilized-amorphous-solid-dispersions-of-fenofibrate
#17
Frank Theil, Johanna Milsmann, Samuel O Kyeremateng, Sankaran Anantharaman, Jörg Rosenberg, Holger van Lishaut
Inhibition of recrystallization of the drug substance in kinetically stabilized amorphous solid dispersions (ASDs) within and beyond shelf life is still a matter of debate. Generally, these ASD systems are considered to be prone to recrystallization, but examples of their long term stability are emerging in the literature. Since, in some cases, the formation of crystals may impact bioavailability, recrystallization may present a relevant risk for patients as it potentially lowers the effective dose of the formulation...
November 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29108128/safety-assessment-of-niacin-in-the-us-food-and-drug-administration-s-mini-sentinel-system
#18
Joshua J Gagne, Monika Houstoun, Marsha E Reichman, Christian Hampp, James H Marshall, Sengwee Toh
PURPOSE: The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial found higher incidence rates of adverse reactions, including bleeding, in patients receiving the combination of extended-release niacin and laropiprant versus placebo. It is not known whether these adverse events are attributable to laropiprant, not approved in the USA, or to extended-release niacin. We compared rates of major gastrointestinal bleeding and intracranial hemorrhage among initiators of extended-release niacin and initiators of fenofibrate...
November 6, 2017: Pharmacoepidemiology and Drug Safety
https://www.readbyqxmd.com/read/29103508/octenylsuccinate-hydroxypropyl-phytoglycogen-a-dendrimer-like-biopolymer-solubilizes-poorly-water-soluble-active-pharmaceutical-ingredients
#19
Ying Xie, Yuan Yao
Effective solubilizers for poorly water-soluble active pharmaceutical ingredients (APIs) are highly desirable. This study introduced an amphiphilic dendrimer-like biopolymer, octenylsuccinate hydroxypropyl phytoglycogen (OHPP) as a new solubilizer. The molar substitution degree of octenylsuccinate and hydroxypropyl groups of OHPP was 0.51 and 1.69, respectively. The weight-average molecular weight, Z-average root mean square radius, and Zeta-potential of OHPP were 1.507×10(7)g/mol, 22.6nm, and -23.6mV, respectively...
January 15, 2018: Carbohydrate Polymers
https://www.readbyqxmd.com/read/29099085/eburicoic-acid-a-triterpenoid-compound-from-antrodia-camphorata-displays-antidiabetic-and-antihyperlipidemic-effects-in-palmitate-treated-c2c12-myotubes-and-in-high-fat-diet-fed-mice
#20
Cheng-Hsiu Lin, Yueh-Hsiung Kuo, Chun-Ching Shih
This study was designed to investigate the antidiabetic and antihyperlipidemic effects and mechanisms of eburicoic acid (TRR); one component of Antrodia camphorata in vitro and in an animal model for 14 weeks. Expression levels of membrane glucose transporter type 4 (GLUT4); phospho-5'-adenosine monophosphate-activated protein kinase (AMPK)/total AMPK; and phospho-Akt/total-Akt in insulin-resistant C2C12 myotube cells were significantly decreased by palmitate; and such decrease was prevented and restored by TRR at different concentrations...
November 2, 2017: International Journal of Molecular Sciences
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