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Drug metabolism

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https://www.readbyqxmd.com/read/28549679/one-should-avoid-retro-orbital-pharmacokinetic-sample-collections-for-intranasal-dosing-in-rats-illustration-of-spurious-pharmacokinetics-generated-for-anti-migraine-drugs-zolmitriptan-and-eletriptan
#1
Harilal Patel, Prakash Patel, Nirav Modi, Shaival Shah, Ashok Ghoghari, Bhavesh Variya, Ritu Laddha, Dipesh Baradia, Nitin Dobaria, Pavak Mehta, Nuggehally R Srinivas
Because of the avoidance of first pass metabolic effects due to direct and rapid absorption with improved permeability, intranasal route represents a good alternative for extravascular drug administration. The aim of the study was to investigate the intranasal pharmacokinetics of two anti-migraine drugs (zolmitriptan and eletriptan), using retro-orbital sinus and jugular vein sites sampling. In a parallel study design, healthy male Sprague-Dawley (SD) rats aged between 8 and 12weeks were divided into groups (n=4 or 5/group)...
May 23, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28549656/glycyrrhizin-and-glycyrrhetinic-acid-inhibits-alpha-naphthyl-isothiocyanate-induced-liver-injury-and-bile-acid-cycle-disruption
#2
Haina Wang, Zhong-Ze Fang, Ran Meng, Yun-Feng Cao, Naoki Tanaka, Kristopher W Krausz, Frank J Gonzalez
Alpha-naphthyl isothiocyanate (ANIT) is a common hepatotoxicant experimentally used to reproduce the pathologies of drug-induced liver injury in humans, but the mechanism of its toxicity remains unclear. To determine the metabolic alterations following ANIT exposure, metabolomic analyses was performed by use of liquid chromatography-mass spectrometry. Partial least squares discriminant analysis (PLS-DA) of liver, serum, bile, ileum, and cecum of vehicle- and ANIT-treated mice revealed significant alterations of individual bile acids, including increased tauroursodeoxycholic acid, taurohydrodeoxycholic acid, taurochenodeoxycholic acid, and taurodeoxycholic acid, and decreased ω-, β- and tauro-α/β- murideoxycholic acid, cholic acid, and taurocholic acid in the ANIT-treated groups...
May 23, 2017: Toxicology
https://www.readbyqxmd.com/read/28549217/surface-enhanced-raman-scattering-active-gold-nanoparticles-with-enzyme-mimicking-activities-for-measuring-glucose-and-lactate-in-living-tissues
#3
Yihui Hu, Hanjun Cheng, Xiaozhi Zhao, Jiangjiexing Wu, Faheem Muhammad, Shichao Lin, Jian He, Liqi Zhou, Chengping Zhang, Yu Deng, Peng Wang, Zhengyang Zhou, Shuming Nie, Hui Wei
Gold nanoparticles (AuNPs) with simultaneous plasmonic and biocatalytic properties provide a promising approach to developing versatile bioassays. However, the combination of AuNPs' intrinsic enzyme mimicking properties with their surface-enhanced Ra-man scattering (SERS) activities has yet to be explored. Here we designed a peroxidase mimicking nanozyme by in situ growing AuNPs into a highly porous and thermally stable metal-organic framework (MOF) called MIL-101. The obtained AuNPs@MIL-101 nanozymes acted as the peroxidase mimics to oxidize Raman inactive reporter leucomalachite green (LMG) into the active malachite green (MG) with hydrogen peroxide, and simultaneously as the SERS substrates to enhance the Raman signals of the as-produced MG...
May 26, 2017: ACS Nano
https://www.readbyqxmd.com/read/28549128/atad3-gene-cluster-deletions-cause-cerebellar-dysfunction-associated-with-altered-mitochondrial-dna-and-cholesterol-metabolism
#4
Radha Desai, Ann E Frazier, Romina Durigon, Harshil Patel, Aleck W Jones, Ilaria Dalla Rosa, Nicole J Lake, Alison G Compton, Hayley S Mountford, Elena J Tucker, Alice L R Mitchell, Deborah Jackson, Abdul Sesay, Miriam Di Re, Lambert P van den Heuvel, Derek Burke, David Francis, Sebastian Lunke, George McGillivray, Simone Mandelstam, Fanny Mochel, Boris Keren, Claude Jardel, Anne M Turner, P Ian Andrews, Jan Smeitink, Johannes N Spelbrink, Simon J Heales, Masakazu Kohda, Akira Ohtake, Kei Murayama, Yasushi Okazaki, Anne Lombès, Ian J Holt, David R Thorburn, Antonella Spinazzola
Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Although high homology complicates genomic analysis of the ATAD3 defects, they can be identified by targeted analysis of standard single nucleotide polymorphism array and whole exome sequencing data...
June 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28548953/from-rapalogs-to-anti-aging-formula
#5
Mikhail V Blagosklonny
Inhibitors of mTOR, including clinically available rapalogs such as rapamycin (Sirolimus) and Everolimus, are gerosuppressants, which suppress cellular senescence. Rapamycin slows aging and extends life span in a variety of species from worm to mammals. Rapalogs can prevent age-related diseases, including cancer, atherosclerosis, obesity, neurodegeneration and retinopathy and potentially rejuvenate stem cells, immunity and metabolism. Here, I further suggest how rapamycin can be combined with metformin, inhibitors of angiotensin II signaling (Losartan, Lisinopril), statins (simvastatin, atorvastatin), propranolol, aspirin and a PDE5 inhibitor...
May 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548950/enolase-1-stimulates-glycolysis-to-promote-chemoresistance-in-gastric-cancer
#6
Xiaoling Qian, Wenxia Xu, Jinye Xu, Qiqi Shi, Jiaqiu Li, Yu Weng, Zhinong Jiang, Lifeng Feng, Xian Wang, Jianwei Zhou, Hongchuan Jin
Chemotherapy is the major choice for the cancer treatment of early and advanced stages. However, intrinsic or acquired drug resistance significantly restricts the clinical efficacy of chemotherapy. It is critical to develop novel approaches to detect and overcome drug resistance. In this study, we demonstrated that accelerated glycolysis played a pivotal role in both intrinsic and acquired cisplatin-resistance of gastric cancer cells. The metabolic reprogramming of cisplatin-resistant cells was characterized by increased glycolysis dependence...
May 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548931/succinate-an-initiator-in-tumorigenesis-and-progression
#7
REVIEW
Ting Zhao, Xianmin Mu, Qiang You
As an intermediate metabolite of the tricarboxylic acid cycle in mitochondria, succinate is widely investigated for its role in metabolism. In recent years, an increasing number of studies have concentrated on the unanticipated role of succinate outside metabolism, acting as, for instance, an inflammatory signal or a carcinogenic initiator. Actually, succinate dehydrogenase gene mutations and abnormal succinate accumulation have been observed in a battery of hereditary and sporadic malignancies. In this review, we discuss the unexpected role of succinate and possible mechanisms that may contribute to its accumulation...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548833/structure-activity-relationship-for-small-molecule-inhibitors-of-nicotinamide-n-methyltransferase
#8
Harshini Neelakantan, Hua-Yu Wang, Virginia Vance, Jonathan D Hommel, Stanton F McHardy, Stanley J Watowich
Nicotinamide N-methyltransferase (NNMT) is a fundamental cytosolic biotransforming enzyme that catalyzes the N-methylation of endogenous and exogenous xenobiotics. We have identified small molecule inhibitors of NNMT with >1000-fold range of activity and developed comprehensive structure-activity relationships (SARs) for NNMT inhibitors. Screening of N-methylated quinolinium, isoquinolinium, pyrididium, and benzimidazolium/benzothiazolium analogs resulted in the identification of quinoliniums as a promising scaffold with very low micromolar (IC50 ~1 μM) NNMT inhibition...
May 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28548464/control-of-cell-death-and-mitochondrial-fission-by-erk1-2-map-kinase-signalling
#9
REVIEW
Simon J Cook, Kate Stuart, Rebecca Gilley, Matthew J Sale
The ERK1/2 signalling pathway is best known for its role in connecting activated growth factor receptors to changes in gene expression due to activated ERK1/2 entering the nucleus and phosphorylating transcription factors. However, active ERK1/2 also translocate to a variety of other organelles including the endoplasmic reticulum, endosomes, golgi and mitochondria to access specific substrates and influence cell physiology. In this article we review two aspects of ERK1/2 signalling at the mitochondria that are involved in regulating cell fate decisions...
May 26, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28548198/-diabetic-ketoacidosis-with-mild-hyperglycemia-associated-with-the-use-of-canagliflozin-report-of-one-case-with-type-1-diabetes
#10
Victoria Novik A, Claudia García B, Daniela Oliva I
Diabetic ketoacidosis with mild hyperglycemia is a major complication of sodium-glucose cotransporter 2 inhibitors. Although its use is not approved for patients with type 1 diabetes mellitus, the drug is often prescribed with the hope of optimizing metabolic control. We report a 20 years old female with hypothyroidism and type 1 diabetes consulting for vomiting and abdominal pain. The patient had used canagliflozin during the two previous months. Laboratory showed a blood glucose of 200 mg/dl, a severe metabolic acidosis (pH 7...
March 2017: Revista Médica de Chile
https://www.readbyqxmd.com/read/28548045/3d-liver-membrane-system-by-co-culturing-human-hepatocytes-sinusoidal-endothelial-and-stellate-cells
#11
Haysam Mohamed Magdy Ahmed, Simona Salerno, Sabrina Morelli, Lidetta Giorno, Loredana De Bartolo
In this study, a designed approach has been utilized for the development of a 3D liver system. This approach makes use of primary human sinusoidal endothelial cells, stellate cells and hepatocytes that are seeded sequentially on hollow fiber membranes (HF) in order to mimic the layers of cells found in vivo. To this purpose modified polyethersulfone (PES) HF membranes were used for the creation of a 3D human liver system in static and dynamic conditions. In order to verify the positive effect of non-parenchymal cells on the maintenance of hepatocyte viability and functions, homotypic cultures of hepatocytes alone on the HF membranes were further investigated...
May 26, 2017: Biofabrication
https://www.readbyqxmd.com/read/28548030/everolimus-inhibited-multiple-isoforms-of-udp-glucuronosyltransferases-ugts
#12
Zuo Du, Guang Wang, Yun-Feng Cao, Cui-Min Hu, Kun Yang, Yong-Zhe Liu, Chun-Ze Zhang, Wei-Hua Zhang, Zhi-Tu Zhu, Hong-Zhi Sun, Xiao-Yu Sun, Mo Hong, Zhong-Ze Fang
1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 uM of everolimus exerted more than 80% inhibition towards UGT1A1, -1A3, and -2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus towards the activity cavity of UGT1A3 and UGT2B7...
May 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28547521/validation-of-the-cingulate-island-sign-with-optimized-ratios-for-discriminating-dementia-with-lewy-bodies-from-alzheimer-s-disease-using-brain-perfusion-spect
#13
Etsuko Imabayashi, Tsutomu Soma, Daichi Sone, Tadashi Tsukamoto, Yukio Kimura, Noriko Sato, Miho Murata, Hiroshi Matsuda
OBJECTIVE: Dementia with Lewy bodies (DLB) is often cited as the second most common dementia after Alzheimer's disease (AD). It is clinically important to distinguish DLB from AD because specific side effects of antipsychotic drugs are limited to DLB. The relative preservation of cingulate glucose metabolism in the posterior cingulate gyri versus that in the precuni, known as the cingulate island sign (CIS), in patients with DLB compared with AD is supposed to be highly specific for diagnosing DLB...
May 25, 2017: Annals of Nuclear Medicine
https://www.readbyqxmd.com/read/28547322/metabolic-engineering-of-saccharomyces-cerevisiae-for-production-of-germacrene-a-a-precursor-of-beta-elemene
#14
Yating Hu, Yongjin J Zhou, Jichen Bao, Luqi Huang, Jens Nielsen, Anastasia Krivoruchko
Beta-elemene, a sesquiterpene and the major component of the medicinal herb Curcuma wenyujin, has antitumor activity against various types of cancer and could potentially serve as a potent antineoplastic drug. However, its current mode of production through extraction from plants has been inefficient and suffers from limited natural resources. Here, we engineered a yeast cell factory for the sustainable production of germacrene A, which can be transformed to beta-elemene by a one-step chemical reaction in vitro...
May 25, 2017: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28547295/high-loading-dose-of-microencapsulated-gliclazide-formulation-exerted-a-hypoglycaemic-effect-on-type-1-diabetic-rats-and-incorporation-of-a-primary-deconjugated-bile-acid-diminished-the-hypoglycaemic-antidiabetic-effect
#15
Svetlana Golocorbin-Kon, Jelena Calasan, Boris Milijasevic, Sasa Vukmirovic, Mladena Lalic-Popovic, Momir Mikov, Hani Al-Salami
BACKGROUND AND OBJECTIVE: Gliclazide is a drug commonly used in type 2 diabetes mellitus. Recently, gliclazide has shown desirable pharmacological effects such as immunoregulatory and anti-clotting effects, which suggests potential applications in type 1 diabetes mellitus (T1DM). Gliclazide has variable absorption after oral administration, and thus using targeted-delivery techniques, such as microencapsulation, may optimise gliclazide absorption and potential applications in T1DM. Bile acids such as cholic acid have shown microcapsule-stabilising and controlled-release effects, and thus their incorporation into gliclazide microcapsules may further optimise gliclazide release, absorption and antidiabetic effects...
May 25, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28546915/label-free-and-regenerative-electrochemical-microfluidic-biosensors-for-continual-monitoring-of-cell-secretomes
#16
Su Ryon Shin, Tugba Kilic, Yu Shrike Zhang, Huseyin Avci, Ning Hu, Duckjin Kim, Cristina Branco, Julio Aleman, Solange Massa, Antonia Silvestri, Jian Kang, Anna Desalvo, Mohammed Abdullah Hussaini, Su-Kyoung Chae, Alessandro Polini, Nupura Bhise, Mohammad Asif Hussain, HeaYeon Lee, Mehmet R Dokmeci, Ali Khademhosseini
Development of an efficient sensing platform capable of continual monitoring of biomarkers is needed to assess the functionality of the in vitro organoids and to evaluate their biological responses toward pharmaceutical compounds or chemical species over extended periods of time. Here, a novel label-free microfluidic electrochemical (EC) biosensor with a unique built-in on-chip regeneration capability for continual measurement of cell-secreted soluble biomarkers from an organoid culture in a fully automated manner without attenuating the sensor sensitivity is reported...
May 2017: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
https://www.readbyqxmd.com/read/28546853/caveolin-1-an-oxidative-stress-related-target-for-cancer-prevention
#17
REVIEW
Shengqi Wang, Neng Wang, Yifeng Zheng, Jin Zhang, Fengxue Zhang, Zhiyu Wang
Aberrant oxidative metabolism is one of the hallmarks of cancer. Reactive species overproduction could promote carcinogenesis via inducing genetic mutations and activating oncogenic pathways, and thus, antioxidant therapy was considered as an important strategy for cancer prevention and treatment. Caveolin-1 (Cav-1), a constituent protein of caveolae, has been shown to mediate tumorigenesis and progression through oxidative stress modulation recently. Reactive species could modulate the expression, degradation, posttranslational modifications, and membrane trafficking of Cav-1, while Cav-1-targeted treatments could scavenge the reactive species...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28546766/abcb1-genetic-variants-in-leukemias-current-insights-into-treatment-outcomes
#18
REVIEW
Ravindran Ankathil
Despite improvements in treatment of different types of leukemia, not all patients respond optimally for a particular treatment. Some treatments will work better for some, while being harmful or ineffective for others. This is due to genetic variation in the form of single-nucleotide polymorphisms (SNPs) that affect gene expression or function and cause inherited interindividual differences in the metabolism and disposition of drugs. Drug transporters are one of the determinants governing the pharmacokinetic profile of chemotherapeutic drugs...
2017: Pharmacogenomics and Personalized Medicine
https://www.readbyqxmd.com/read/28546420/alterations-of-histone-modifications-contribute-to-pregnane-x-receptor-mediated-induction-of-cyp3a4-by-rifampicin
#19
Liang Yan, Yiting Wang, Jingyang Liu, Yali Nie, Xiaobo Zhong, Quancheng Kan, Lirong Zhang
Cytochrome P450 3A4 (CYP3A4) is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of the clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that the induction of CYP3A4 mRNA by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3 acetylation and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3) in the CYP3A4 promoter...
May 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28545639/novel-diabetes-drugs-and-the-cardiovascular-specialist
#20
REVIEW
Naveed Sattar, Mark C Petrie, Bernard Zinman, James L Januzzi
Recently, treatment with 2 newer classes of type 2 diabetes drugs were found to reduce events in patients with diabetes and cardiovascular (CV) disease, a group common in cardiology clinics. The sodium-glucose cotransporter 2 inhibitor, empagliflozin, markedly and rapidly reduced CV death and heart failure hospitalization, likely with hemodynamic/metabolic-driven mechanisms of action. More recently, the glucagon-like peptide-1 receptor agonists liraglutide and semaglutide also reduced CV death and/or major adverse CV events, but did so more slowly and did not influence heart failure risks, suggesting alternative mechanisms of benefit...
May 30, 2017: Journal of the American College of Cardiology
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