bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Infarct Volume and Altered Repair Following Ischemic Stroke in Mice Lacking the Brain‐Expressed Orphan G Protein‐Coupled Receptor GPR37
Authors: Owino Sharon , Giddens Michelle , Jiang Micheal , Gu Xiaohuan , Wei Ling , Yu Shan Ping , Hall Randy 
Published: June 2021

GPR37 is an orphan G protein‐coupled receptor expressed almost exclusively in the nervous system. Since its initial discovery as a substrate for parkin, the majority of studies on GPR37 have focused on its role in Parkinson's disease. Remarkably little is known about GPR37 in other models of neuronal damage/disease. We've previously shown that GPR37 mediates protection from oxidative stress in cultured astrocytes, which led us to assess the role of GPR37 in vivo in a rodent model of ischemic stroke. Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in WT and GPR37−deficient mice. Infarct size, histochemical observations, and protein expression levels were analyzed within the brain 72 hrs. following MCAO. Following occlusion, infarct volume was markedly increased in GPR37 deficient mice compared to WT mice. Interestingly, this coincided with a decrease in the abundance of reactive astrocytes (as assessed by the upregulation of GFAP) within the stroke penumbra region of the GPR37‐deficient mice relative to WT mice. Examination of receptor expression levels within the brain also revealed that GPR37 was massively upregulated within multiple brain regions following ischemia, suggesting a critical role for this receptor in the ischemic response. Furthermore, GPR37‐deficient mice exhibited substantially decreased levels of HIF‐1α and nest in positive cells, indicative of diminished reparative processes following hypoxia. Taken together, these studies demonstrate that GPR37 plays an important role in regulating the generation of reactive astrocytes in vivo and modulating repair following ischemic insults.Support or Funding InformationThis study is supported by grant R01‐NS088413 from the National Institutes of Health.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
L‐arginine Supplementation and Thromboxane Synthase Inhibition Reverse Cerebral Ischemia in Murine Cerebral Malaria by Plasmodium berghei ANKA
Authors: da Silva Moreira Aline , de Freitas Almeida Vanessa Estato , Bianco‐Júnior Cesare , Daniel‐Ribeiro Claudio Tadeu , Tibiriçá Eduardo Vera , de Moura Carvalho Leonardo José 
Published: June 2021

Cerebral malaria (CM) is one of the most severe and lethal complications of Plasmodium falciparum infection. The mainstay treatment for CM is intravenous artesunate, nevertheless 15–20% of the patients receiving this drug still die. Vascular dysfunction, with vasoconstriction, leads to decreased cerebral blood flow, ischemia, tissue hypoxia and death in CM. Nitric oxide (NO) and arachidonic acid metabolites are important regulators of physiological cerebral blood flow through their vasodilator or vasoconstrictive properties. The objective of this study was to determine the effects of L‐arginine supplementation and pharmacological inhibition of thromboxane A2 (TXA2) synthesis on the reversal of ischemia in experimental cerebral malaria (ECM). C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) and showing clinical signs of ECM were treated subcutaneously with the NO precursor L‐arginine (50mg/kg) and/or the thromboxane synthase inhibitor ozagrel (100mg/kg). Cerebral blood flow was measured by Laser Speckle Contrast Imaging (LSCI). The adjuvant effect of L‐arginine in combination with artesunate on survival of mice with late‐stage ECM was evaluated. Animals that developed ECM showed a significant decrease (25%) in cerebral blood flow compared to non‐infected control animals. L‐arginine induced a marked increase (22.5%) in cerebral blood flow in mice with ECM one hour after administration. The administration of ozagrel, which prevents the generation of the vasoconstrictor metabolite TXA2, also led to increased (16.5%) cerebral blood flow in animals with ECM, and this was consistent with decreased levels of brain TXA2 in ozagrel‐treated compared to saline‐treated animals. The combination of ozagrel and L‐arginine showed no synergistic effect on cerebral blood flow. Treatment of animals with late‐stage ECM with artesunate plus L‐arginine increased survival compared to artesunate plus saline. Conclusion: L‐arginine and ozagrel increase cerebral blood flow, and L‐arginine increase survival in mice with cerebral malaria and show potential as adjuvant therapy for this malaria complication.Support or Funding InformationCAPES, FAPERJ, IOC‐FiocruzThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
In Silico Molecular Docking of Fisetin with the Amyloidogenic Peptides Human Amylin and Aβ42
Authors: Villanueva James Amador , Bamigboje Tobiloba , Hari Saran Krishnan , Boluwaduro Adeyemi , Gautham Sakthi , Ibrahim Adam 
Published: June 2021

Amylin is a 37‐residue polypeptide which is co‐secreted with insulin from pancreatic beta cells. In diabetics, this protein has been shown to misfold and form amyloids which cause pancreatic cell death. The exact mechanism by which hIAPP causes cell death remains unknown. However, it has been associated with an aggregation of the protein and an increase in the oxidative stress in the cell. Amylin has similarities with Aβ42, the main protein implicated in the pathogenesis of Alzheimer's disease. Fisetin, a naturally occurring substance which is found in strawberries, apples and cucumbers has been shown to slow down the rate of aggregation of Aβ42. Fisetin has also been proven to have antioxidant properties. Based on the structural and molecular similarities between Aβ42 and human IAPP, we have used molecular alignment and docking experiments to study and show the possibility that fisetin may also slow down the rate of aggregation of human IAPP by binding to single IAPP chains before they form aggregates. Using Autodock Vina, Autodock Tools and Discovery Studio Visualizer, the binding sites of fisetin to both proteins were determined. Binding energies and protein conformations were also determined and analyzed.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
DESIGN, SYNTHESIS AND IN‐VITRO EVALUATION OF ATP‐COMPETITIVE INHIBITORS OF AURORA KINASE‐A USING STRUCTURE‐BASED DRUG DESIGN (SBDD)
Authors: Abdullah Omeima Alhaj , Mehanna Ahmed 
Published: June 2021

Aurora‐A kinase inhibitors are small molecule ATP – competitive inhibitors that have been emerged as promising chemotherapeutic agents for cancer. In this study, Structure‐based drug design (SBDD), is mainly used to investigate and to study the molecular interactions between selective ATP‐competitive inhibitor (alisertib) along with the proposed compounds and the existing X‐ray structure of Aurora‐A kinase protein (PDB: 2W1C). Based on SBDD, different proposed compounds (p‐aminobenzoic acid derivatives) were designed from alisertib (reference compound) by replacing the lipophilic moiety (benzazepine) with simpler lipophilic cyclic moieties, such as naphthalene, fluorene, and benzothiazole through amide bond as a linker. This structure‐based design was based on the primary interactions of alisertib with key residues of the hinge and hydrophobic regions of ATP‐binding site (Glu‐211, Ala‐213, Lys‐162, Val‐147, Leu‐139, and Leu‐263). p‐aminobenzoic acid derivatives were synthesized and their inhibitory activity was in‐vitro tested by PhosphoSens ® assay. All the designed p‐aminobenzoic acid compounds bound to the ATP‐active site and exhibited similar interactions as other scaffolds of Aurora‐A inhibitors. However, they presented less inhibitory activity against Aurora‐A compared to alisertib (IC50= 6 nM). Compound‐5 (IC50= 46μM) was the most active compound and will be further modified to enhance the inhibitory activity of Aurora‐A kinase.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Methodology for Prioritizing Pediatric Pharmacokinetic Studies and Pharmacogenomic Implementation using Evidence from Patient Drug Safety Data
Authors: Eugene Andy Roger , Eugene Beata , DiCenzo Robert , Harralson Arthur 
Published: June 2021

IntroductionPhysicians attempting to integrate pharmacogenomic testing into routine patient care have been limited due to insurance company reimbursements. However, hospitals committed to improving patient safety outcomes are integrating pharmacogenomic consultations from board‐certified pharmacologists and clinical pharmacists to provide personalized dosing via pharmacogenomic and pharmacometrics tools. Therefore we sought to identify and prioritize drug‐gene pairs associated with the most frequently reported adverse drug reactions (ADRs).MethodsDrug safety data from the first and second quarter of 2017 were downloaded as ASCII text files from the United States Food and Drug Administration's Adverse Events Reporting System (FAERS). The quarterly FAERS files were merged with the ‘primaryid’ column defining the unique case sequence identifier and manufacturer version numbers. Data homogenization and summary statistics were computed in R for statistical programming (version 3.3.2, Vienna, Austria). The most frequently reported drugs and adverse drug events (ADRs) are reported and stratified using the following pediatric age groups: neonate, infant, child, and adolescent. Drug‐Gene associations were referenced from GeneCards data base (http://www.genecards.org/).ResultsIn the first and second quarters of 2017, the most frequently reported drugs (% of total reported cases) [top 5 ranked genes] within the pediatric age groups were: Neonate – Ondansetron (71%) [HTR3A, CYP2D6, ABCB1, TACR1, CCK], Infant – Valproate Sodium (8%) [SCN1A, SCN4A, SLC2A1, SCN5A], Child – Risperidone (43%) [PRL, DRD2, HTR2A, CYP2D6, ABCB1], and Adolescent – Risperidone (28%) [PRL, DRD2, HTR2A, CYP2D6, ABCB1]. The top reported ADRs were: Neonate – Foetal exposure during pregnancy (8%), Infant – off label use (4%), Child – gynaecomastia (12%), and Adolescents – gynaecomastia (8%).ConclusionIn the pediatric aged patients, drugs modulating serotonergic receptors, transported via ABCB1, and metabolized by CYP2D6 (Ondansetron and Risperidone) are most frequently associated with reported adverse drug reactions in children. Genotyping pregnant mothers prior to prescribing Ondansetron for anti‐nausea and vomiting may improve drug safety outcomes by mitigating unnecessarily high fetal drug exposure in utero in potential poor metabolizers. Similarly, genotyping children for CYP2D6 prior to prescribing, the antipsychotic, Risperidone may improve drug safety outcomes and should be communicated as an option to parents. Pediatric drug safety opportunities exist for Obstetrics & Gynecology and Psychiatry clinics for integrating clinical pharmacogenomics into routine patient care.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acetaminophen and Aspirin Overdose in an Extremely Preterm Neonate
Authors: Pavlek Leeann , Rogers Lynette 
Published: June 2021

IntroductionAcetaminophen (N‐acetyl‐p‐aminophenol; APAP) is a widely available over‐the‐counter analgesic which is considered safe at standard dosing, but can produce significant drug‐induced liver injury and acute liver failure when taken in excess. Aspirin (acetylsalicylic acid) is a commonly used non‐steroidal anti‐inflammatory and anti‐platelet medication, which can produce significant respiratory and metabolic derangements when taken in large amounts. Accidental and intentional overdoses of these two medications are often encountered in children and adults and have widely accepted treatment protocols. There are currently no reported cases describing the presentation and treatment of a combined acetaminophen and aspirin overdose in a premature neonate.Case ReportThis case describes a premature infant born at 26 weeks gestation one day after her mother is hospitalized for management of an overdose of acetaminophen and aspirin. The mother had significantly elevated blood levels of both drugs, and underwent treatment with N‐acetylcysteine (NAC) and sodium bicarbonate. Acetaminophen and aspirin are both known to cross the placenta and can cause neonatal hepatotoxicity and coagulopathy respectively. NAC acts as an antidote to acetaminophen toxicity and also crosses the placenta, so administration is recommended to treat acetaminophen overdose in pregnancy. In this case, the baby was delivered before the treatment course was completed and subsequently showed signs of liver injury. The infant had laboratory results showing elevated acetaminophen and aspirin levels, metabolic acidosis, and prolonged PT, PTT, and INR. The neonate had resolution of her metabolic acidosis with administration of fluids containing sodium acetate. It was recommended by our neonatal pharmacist and toxicology experts to administer NAC, but the standard dosing regimen and concentration of NAC would provide an unsafe excess of fluid. This case report describes our novel treatment protocol that was formulated to provide this extremely low birth weight neonate with appropriate weight‐based doses of NAC. She clinically improved and did well while in the neonatal intensive care unit, with no further consequences of the overdose.ConclusionThis is the first case report describing the presentation and unique management strategies of an acetaminophen and aspirin overdose in an extremely premature baby.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Aqueous extract of Alhagi Maurorum protects from norfloxacin‐induced hepato‐nephrotoxicity in rats
Authors: Khalifa Hesham Ahmed Mohammed Ismail , Abdelrahman Ahmed Shaban Abdelaziz , Sahu Ravi P 
Published: June 2021

ObjectivesTo determine the effects of aqueous extract of Alhagi maurorum against the adverse effects including hepato‐nephrotoxicity induced by a broad‐spectrum antibiotic norfloxacin in rats.MethodsAdult male albino rats were treated with or without norfloxacin (10 mg/kg) and Alhagi maurorum (300 mg/kg). Serum samples were collected to evaluate liver and kidney function tests, and hepatic and renal tissue samples were obtained to assess antioxidant activity and histopathological examination.ResultsAlhagi maurorum ameliorated norfloxacin induced elevated levels of serum alkaline phosphatase (ALP), aminotransferases (AST), urea, creatinine, and uric acid. In addition, Alhagi maurorum significantly reduced the tissue levels of malondialdehyde (MDA), and increased glutathione peroxidase (GPx) and superoxide dismutase (SOD) compared to norfloxacin alone treated group. Histological analysis demonstrate that Alhagi maurorum conserved the hepatic and renal tissue damages induced by norfloxacin.ConclusionThese findings indicate that Alhagi maurorum aqueous extract possesses a potent antioxidant activity and could be used to attenuate norfloxacin induced oxidative stress and hepatorenal damage in experimental models.Support or Funding InformationNo funding supportThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Trichloroacetate‐Induced Developmental Toxicity and the Production of Reactive Oxygen Species in Zebrafish Embryos (Danio rerio)
Authors: Issa Omar N , Hassoun Ezdihar A , Williams Frederick E 
Published: June 2021

Trichloroacetic acid (TCA) is one of the toxic haloacetate by‐products formed as a result of the chlorination of drinking water as a part of the disinfection process. In this report, the developmental toxic effects of TCA were investigated in a nonmammalian vertebrate species: zebrafish (Danio rerio) embryos. The exposure of zebrafish embryos to (24, 32, 40, and 48 mM) TCA occurred at 4 hours post‐fertilization (hpf), and the embryos were monitored at 8, 24, 32, 55, 80, and 144 hpf for developmental landmarks from proper gastrulation to swimming and feeding success. At 32 hpf, TCA elicited a significant YSE at all of TCA concentrations when compared with the untreated controls. However, when compared with the untreated controls at the 55 and 80 hpf, a significant amount of CSE and YSE was observed in animals exposed to all of the tested TCA concentrations. Hatching delay was also produced in zebrafish embryos due to exposure to TCA concentrations of 24 and 40 mM at the 55hpf developmental time point. The hatching delay was more pronounced at the 55 hpf than 80 hpf time point. In addition, embryos developed lordosis resulting in behavioral abnormalities like abnormal feeding and swimming. The lethal dose‐50 (LD50) of TCA in zebrafish embryos was calculated as 29.72 mM. Along with the induced developmental toxicity, TCA elicited the release of superoxide anion (SA) in zebrafish embryos at 32, 55, and 80 hpf of development.The reactive oxygen species (ROS) produced by TCA exposure coincides with the developmental abnormalities which were observed in exposed embryos. This indicates that the ROS generated may cause the developmental toxic effects of TCA exposure in zebrafish embryos.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dynamic Culturing of Rat Hepatocytes in Sandwich‐Configuration Enhances and Maintains Formation of Biliary Networks
Authors: Deferm Neel , Stam Janine , de Witte Peter , Bouillon Thomas , Annaert Pieter 
Published: June 2021

Primary hepatocytes are currently the ‘gold standard’ for evaluating hepatotoxicity of drugs and other xenobiotics in vitro, as they ensure a close resemblance to the in vivo situation in terms of activity levels of drug metabolizing enzymes and transport proteins. Hepatocyte phenotype and cell polarity is commonly maintained for several days by culturing human or animal hepatocytes between two layers of collagen in a sandwich‐configuration. Despite the pronounced positive effects of culturing hepatocytes in sandwich‐configuration, decreases in metabolic enzyme expression and activity occur rapidly. Moreover, this static in vitro system does not adequately resemble the in vivo microenvironment where hepatocytes are in close proximity with the microvascular network, which continuously exposes the cells to hemodynamic stresses such as wall shear stress. We therefore hypothesized that restoring hemodynamics by dynamically culturing hepatocytes using a shaking incubator would improve metabolic function and hepatocyte phenotype. Rat hepatocytes were cultured for 11 days either in sandwich‐configuration under static (i.e. non‐shaking) or dynamic conditions (i.e. continuous shaking). Hepatocyte phenotype, functionality, viability as well as bile canalicular morphology were assessed at multiple days of culture. Hepatocytes undergoing continuous shaking exhibited a uniform and polygonal morphology. Moreover, both static and dynamic cultures developed extensive biliary networks at day 3 of culture time. Mean (± SEM) biliary excretion index (BEI) values of dynamically cultured cells, as determined by the quantitative evaluation of multidrug‐resistance associated protein 2 (Mrp 2; Abcc2) mediated excretion of 5‐(6)‐carboy‐2′,7′‐dichlorofluorescein (CDF), did not decrease through 11 days in culture (day 3: 46 ± 3%, day 11: 45 ± 1%), whereas mean BEI values (± SEM) of static cultures declined from day 3 onwards (day 3: 45 ± 3%, day 11: 34 ± 2%). No significant difference in overall biochemical integrity between both cultures was observed, as measured by the capability of the hepatocytes to convert toxic ammonia to non‐toxic urea. Consistently, viability of the cultured cells, which was monitored longitudinally by determining the cellular release of lactate dehydrogenase (LDH), did not differ significantly between static and dynamic cultures. In conclusion, although both cultures did not differ in terms of biochemical integrity and viability, our results show that dynamically culturing rat hepatocytes in sandwich‐configuration improves maintenance of functional biliary networks for up to 11 culture days.Support or Funding InformationFinancial support for this research was provided by the Research Foundation ‐ Flanders (FWO)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The marine natural product coibamide targets expression of HER family receptors
Authors: Kazemi Soheila , Serrill Jeffrey D. , McPhail Kerry L. , Ishmael Jane E. 
Published: June 2021

Natural products have historically been a significant source of inspiration for drug design and development, particularly in the areas of cancer and infectious disease. The utility of natural products as drug leads is attributed to the fact that these molecules have evolved to bind specific biological targets and have the potential to reveal new aspects of cell signaling. We previously reported the discovery of coibamide, a cytotoxic N‐methyl‐stabilized depsipeptide isolated from a marine cyanobacterium growing within Coiba National Park, Panama. Initial testing of coibamide in the National Cancer Institute in vitro 60 (NCI60) cancer cell line panel revealed pM to nM potency as a growth inhibitor, an unmatched selectivity profile and histological selectivity for breast, CNS‐derived tumors, ovarian and colon cancer cells.We have undertaken studies to determine the mechanism of action of coibamide and have determined that coibamide selectively targets the ER secretory pathway. To date, these relatively rare natural products are known for their ability to selectively inhibit biosynthesis receptor tyrosine kinases, growth factors and cell adhesion proteins. We studied the relative expression of human epidermal growth factor receptor (HER) proteins in human HER2‐amplified and triple negative breast cancer cells following exposure to coibamide. Coibamide inhibited expression of HER family members with differential sensitivity (EGFR=HER3<<HER2). Time‐ and concentration‐dependent decreases in HER protein expression were accompanied by a dampening in AKT/MAPK signaling. Coibamide promoted proteasomal degradation of HER family proteins consistent with the action of an ER secretory pathway inhibitor. These results suggest that coibamide preferentially inhibits the biosynthesis of a subset of ER secretory pathway proteins to induce cancer cell death rather than a total inhibition of cellular secretory function. The HER family of proteins are associated with drug resistance and treatment failure in response to many modern, targeted anti‐cancer medicines and thus this work has the potential to reveal a new way to target HER signaling.Support or Funding InformationThis work was supported by the Oregon State University (OSU) College of Pharmacy, the American Brain Tumor Association (JEI) and an American Foundation for Pharmaceutical Education (AFPE) Pre‐Doctoral Fellowship in the Pharmaceutical Sciences (JDS)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.