bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defects of Oligodendrocyte Migration in the Scn1b−/− Mouse Model of Dravet Syndrome
Authors: Clemons Krisyah , O'Malley Heather A. , Isom Lori L. 
Published: June 2021

The Scn1b−/− mouse is a model of Dravet Syndrome (DS), a severe pediatric and developmental epileptic encephalopathy that begins in the first year of life and has multiple comorbidities. Scn1b−/− mice have severe seizures beginning at postnatal day (P)10 and die prior to ~P21. DS patients display defects in white matter, which may contribute to cognitive impairment, language issues, and problems with movement. Our previous research demonstrated that there are fewer nodes of Ranvier and that neuronal migration is impaired in Scn1b−/− brain. The purpose of this study is to determine if Scn1b−/− oligodendrocytes (OLs) migrate correctly from birth in the ventricles to destinations in the cortex. We chose to look at migration from the ventricles to cortical layers II/III and layers V/VI. We hypothesized that we would observe impairments in OL migration in Scn1b−/− animals compared to wildtype. We tested this hypothesis using Scn1b wildtype and Scn1b−/− mice in which OL lineage cells have been genetically labeled with green fluorescent protein (GFP). We performed immunocytochemistry on brain slices from mice of both genotypes at P13‐14 and P17‐18, using CDP as a marker for cortical layers II/III and CTIP2 as a marker of cortical layers V/VI, and then counting the number of GFP+ cells which had migrated to each of these regions. Our data demonstrate that, although the numbers of OLs in layers V/VI were similar between genotypes at both ages, there were fewer OLs in layers II/III in Scn1b−/− brain, suggesting that OL migration in these mice is impaired.Support or Funding InformationFunded by: R37NS076752 to LLI.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
RGS2 Modulation of Angiotensin II Receptor Type 1 Trafficking and Signaling in Neuroblastoma Cells
Authors: Wiley Aidan P , Luessen Deborah J , Hagstrom Michael , Sun Haiguo , Chen Rong 
Published: June 2021

IntroductionAltered expression and function of brain angiotensin II receptor type 1 (AT1R) has been implicated in the pathophysiology of various neuropsychiatric diseases such as drug addiction and Alzheimer's disease. However, there is a knowledge gap in understanding the molecular mechanisms of altered AT1R trafficking and function. Regulators of G‐protein signaling (RGS) proteins are negative modulators of G‐protein coupled receptors (GPCRs). Mechanistically, RGS proteins terminate signaling by accelerating the hydrolysis of GTP bound to active G‐alpha subunits. Among all the RGS subtypes, our lab found that RGS2 co‐localizes with AT1R in the brain, suggesting a potential role of RGS2 regulation of AT1R signaling. Additionally, our lab previously found that RGS2 regulates the constitutive and agonist‐induced trafficking of dopamine D2 receptors. Therefore, this project assessed the role of RGS2 in regulation of AT1R trafficking and signaling using a neuroblastoma 2a (N2A) cell model. Knowledge learned from this project may be relevant to the physiological function of RGS2 in the brain.MethodsWe generated stable expression of the human Angiotensin Type I receptor (HA‐AT1R) in N2A cells. N2A‐AT1R cells were then transiently transfected with RGS2 siRNA to knock down RGS2 expression. Cells were then treated with vehicle or angiotensin II (AngII, 10 μM) for 2, 5, or 15 minutes for western blotting of phosphorylated Akt and total Akt. Immunocytochemistry and confocal microscopy were performed on cells treated with AngII for various times to measure the trafficking of AT1R.ResultsWe found that the knockdown of RGS2 enhanced AT1R‐mediated signaling by increasing Akt phosphorylation. RGS2 knockdown also showed to increase AngII‐induced internalization of AT1R. This is the first report on the role of RGS2 in regulation of AT1R trafficking. Further study is necessary to investigate the molecular mechanisms underlying RGS2 modulation of the signaling and trafficking of AT1R in neuronal cells.Support or Funding InformationThis work is supported by NIH R01DA042862, P50DA006634, F31AA025532This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regulator of G protein Signaling 2 and 5 Coordinate Their Activity to Control Cardiac Contractility
Authors: Osei‐Owusu Patrick , Bernadyn Tyler F , Dahlen Shelby A 
Published: June 2021

Fine‐tuning of signaling via heterotrimeric G proteins by regulators of G protein signaling (RGS) proteins is critical to maintaining physiological homeostasis. Abnormal G protein signaling due to the loss of G protein regulation by RGS proteins is implicated in several diseases including cardiovascular disorders such as hypertension, cardiac hypertrophy, and heart failure. RGS proteins act as GTPase activating proteins (GAPs) to control the kinetics and amplitude of G protein signaling. Multiple RGS proteins are prominently expressed in the cardiovascular system; however, whether their activities/functions are coordinated to control G protein signaling and cardiovascular function is unknown. Here, we generated mice concurrently lacking RGS2 and 5 (Rgs2/5 dbKO) to determine how the dual absence of potent GAPs for Gq/11 and Gi/oclass G proteins affects cardiovascular function. Blood pressure and heart rate were monitored in conscious, freely moving mice via radiotelemetry. Surgical implantation of the radiotelemetry device induced marked systolic blood pressure increase in Rgs2/5 dbKO mice (WT: 140 ± 6 vs. dbKO: 170 ± 2 mmHg; p<0.01) at baseline, which gradually declined but remained elevated in Rgs2/5 dbKO relative to wild type (WT) mice, several days later. Whereas all WT mice survived the surgery, ~70–80% of male Rgs2/5 dbKO mice surprisingly died 72–96 hr post‐surgery. When subjected to cardiac stress test using acute dobutamine infusion and echocardiography or the invasive pressure‐volume loop analysis of cardiac function, male Rgs2/5 dbKO mice showed hypocontractile response and decreased ejection fraction relative to WT mice. Freshly isolated ventricular cardiomyocytes from male Rgs2/5 dbKO mice showed decreased fractional shortening (WT: 16.1 ± 4.3 vs. dbKO: 7.4 ± 1.1 %; p<0.01) but high calcium transients (WT: 117 ± 20 vs. dbKO: 198 ± 50 au; p=0.07) at baseline, and application of electrical field stimulation or low concentration of the non‐selective β‐adrenergic receptor agonist, isoproterenol (ISO), triggered premature calcium transients, tachyarrhythmia and death of cells from Rgs2/5 dbKO mice. Interestingly, cells from mice harboring just one copy of Rgs2 (Rgs2+/−, Rgs5−/−) but not Rgs5 (Rgs2−/−, Rgs5+/−) were resistant to low‐dose ISO‐induced arrhythmia. These results together suggest that RGS2 and 5 coordinate their activity to control cardiomyocyte excitation‐contraction coupling and normal cardiac rhythm.Support or Funding InformationNIH – NHLBI (1R01 HL139754‐01) and AHA Scientist Development Grant (16SDG27260276)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Structure Activity Relationship Optimization of a 1,3‐Disubstituted Urea‐based Inhibitor of Zika Virus Infection
Authors: Khachatoorian Ronik , Buzzanco Anthony S , Ruchala Piotr , Micewicz Ewa , French Samuel W 
Published: June 2021

Zika Virus (ZIKV), a member of the Flaviviridae family of viruses, has recently led to major epidemics in South American countries and has been reported in several other countries as well. ZIKV is the cause of microcephaly and other developmental neuroimmunopathologies in fetuses of pregnant women and Guillain‐Barre Syndrome in adults, and to date, no therapeutics or vaccines are approved for ZIKV infection. In this study, we conducted rigorous structure activity relationship (SAR) studies on one of the three classes of compounds that we previously reported to display significant anti‐ZIKV activity in vitro. We synthesized and tested 50 derivatives of the parental compound (ASN07115927), a 1,3‐Disubstituted Urea‐based thiadiazole. We were able to identify a few derivatives with improved antiviral activity as well as structural features that will guide further SAR studies. Most notably, we found that the urea moiety at the center of the molecule is essential as all but one of the thiourea substituents were completely or significantly inactive. Presence of chlorine on the aromatic ring demonstrated the highest activity compared to its bromo‐, and iodo‐ counterparts. Furthermore, we tested derivatives with allylthio‐, allylamino‐, and propargylthio‐ moieties on the thiadiazole ring and found that the allylthio‐derivatives had higher activity overall. In addition, the location of the allylthio‐ moiety on the ring as well as the orientation of the thiadiazole ring affected the antiviral activity. These results identify compounds with improved antiviral activity which may be utilized/further optimized for the development of inexpensive and orally available anti‐ZIKV drugs. These compounds may also be beneficial for treatment of other viruses in the same family including Dengue virus.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
New strategy of drug repositioning through anti‐fibrosis characteristic
Authors: Li Xiaoyi , Wu Dingfeng , Yang Zihuan , Jiao Na , Yuan Meifei , Zhu Lixin , Zhu Ruixin 
Published: June 2021

BackgroundFibrosis is a common pathogenesis in most diseases, thus different diseases may share targets and drugs related to fibrosis. For a drug that targets fibrotic process, it is likely an effective drug for treating diseases other than its original purpose. Therefore, the current study aimed to investigate the anti‐fibrosis characteristic of drugs for repositioning purpose.MethodAnti‐fibrosis compounds identified from PubMed and ClinicalTrials.gov were selected as positive samples. FDA‐approved drugs from DrugBank and compounds from Connectivity Map (CMap) were selected as potential negative samples after excluding those compounds known as anti‐fibrosis drugs. MACCS Keys fingerprint (RDKit) and molecule‐stimulated gene signatures (CMap) are collected as the structural descriptors and transcriptomic profiles of compounds respectively. OneClassSVM was used to remove outliers. Gradient Boosting Classifier was performed to build a Structural Model based on molecular structures and to build a Gene Model based on gene signatures to predict the anti‐fibrosis potentials of the compounds. Three external molecular sets: TCMID, ChEMBL and experimental drugs from DrugBank were used for model testing.Result526 positive samples and 1248 negative samples were used to build the Structural Model that could predict the anti‐fibrosis potential of candidate compounds with an AUC value of 0.79. With the three molecule sets (TCMID, ChEMBL and DrugBank), 76.76%, 21.92% and 30.02% of the molecules, respectively, were identified as anti‐fibrosis molecules based on this Structural Model. As expected, most traditional chinese medicines with long history of clinical applications possess greater anti‐fibrosis potential that is consistent with their multi‐targeting effects. Among these candidates, 1‐peroxyferolide, peroxyparthenolide and formic acid are ranked to have higher success rates in drug repositioning. Similarly, the Gene Model was build with 851 positive samples and 1588 negative samples with an AUC value of 0.84. RPL30, PPIA and KLHL24 are identified as the preferred targets of drugs with anti‐fibrosis potential.ConclusionWe first implemented a new strategy of drug repositioning through anti‐fibrosis characteristic, which may increase the success rate of novel applications of existing drugs. In addition traditional chinese medicines were found to have the highest anti‐fibrosis potentials and were considered the first choice in drugs repositioning for further studies.Support or Funding InformationThis work was supported by National Natural Science Foundation of China 81770571 (to LZ), 81774152(to RZ), 41530105 (to RZ).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Nephroprotective properties of the methanol stem extract of Abrus precatorius on gentamicin‐induced renal damage through suppression of NF‐κB/CRP and enhancement of Bcl‐2 signaling pathways
Authors: Falayi Olufunke Olubunmi , Oyagbemi Ademola Adetokunbo , Omobowale Temidayo Olutayo , Ayodele Emmanuel , Adedapo Aduragbenro , Yakubu Momoh Audu , Adedapo Adeolu Alex 
Published: June 2021

The nephroprotective properties of methanol stem bark extract of Abrus precatorius against gentamicin‐induced renal damage in rats was evaluated in this study. Thirty (30) male Wistar rats were divided into five equal groups. Group A was the negative control group while B was the positive control group which received gentamicin 100 mg/kg intra‐peritoneally for six days. Group C were pretreated with 100 mg/kg extract for the three days and then concurrently with gentamicin 100 mg/kg for three days and group D were pretreated with 200 mg/kg extract for three days and then concurrently with gentamicin 100mg/kg for three days. Group E received gentamicin intraperitoneally for six days followed by administration of 200 mg/kg of the extract for 3 days. Blood samples, kidneys and kidney homogenates were collected for haematological, biochemical, histopathological and immunohistochemical analysis. The results showed that no significant haematological changes were noted. The groups treated with extract exhibited significant increase in body weight gain. While group B significantly exhibited focal areas of inflammation, fatty degeneration, congestion of vessels, tubular necrosis and glomerular atrophy, the lesions were mild with the treated groups. Treated groups exhibited a dose dependent significant decrease in serum creatinine, urea, XO, NO and Myeloperoxidase, AOPP, Protein carbonyl, H2O2, MDA levels when compared with gentamicin treatment group. There were significant dose dependent improvements in SOD, GST, GSH, Protein thiol, and non‐protein thiol levels in the treated groups when compared with group B. In immunohistochemistry, gentamicin treatment group exhibited over expression of CRP and NF‐κB levels, and marked reduction in expression of Bcl‐2 while the reverse was seen in the groups treated with methanol extracts of Abrus precatorius.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glomerular Mesangial Proliferation is Mitigated by sEH/COX‐2 Dual‐Inhibition
Authors: Barnett Scott D , Khan Abdul Hye , Chesnik Marla Ann , Yeboah Michael , Imig John D 
Published: June 2021

Chronic kidney disease afflicts millions across the globe, with focal segmental glomerulosclerosis (FSGS) being the most prevalent type of renal disorder. FSGS can result in irreparable damage to the kidney, and even death, if untreated. The kidney filters blood via a network of highly vascularized modules called glomeruli, of which each kidney has approximately one million, and those afflicted with FSGS exhibit damage to these filters. Intraglomerular capillaries are supported by a matrix of cells called the mesangium, and it believed that signals triggering mesangial hypertrophy and proliferation may exacerbate damage to the glomerulus in those with FSGS. Epoxyeicosatrienoic acids (EETs) are positive mediators of renal health and function. Conversely, some EET metabolites are intimated to stimulate mesangial proliferation, which is known to damage the glomerulus. EETs are most notably metabolized by soluble epoxide hydrolase (sEH), but they can also be modified by other enzymes such as cyclooxygenase‐2 (COX‐2), and we have developed a novel drug, PTUPB, that serves as a dual sEH/COX‐2 inhibitor. The objective of this research is to determine if either our non‐hydrolyzable 8,9‐EET analog, or PTUPB, reduces angiotensin II‐associated mesangial proliferation by decreasing the formation of potentially deleterious EET metabolites. Our long term goal is to mitigate the damage caused by FSGS through a better understanding of the role of EETs and their metabolites in glomerular function.Methodshuman primary mesangial cells (p4‐p8) were stimulated in serum‐free media with 100nM angiotensin II (+/−) 100nm or 300nM PTUPB, or 100nM angiotensin II (+/−) 300nM or 1000nM 8,9‐EET analog, for 72‐hours, at which point cells were counted and compared to the control values.ResultsThe administration of 300nM PTUPB or 1000nM 8,9‐EET analog decreased angiotensin II‐mediated mesangial proliferation by 56.01% ± 2.5 (p = 0.0172) and 55.25% ± 5.1 (p = 0.0138), respectively, as compared to the relative increase in proliferation caused by 100nM angiotensin II alone.ConclusionThe mesangium is an important structural component of the glomerulus, but it also serves as a more nuanced mediator or communication in the glomerulus as it directly interfaces with the endothelium and epithelial podocytes. Mesangial proliferation is a known destructive force in FSGS and we have identified two drugs that mitigate the proliferative phenotype in human mesangial cells.Support or Funding InformationR01 DK103616‐01 (John D. Imig). Dr. Ralph and Marian Falk Medical Research Trust ‐ Phase II (John D. Imig).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ferulic Acid, A Component of Angelica Tenuissima Root Extract Induces Anti‐Melanogenic and Anti‐Oxidative Effects
Authors: Koo Hyun Jung , Park Yuna , So Gyeongseop , Kim Sung Hyeok , Ha Chang Woo , Lee Sang Eun , Namkoong Seung , Kim Tae‐Hyung , Sohn Eun‐Hwa 
Published: June 2021

Angelica tenuissima Nakai (Umbelliferae) has been used as a traditional medicine in Asia. The present study investigated the anti‐oxidative and anti‐melanogenic effects of ferulic acid (FA) derived from A. tenuissima root extract (ATE). Anti‐melanogenic activity was determined by intracellular melanin content and tyrosinase activity in α‐MSH (melanin stimulating hormone)‐stimulated B16F10 cells. The anti‐oxidative property of FA was measured using the 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) and 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) scavenging free radical activity assays. FA significantly suppressed the production of melanin and the tyrosinase activity in α‐MSH‐induced cells. FA also showed the significant tyrosinase inhibitory activity and the DPPH/ABTS radical scavenging activities under cell‐free conditions. These results suggest that FA is responsible for the whitening effect of ATE and could be used as an ingredient in cosmeceutical skincare products.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluation of the Toxicity Profile and Analgesic Property of Ethanol Extract of Lophira alata Stem Bark in Rodents
Authors: Iniaghe Loretta Oghenekome , Okpakpor Elohor Emma , Kaluaso Smart Chukwudi 
Published: June 2021

IntroductionLophira alata a woody tree found in West Africa is used in the management of pain, schizophrenia and convulsion. This study was carried out to evaluate the toxicity profile and analgesic activity of the of ethanol extract of Lophira alata in rats and mice respectively.MethodsStem bark of Lophira alata obtained were identified, authenticated, dried and reduced to fine powder. Phytochemical screening and determination of the mean lethal dose were carried out. Rats (n=30) in different groups were treated with 100–800 kg/mg of the extract daily for 28 days and monitored for weight loss and signs of toxicity. These animals where sacrificed at the end of the study and visceral organs isolated for histo‐pathological, biochemical and hematological assays.Analgesic property was evaluated in mice treated with graded doses (50–800 mg/kg) of the Lophira alata and subjected to either the mouse writhing assay or hot plate test. The tail flick test was used to determine analgesic activity in rats.ResultsThe mean lethal dose was determined to be 5000 mg/kg. No significant difference was observed between weights of animals treated with Lophira alata and the control groups. There was also no significant difference in organ weight ratios between treated and untreated animals. In the hematological assays, there was a decrease in erythrocytes with 800 mg/kg dose levels while a reduction in low density cholesterol was observed in the treated animals. In the mouse writhing test, treatment with Lophira alata decreased number of writhes but did not significantly affect the latency time in the tail flick test.ConclusionLophira alata is relatively safe for use and reduces algesia possibly via peripherally mediated mechanisms.Support or Funding InformationNo honorarium receivedThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.