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https://www.readbyqxmd.com/read/28213512/27-hydroxycholesterol-impairs-neuronal-glucose-uptake-through-an-irap-glut4-system-dysregulation
#1
Muhammad-Al-Mustafa Ismail, Laura Mateos, Silvia Maioli, Paula Merino-Serrais, Zeina Ali, Maria Lodeiro, Eric Westman, Eran Leitersdorf, Balázs Gulyás, Lars Olof-Wahlund, Bengt Winblad, Irina Savitcheva, Ingemar Björkhem, Angel Cedazo-Mínguez
Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced (18)F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)-mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N)...
February 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28069385/changes-of-renin-angiotensin-system-related-aminopeptidases-in-early-stage-alzheimer-s-disease
#2
Paul Richard Gard, Sara Fidalgo, Isabelle Lotter, Cassandra Richardson, Nicolas Farina, Jennifer Rusted, Naji Tabet
Activities of aminopeptidases A, B, and N (ApA, ApB & ApN) and insulin-regulated aminopeptidase (IRAP) have been seen to be decreased amongst patients with Alzheimer's disease (AD). All of these enzymes are involved with the brain renin-angiotensin system which is believed to be involved with learning and memory. This study aimed to explore the time course and the mechanisms underlying these changes. Serum samples were collected from 45 AD patients at the start of the study, and again 13months later (n=37)...
January 7, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28035472/insulin-regulated-aminopeptidase-immunoreactivity-is-abundantly-present-in-human-hypothalamus-and-posterior-pituitary-gland-with-reduced-expression-in-paraventricular-and-suprachiasmatic-neurons-in-chronic-schizophrenia
#3
Hans-Gert Bernstein, Susan Müller, Hendrik Dobrowolny, Carmen Wolke, Uwe Lendeckel, Alicja Bukowska, Gerburg Keilhoff, Axel Becker, Kurt Trübner, Johann Steiner, Bernhard Bogerts
The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls...
December 29, 2016: European Archives of Psychiatry and Clinical Neuroscience
https://www.readbyqxmd.com/read/27936390/irap-inhibition-using-hfi419-prevents-moderate-to-severe-acetylcholine-mediated-vasoconstriction-in-a-rabbit-model
#4
Aisha El-Hawli, Tawar Qaradakhi, Alan Hayes, Emma Rybalka, Renee Smith, Martin Caprnda, Radka Opatrilova, Katarina Gazdikova, Maria Benckova, Peter Kruzliak, Anthony Zulli
Coronary artery vasospasm (constriction) caused by reduced nitric oxide bioavailability leads to myocardial infarction. Reduced endothelial release of nitric oxide by the neurotransmitter acetylcholine, leads to paradoxical vasoconstriction as it binds to smooth muscle cell M3 receptors. Thus, inhibition of coronary artery vasospasm will improve clinical outcomes. Inhibition of insulin regulated aminopeptidase has been shown to improve vessel function, thus we tested the hypothesis that HFI419, an inhibitor of insulin regulated aminopeptidase, could reduce blood vessel constriction to acetylcholine...
February 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27834335/a-pcr-rflp-method-for-detection-of-the-lnpep-encoding-human-insulin-regulated-aminopeptidase-irap-rs4869317-polymorphism
#5
MarIa Jesús RamIrez-Expósito, Jos Manuel MartInez-Martos, Teresa Palomeque, Pedro Lorite
BACKGROUND & OBJECTIVES: Insulin regulated aminopeptidase (IRAP) has been related to certain pathologies such as breast cancer, Alzheimer΄s disease and septic shock. IRAP is encoded by the leucyl/cystinyl aminopeptidase (LNPEP) gene. The genetic variation in the LNPEP gene has been analyzed in relation with the mortality and vasopressin clearance in septic shock. The LNPEP rs4869317 SNP (single nucleotide polymorphism) was the most significantly associated SNP with vasopressinase activity, being TT genotype associated with increased mortality...
July 2016: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/27769857/staurosporine-as-an-agonist-for-induction-of-glut4-translocation-identified-by-a-ph-sensitive-fluorescent-irap-morange2-probe
#6
Yufeng Li, Zheng Li, Dan Wang, Xiang Zhang, Jia Li, Sher Ali, Jingze Lu, Hao Zong, Xiaolan Xu
Insulin-stimulated GLUT4 translocation from GLUT4 storage vesicles (GSVs) to the plasma membrane (PM) constitutes a key process for blood glucose control. Therefore, compounds that could promote GLUT4 translocation into the PM represent potential drugs for the treatment of diabetes. In this research, we screened for agonists that induce GLUT4 translocation by using a novel pH-sensitive fluorescent probe, insulin-regulated aminopeptidase (IRAP)-mOrange2. We identified as well as validated one agonist, staurosporine, from a 64,000 compound library...
October 18, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27734175/a-deeper-look-at-implicit-weight-bias-in-medical-students
#7
Timothy K Baker, Gregory S Smith, Negar Nicole Jacobs, Ramona Houmanfar, Robbyn Tolles, Deborah Kuhls, Melissa Piasecki
The Implicit Relational Assessment Procedure (IRAP, Barnes-Holmes et al. in Psychol Rec 60:527-542, 2010) was utilized as a relatively new tool to measure implicit weight bias in first- and third-year medical students. To date, only two studies (Miller et al. in Acad Med 88:978-982, 2013; Phelan et al. in Med Educ 49:983-992, 2015) have investigated implicit weight bias with medical students and both have found pro-thin/anti-fat implicit attitudes, on average, using the Implicit Association Test (IAT, Greenwald and Banaji in Psychol Rev 102:4-27, 1995) as the assessment tool...
October 12, 2016: Advances in Health Sciences Education: Theory and Practice
https://www.readbyqxmd.com/read/27713012/forebrain-neurone-specific-deletion-of-insulin-regulated-aminopeptidase-causes-age-related-deficits-in-memory
#8
Holly R Yeatman, Anthony L Albiston, Peta Burns, Siew Yeen Chai
Central infusion of Insulin-Regulated Aminopeptidase (IRAP) inhibitors improves memory in both normal rodents and in models of memory deficit. However, in contrast, the global IRAP knockout mice (KO) demonstrate age-accelerated spatial memory deficits and no improvements in performance in any memory tasks. Potentially, the observed memory deficit could be due to the absence of IRAP in the developing brain. We therefore generated a postnatal forebrain neuron-specific IRAP knockout mouse line (CamKIIalphaCre; IRAPlox/lox)...
December 2016: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/27606886/sex-difference-in-oxytocin-induced-anti-hyperalgesia-at-the-spinal-level-in-rats-with-intraplantar-carrageenan-induced-inflammation
#9
Lok-Hi Chow, Yuan-Hao Chen, Wan-Chuan Wu, En-Pei Chang, Eagle Yi-Kung Huang
Previously, we demonstrated intrathecal administration of oxytocin strongly induced anti-hyperalgesia in male rats. By using an oxytocin-receptor antagonist (atosiban), the descending oxytocinergic pathway was found to regulate inflammatory hyperalgesia in our previous study using male rats. The activity of this neural pathway is elevated during hyperalgesia, but whether this effect differs in a sex-dependent manner remains unknown. We conducted plantar tests on adult male and female virgin rats in which paw inflammation was induced using carrageenan...
2016: PloS One
https://www.readbyqxmd.com/read/27606717/optimization-and-structure-activity-relationships-of-phosphinic-pseudotripeptide-inhibitors-of-aminopeptidases-that-generate-antigenic-peptides
#10
Paraskevi Kokkala, Anastasia Mpakali, Francois-Xavier Mauvais, Athanasios Papakyriakou, Ira Daskalaki, Ioanna Petropoulou, Sofia Kavvalou, Mirto Papathanasopoulou, Stefanos Agrotis, Theodora-Markisia Fonsou, Peter van Endert, Efstratios Stratikos, Dimitris Georgiadis
The oxytocinase subfamily of M1 aminopeptidases, consisting of ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2), and insulin-regulated aminopeptidase (IRAP), plays critical roles in the generation of antigenic peptides and indirectly regulates human adaptive immune responses. We have previously demonstrated that phosphinic pseudotripeptides can constitute potent inhibitors of this group of enzymes. In this study, we used synthetic methodologies able to furnish a series of stereochemically defined phosphinic pseudotripeptides and demonstrate that side chains at P1' and P2' positions are critical determinants in driving potency and selectivity...
October 13, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27588541/implicit-alcohol-related-expectancies-and-the-effect-of-context
#11
Rebecca L Monk, Charlotte R Pennington, Claire Campbell, Alan Price, Derek Heim
OBJECTIVE: The current study examined the impact of varying pictorial cues and testing contexts on implicit alcohol-related expectancies. METHOD: Seventy-six participants were assigned randomly to complete an Implicit Relational Assessment Procedure (IRAP) in either a pub or lecture context. The IRAP exposed participants to pictorial cues that depicted an alcoholic beverage in the foreground of a pub (alcohol-congruent stimuli) or university lecture theater (alcohol-incongruent stimuli), and participants were required to match both positive and negative alcohol-related outcome expectancies to these stimuli...
September 2016: Journal of Studies on Alcohol and Drugs
https://www.readbyqxmd.com/read/27578509/prss1-spink1-cftr-and-ctrc-pathogenic-variants-in-korean-patients-with-idiopathic-pancreatitis
#12
Sun Mi Cho, Saeam Shin, Kyung A Lee
BACKGROUND: This study aimed to identify pathogenic variants of PRSS1, SPINK1, CFTR, and CTRC genes in Korean patients with idiopathic pancreatitis. METHODS: The study population consisted of 116 Korean subjects (65 males, 51 females; mean age, 30.4 yr, range, 1-88 yr) diagnosed with idiopathic chronic pancreatitis (ICP), idiopathic recurrent acute pancreatitis (IRAP), or idiopathic acute pancreatitis (IAP). We analyzed sequences of targeted regions in the PRSS1, SPINK1, CFTR, and CTRC genes, copy numbers of PRSS1 and SPINK1, and clinical data from medical records...
November 2016: Annals of Laboratory Medicine
https://www.readbyqxmd.com/read/27501164/aryl-sulfonamide-inhibitors-of-insulin-regulated-aminopeptidase-enhance-spine-density-in-primary-hippocampal-neuron-cultures
#13
Shanti Diwakarla, Erik Nylander, Alfhild Grönbladh, Sudarsana Reddy Vanga, Yasmin Shamsudin Khan, Hugo Gutiérrez-de-Terán, Jonas Sävmarker, Leelee Ng, Vi Pham, Thomas Lundbäck, Annika Jenmalm-Jensen, Richard Svensson, Per Artursson, Sofia Zelleroth, Karin Engen, Ulrika Rosenström, Mats Larhed, Johan Åqvist, Siew Yeen Chai, Mathias Hallberg
The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models...
August 8, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27450967/endoscopic-sphincterotomy-es-may-not-alter-the-natural-history-of-idiopathic-recurrent-acute-pancreatitis-irap
#14
Rohit Das, Bridger Clarke, Gong Tang, Georgios I Papachristou, David C Whitcomb, Adam Slivka, Dhiraj Yadav
BACKGROUND: The role of endoscopic sphincterotomy (ES) in idiopathic recurrent acute pancreatitis (IRAP) is unclear. We hypothesized that ES will alter the natural history of IRAP. METHODS: We retrospectively studied the course of 50 IRAP patients from the NAPS2 study from UPMC based on whether they underwent ES or were managed medically. Data included age at first AP, rate of attacks, and history of severe AP. Primary outcomes were any subsequent AP and rate of attacks; secondary outcome was chronic pancreatitis (CP) diagnosis during follow-up...
September 2016: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
https://www.readbyqxmd.com/read/27437077/screening-identifies-thimerosal-as-a-selective-inhibitor-of-endoplasmic-reticulum-aminopeptidase-1
#15
Athanasios Stamogiannos, Athanasios Papakyriakou, Francois-Xavier Mauvais, Peter van Endert, Efstratios Stratikos
We employed virtual screening followed by in vitro evaluation to discover novel inhibitors of ER aminopeptidase 1, an important enzyme for the human adaptive immune response that has emerged as an attractive target for cancer immunotherapy and the control of autoimmunity. Screening hits included three structurally related compounds carrying the (E)-N'-((1H-indol-3-yl)methylene)-1H-pyrazole-5-carbohydrazide scaffold and (2-carboxylatophenyl)sulfanyl-ethylmercury as novel ERAP1 inhibitors. The latter, also known as thimerosal, a common component in vaccines, was found to inhibit ERAP1 in the submicromolar range and to present strong selectivity versus the homologous aminopeptidases ERAP2 and IRAP...
July 14, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27425647/tankyrase-as-a-novel-molecular-target-in-cancer-and-fibrotic-diseases
#16
Vijaya Lakshmi Tiruveedi, Swarna Bale, Amit Khurana, Chandraiah Godugu
Tankyrases belong to a group of enzymes called poly ADP ribosyl polymerases (PARPs). With the advent of a new class of small molecule inhibitors of PARP for clinical use like OLAPARIB; that gained accelerated approval by the USFDA in treating ovarian and breast cancers, the horizons of the PARPs as a novel target in various disease conditions has risen. Tankyrases (PARP 5) are yet another class of PARPs that perform poly ADP ribosylation on different substrate proteins aiding in progression of many diseases like cancer, fibrosis, diabetes and neurological disorders even...
July 15, 2016: Current Drug Targets
https://www.readbyqxmd.com/read/27357270/cytokine-and-growth-factor-concentrations-in-canine-autologous-conditioned-serum
#17
Dominique M Sawyere, Otto I Lanz, Linda A Dahlgren, Sabrina L Barry, Anne C Nichols, Stephen R Werre
OBJECTIVE: To compare cytokine and growth factor concentrations in canine autologous conditioned serum (ACS) to canine plasma. STUDY DESIGN: Experimental in vivo study. ANIMALS: Client-owned, adult dogs (n=22). METHODS: Blood collected from 16 medium to large breed dogs was used to produce ACS (Orthokine(®) vet irap 10 syringes) and citrated plasma (control). Canine-specific ELISA assays were run per manufacturers' instructions for interleukin (IL)-10, IL-4, tumor necrosis factor (TNF)-α, insulin-like growth factor (IGF)-1, fibroblast growth factor (FGF)-2, transforming growth factor (TGF)-β1, IL-1β, and interleukin-1 receptor antagonist (IL-1ra)...
July 2016: Veterinary Surgery: VS
https://www.readbyqxmd.com/read/27173211/variability-of-colletotrichum-spp-in-common-bean
#18
S F Mota, Q L Barcelos, M A Dias, E A Souza
The Colletotrichum genus presents large genetic variability, as demonstrated by the occurrence of several pathogenic races and phenotypic traits. The objective of this study was to characterize 22 strains of C. lindemuthianum and Colletotrichum spp recovered from anthracnose lesions and bean scab, and to verify the relationship between species of the Colletotrichum genus, which inhabit anthracnose and scab lesions. Colony morphology, conidium size, the presence of septa, germination, sporulation, and mycelium growth rates, were analyzed in addition to the presence of mating-type genes, IRAP markers, and pathogenicity...
April 7, 2016: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/27173210/development-of-retrotransposon-based-markers-irap-and-remap-for-cassava-manihot-esculenta
#19
B C Kuhn, C A Mangolin, E R Souto, C M Vicient, M F P S Machado
Retrotransposons are abundant in the genomes of plants. In the present study, inter-retrotransposon amplified polymorphism (IRAP) and retrotransposon-microsatellite amplified polymorphism (REMAP) markers were developed for the cassava genome (Manihot esculenta Crantz). Four cassava cultivars (Fécula Branca, IPR-União, Olho Junto, and Tamboara, two samples per cultivar) were used to obtain IRAP and REMAP fingerprints. Twelve designed primers were amplified alone and in combinations. The 42 IRAP/REMAP primer combinations amplified 431 DNA segments (bands; markers) of which 36 (8...
April 7, 2016: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/27160165/chloroquine-increases-glucose-uptake-via-enhancing-glut4-translocation-and-fusion-with-the-plasma-membrane-in-l6-cells
#20
Qi Zhou, Xinzhou Yang, Mingrui Xiong, Xiaolan Xu, Li Zhen, Weiwei Chen, Yan Wang, Jinhua Shen, Ping Zhao, Qing-Hua Liu
BACKGROUND/AIMS: Chloroquine can induce an increase in the cellular uptake of glucose; however, the underlying mechanism is unclear. METHODS: In this study, translocation of GLUT4 and intracellular Ca2+ changes were simultaneously observed by confocal microscope in L6 cells stably over-expressing IRAP-mOrange. The GLUT4 fusion with the plasma membrane (PM) was traced using HA-GLUT4-GFP. Glucose uptake was measured using a cell-based glucose uptake assay. GLUT4 protein was detected by Western blotting and mRNA level was detected by RT-PCR...
2016: Cellular Physiology and Biochemistry
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