bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impacts of UT‐A2 inhibition on urine composition: a mathematical model (1137.8)
Authors: Moss Rob , Layton Anita 
Published: June 2021

The urea transporter UT‐A2 is expressed in the inner‐stripe segments of the thin descending limb of Henle in superficial nephrons (SDL), and in the initial inner medullary (IM) segments of the descending limb in juxtamedullary nephrons. It was previously assumed that some of the urea ascending from the IM in the ascending vasa recta was “recycled” in the SDL, which run in close proximity to the vascular bundles in rats and mice. However our model simulations suggest that when urea is actively secreted into the pars recta, a hypothetical scenario has yet to be demonstrated experimentally, there is net urea reabsorption along the SDL. We use a dynamic model of the urine concentrating mechanism to investigate the hypothesis that the role of the SDL UT‐A2 lies in the transient buildup of urea and osmolality gradient of the IM, rather than in the maintenance of the steady‐state gradients. This motivation for this hypothesis is that the transit time for urea reabsorbed in the SDL to return to the IM via the descending vasa recta is significantly shorter than for urea to traverse the thick ascending limb and subsequently be reabsorbed in the terminal collecting duct. Also, during the generation of the IM urea gradient, active urea secretion into the pars recta of the long loops may yield a transepithelial gradient favorable for urea delivery by the long thin descending limbs into the interstitium, thereby adding to the urea delivered to the IM interstitium through the terminal collecting duct. This research was supported in part by NIH grant DK‐89066.Grant Funding Source: NIH DK089066
DNA methylation in genes related with cartilage, obesity, and thrombosis in LCPD patients (1138.7)
Authors: Lee Gyuhwi , Park Kwang‐Won , Jo Inho , Song Hae‐Ryong , Park Yoon Jung 
Published: June 2021

LCPD (Legg‐Calve‐Perthes disease) is a kind of osteonecrosis of the hip found only in children. It has been associated with few genetic mutations and rather with obesity and thrombosis. This study was designed to investigate whether epigenetic alteration might be related with its etiology. We analyzed DNA methylation in genes commonly involving cartilage, obesity, and thrombosis in blood from patients and healthy donors (HD) using the quantitative MassArray analysis. Total 6 amplicons covering the promoters of Col2A1, FII, FV, and FVIII genes were measured for DNA methylation. All genes, except FVIII, showed no difference between LCPD and HD. Also, the difference in FVIII was significant, but was only about 1%, which might not result in any changes physiologically.Therefore, the results suggested that the genes might be disturbed in the pathogenesis of LCPD, at least not by epigenetic alterations, although this study was, to our knowledge, the first trial to investigate the involvement of epigenetic alterations in LCPD.Grant Funding Source: supported by Korean NRF (22A20130012143) & Korean HealthTech R&D(HI11C0388)
Oral cavity morphometric evaluation in 7,12 dimethylantracene administration (1139.11)
Authors: Cabeças José Ricardo , Costa Eduardo , Alves Gonçalo , Jesus Patrícia , Cabrita António 
Published: June 2021

Many injuries which occur in human body is mainly caused by the action of xenobiotics present in the environment and coming into contact with the body.舲 The xenobiotics they induce a good morphological identifiable damage, also cause functional alterations of varying severity. The action of xenobiotics on the body depends on many factors among which we highlight: the chemical nature of the molecule, its concentration in the environment, the repeated contact, the gate of entry and the physiological activity of the organism. DMBA is a toxic present in the contaminated environment, in some foods and also in tobacco smoke 7. The aim of this work is to evaluate the influence of DMBA in morphological changes of the periodontal ligament.舲 In this study was used 20 male Wistar rats with eight weeks old at the beginning of the study. The rats were distributed into two groups of 10 animals each. Group I, the control group, was maintained for 8 weeks without any inducing manipulation changes. Group II was subjected to the administration of 7,12‐dimethyl‐benzanthracene (DMBA) three times a week, for 4 weeks at a dose of 20 mg / kg in each takes.舲 At the end of the administration's, the animals were sacrificed and their necropsy was made.In group I, the value of R1 was 0.07 ± 0.07 and R2 was 0.79 ± 0.25, not checking the presence of DMBA in adipocytes. The distribution of R2 values in this group was as follows: 15.38% small, 69.23% medium,10.99% large and 3.30% very large.In group II, the value of R1 was 0.07 ± 0.04 and R2 was 0.84 ± 0.35. The distribution of R2 values in this group was as follows: 15.07% small, 63.01% medium, 8.22% large and 12.33% very large. The animals in this group was detected the presence of DMBA in adipose tissue at all.DMBA in the studied conditions does not significantly interfere with the periodontal ligament in morphological terms.
Expression of cytochrome P450 genes in human cord blood hematopoietic stem and progenitor cells (1139.7)
Authors: Xu Shuoqi , Ding Xinxin , Jiang Yongping , Wang Yanan , Ren Zhihua 
Published: June 2021

The human cytochrome P450 (CYP) superfamily comprises 57 genes, which encode enzymes important in the biotransformation of numerous endogenous and exogenous compounds. The aim of this study is to characterize the expression of all CYP genes in CD34(+) human cord blood hematopoietic stem and early progenitor cells (CBHSPCs), as a first step toward assessment of their biological functions in these cells. CD34(+) CBHSPCs were purified from umbilical cord blood via antibody affinity chromatography, using magnetically‐assisted chemical separation. Purity of CD34(+) cells was assessed using fluorescence‐activated cell sorting. RNA was isolated from purified CD34(+) cells for RNA‐PCR analysis, using primers specific for each of the 57 CYPs. Of the 57 CYPs, only 14 were detected by RNA‐PCR in CD34(+) CBHSPCs, including CYP2E1, CYP2U1, CYP2R1, CYP2S1, CYP2J2, CYP4F2, CYP20A1, and CYP27A1. CYP identification was confirmed by sequencing analysis of the detected, mRNA‐derived, PCR products. Preliminary quantitative analysis of CYP transcripts using real‐time RNA revealed preferential expression of multiple CYPs, such as CYP2R1, in CD34(+) CBHSPCs, compared to total lymphocytes or CD34(‐) cells from the cord blood. Additional studies on detection of CYP protein expression are underway.Grant Funding Source: Supported by State Scientific Key Projects for New Drug Research and Development(2011ZX09102‐010‐04)
Identification of orphan receptor GPR88, GPR99, GPR107 and GPR124 in Wistar Kyoto and spontaneous hypertensive rats (1140.13)
Authors: Calderon‐Zamora Loranda , Leon‐Sicairos Nidia , Canizalez‐Roman Adrian , Hong Enrique , Villafaña Santiago 
Published: June 2021

Hypertension is a chronic disease characterized by a continuous increase of blood pressure, this is one of the most important cardiovascular diseases although there are many treatments, hypertension has been associated with 9.4 million deaths per years, therefore is necessary to study new mechanisms that could contribute to explain the hypertension. Recently, a new class of receptor has been reported that are called orphan receptors because the ligand is not known, these receptors have been associated with some pathologies. For that reason, the aim of this work is to study the distribution of orphan receptors GPR88, GPR99, GPR107 and GPR124 in kidney, heart and brain in wistar kyoto (WKY) and spontaneously hypertensive rats (SHR). We used WKY and SHR male rats with 10‐12 weeks old and we measured weight, blood pressure, cardiac frequency and mRNA from kidney, heart and brain by RT‐PCR. The results obtained showed that SHR presents higher values of systolic blood pressure compared than WKY, and that the levels of orphan receptors GPR88, GPR99, GPR107 and GPR124 are expressed in both strains. In conclusion, this study suggests that GPR88, GPR99, GPR107 and GPR124 are expressed in both strain and could be associated in the hypertension process.Grant Funding Source: SIP‐20130041/COFAA
Modulation of the cannabinoid‐1 receptor by angiotensin II in astrocytes isolated from spontaneously hypertensive rats (1140.8)
Authors: Haspula Dhanush , Clark Michelle 
Published: June 2021

Objective: To determine whether a mediator of neuroprotection, the Cannabinoid Type 1 receptor (CB1R), is altered by Angiotensin (Ang) II in astrocytes. Background: Along with an elevated Ang II level, neuroinflammation in the brainstem (BS) has been shown to shift the balance towards an augmented sympathetic drive, the latter being associated with hypertension. Astrocytes play a central role in the bidirectional modulation of inflammation Methods: BS astrocytes isolated from Spontaneously Hypertensive Rats (SHR) were used as a hypertension model to determine whether Ang II induces CB1R protein and mRNA expression. The results were compared to normotensive Wistar rats. The cells were treated with 100nM Ang II in a time‐dependent manner, and the effect of Ang II on CB1R protein and mRNA levels were measured using Western blotting and qt‐PCR techniques, respectively. Results: In Wistar cells, Ang II increased the CB1R protein and mRNA levels in a time‐dependent manner. In SHR astrocytes, Ang II down‐regulated or had no effect on CB1R protein and mRNA levels. Compared with Wistar astrocytes, the CB1R protein and mRNA levels in SHR astrocytes were significantly different. Conclusion: Our findings suggest that the CB1R is differentially regulated in SHR versus normotensive astrocytes. This interaction may serve as a potential target to restore an elevated sympathetic drive in hypertension.Grant Funding Source: NSU PFRDG 2013‐14: Grant # 335309
CYP2C9*8 frequency distribution in Puerto Ricans: implications for warfarin dosing (1141.10)
Authors: Claudio‐Campos Karla , Orengo‐Mercado Carmelo , Berrios Lorena , Pagan Robert , Renta Jessicca , Cadilla Carmen , Duconge Jorge 
Published: June 2021

Warfarin is an oral anticoagulant that requires individual monitoring since serious adverse events are common. CYP2C9 encodes for the enzyme mainly responsible of S‐warfarin’s metabolism. Polymorphisms in CYP2C9 have been previously found to be strongly associated with observed warfarin dose variability in different populations, but not in Caribbean Hispanics. Caribbean Hispanics originated as a result of a complex admixture among Caucasians, Africans and Amerindians ancestors‐a characteristic that should be considered for warfarin management. The rare loss‐of‐function CYP2C9*8 allelic variant is reportedly more prevalent among individuals with African heritage. Since Puerto Ricans has a significant contribution of African ancestry in their genetic backgrounds, this cross‐sectional study was aimed to determine the frequency of CYP2C9*8 in a cohort of 150 Puerto Rican patients undergoing warfarin therapy. DNA specimens were extracted and genotyped for the CYP2C9*8 using a PCR‐based Taqman genotyping assay. We found 3 heterozygous for the CYP2C9*8 variant in our study cohort, corresponding to a minor allele frequency of 1% (95%CI: 0.0026‐0.031). The observed frequency met Hardy‐Weinberg equilibrium. Allele frequency in our cohort was found to be significantly lower than that from a previous report in African‐Americans (0.01 versus 0.047, respectively, p=0.045 by two‐tailed z‐test), with a carrier frequency of 1 in 50 (Puerto Ricans) versus 1 in 11 (African‐Americans). Due to the CYP2C9*8 prevalence found among Puerto Ricans, we concluded that this variant should be included in any pharmacogenetic‐guided algorithm for warfarin dose predictions in this population. Approved by University of Puerto Rico, Medical Sciences Campus Institutional Review Board protocol A4070109.Grant Funding Source: Supported by NIH grants# 5SC2HL110393 (NHLBI) and grant# G12RR‐03051 (RCMI‐ NCRR).
A potential role for human UDP‐glucuronosyltransferase 1A4 promoter SNPs in the pharmacogenomics of Tamoxifen and its derivatives (1141.13)
Authors: Dates Centdrika , Greer Aleksandra , Bratton Stacie , Koroth Edavana Vineetha , Kadlubar Susan , Radominska‐Pandya Anna 
Published: June 2021

Tamoxifen (Tam) is a selective estrogen receptor modulator used to inhibit breast tumor growth. Tam can be directly N‐glucuronidated via the tertiary amine group or O‐glucuronidated after cytochromes P450 mediated hydroxylation. In this study, the glucuronidation of Tam and its hydroxylated and/or chlorinated derivatives [4OHTamoxifen (4OHTam), Toremifene (Tor), and 4OHTor] has been studied using recombinant human UGTs from the 1A family and human hepatic microsomes (HLM). Recombinant UGT1A4 was found to catalyze the formation of N‐ glucuronides of Tam and its derivatives and to be the most active UGT isoform toward these compounds. Therefore, it was hypothesized that single nucleotide polymorphisms (SNPs) in the promoter of UGT1A4 have the potential to significantly decrease the glucuronidation rates of Tam metabolites in the human liver. In vitro assays using 64 genotyped HLM were used to determine the association between UGT1A4 promoter and coding region polymorphisms and the glucuronidation rates of Tam, 4OHTam, Tor, and 4OHTor. Significant decreases in enzymatic activity were observed in microsomes for individuals heterozygous for ‐163G<A and ‐217T<G. These alterations in glucuronidation could lead to prolonged circulating half‐lives and potentially modify the effectiveness of these drugs in the treatment of breast cancer.Grant Funding Source: Supported by DoD‐W81XWH1110795 and UAMS TRI (CTSA Grant Award #UL1TR000039) ABCRP funds to AR‐P
Gestational age‐dependent maternal‐fetal glyburide disposition in pregnant mice (1141.5)
Authors: Shuster Diana , Risler Linda , Liang Jason , Rice Kenneth , Shen Danny , Hebert Mary , Thummel Kenneth , Mao Qingcheng 
Published: June 2021

Glyburide (Gly) is routinely used to treat hyperglycemia during pregnancy. Our objective was to determine if maternal‐fetal disposition of Gly and metabolites is dependent on gestational age in pregnant mice because similar studies cannot be done in humans. Following retro‐orbital injection of Gly, maternal plasma and fetuses were collected at 0.5‐240 min after dosing. Pharmacokinetic parameters were determined using a pseudo‐profile based bootstrap approach and compartmental/noncompartmental analyses. Maternal Gly clearance increased 2‐fold on gestation day (gd) 15 and 19 versus gd 0. Gly depletion analysis using mouse liver microsomes confirmed that gestational age‐dependent changes in Gly clearance is caused by increases in hepatic metabolism. Maternal metabolite/Gly area under the curve (AUC) ratios were low throughout gestation (~0.004), indicating an increase in both metabolite formation and clearance. Fetal/maternal Gly AUC ratios doubled from gd 15 to 19 (0.02 to 0.04), which is likely due to decreased expression of placental efflux transporter Bcrp1 on gd 19 versus 15. Our data suggest that clinical dosages of Gly may need to be doubled to treat hyperglycemia in pregnant women compared to nonpregnant women.Grant Funding Source: Supported by the NICHD [U10HD047892], NCATS [TL1 RR025016], and NIH [T32 GM 007750]
Comparison of the prevalence of hypertriglyceridemic‐waist phenotype in university students from two regions of Mexico (1142.2)
Authors: Villalobos‐Molina Rafael , Rodríguez‐Tadeo Alejandra , Wall‐Medrano Abraham , Ramos‐Jiménez Arnulfo , Urquidez‐Romero René , Hernández Rosa Patricia 
Published: June 2021

The prevalence of HW is unknown among Mexican young, although cardiovascular disease (CVD) is an outcome of it. We evaluated the prevalence for HW (hypertriglyceridemic‐waist) phenotype and related factors, in university students from Juarez City and Mexico City. 12,966 students (<25 y) from “Healthy University” Project’s data base (7,687 of Juarez City and 5,279 of Mexico City) were screened for anthropometry and biochemical indicators. The significance of these factors to the HW phenotype was analyzed in groups segmented by university and sex. In both sexes, Mexico City students had higher abdominal obesity, triglycerides, glycemia and HW, but lower systolic blood pressure than Juarez students. In both populations the HW phenotype was associated with higher body weight, BMI, glucose, cholesterol, and blood pressure. Except for women in Juarez City, HW phenotype was associated to greater height. Simultaneous concurrence of hypertriglyceridemia and waist circumference increase risks factors for CVD in young adults from two regions of Mexico. It is necessary to evaluate other aspects to know the differences between these two populations to identify areas of intervention during their college stay.Grant Funding Source: RV‐M is supported by PASPA, DGAPA, UNAM
Refractory wound healing and FoxO1/iNOS pathway in type 1 diabetes (1142.3)
Authors: Tie Lu , Li Xuejun 
Published: June 2021

Aims/hypothesis Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens. The present study was designed to determine the role of FoxO1/iNOS pathway and effect of the soy isoflavone genistein on diabetic wound healing.Methods Streptozotocin (STZ)‐induced type 1 diabetic mice with full‐thickness excisional wounds given intragastrically 1 and 3 mg/kg/day of iNOS selective inhibitor (L‐NIL) or received 0.2, 1 and 5 mg/kg/day of genistein via subcutaneous injection.Results In diabetic wound tissues, the inducible nitric oxide synthase (iNOS) was activated, silent information regulator 1 (SIRT1) and forkhead box O transcription factor 1 (FoxO1) were elevated. Genistein administration prevented increased iNOS activity and attenuated diabetic cutaneous SIRT1 and FoxO1 levels in a dose‐dependent manner. Diabetic conditions significantly increased superoxide anion (O2.‐) production, nitrotyrosine formation, and decreased nitrite levels in wound tissues. L‐NIL and genistein treatments normalized the elevated O2.‐ production, nitrotyrosine formation and reversed the attenuated nitrite level. L‐NIL and genistein dose‐dependently rescued the delay of wound closure in diabetic mice. Five mg/kg/day of genistein treatment significantly increased the mean perfusion rate, and in vitro treatment with genistein protected against high glucose‐induced impairment of capillary tube formation in cultured endothelial cells.Conclusions/interpretation FoxO1/iNOS signaling may contribute to the delayed wound healing in type 1 diabetes. Genistein could rescue the impaired wound healing and improved wound angiogenesis in type 1 diabetic mice, at least in part, by suppression of FoxO1, iNOS activity and oxidative stress.Grant Funding Source: This work was supported by the NSFC and Beijing Higher Education Young Elite Teacher Project
Farnesol suppresses lipid accumulation in a HepaRG‐based model of hepatic steatosis (1142.8)
Authors: Pant Asmita , Kocarek Thomas 
Published: June 2021

Non‐alcoholic fatty liver disease is one the most common metabolic syndromes characterized by accumulation of triglycerides (TG) in liver. Treatment with the endogenous isoprenoid farnesol lowers hepatic TG levels in rodents, and this effect appears to involve at least two nuclear receptors, peroxisome proliferator‐activated receptor α and farnesoid X receptor (FXR). Activation of constitutive androstane receptor (CAR) has also been shown to ameliorate hepatic steatosis in rodents. However, farnesol’s effects on human hepatic lipid metabolism are currently unknown. In this study, we evaluated the effect of farnesol treatment on human hepatic lipid accumulation in a cellular model of hepatic steatosis that was created by incubating the hepatocyte‐like HepaRG cell line with oleic acid. Incubation of differentiated HepaRG cells with oleic acid produced concentration‐ and time‐dependent increases in intracellular lipid droplets labeled with Oil Red O as well as in TG levels. This TG accumulation was suppressed by 32% when the oleate‐loaded HepaRG cells were co‐treated with farnesol. Farnesol treatment also caused concentration‐ and time‐dependent increases in the mRNA levels of small heterodimer partner and CYP2B6 in HepaRG cells, which are the targets of FXR and CAR, respectively. These results suggest that farnesol treatment can decrease fatty acid‐induced hepatic lipid accumulation in HepaRG cells, possibly by activating FXR and/or CAR.Grant Funding Source: Supported by NIH grant HL050710
Compounds in Psoralea corylifolia as human MAOb natural inhibitors (1143.12)
Authors: Zarmouh Najla , Mazzio Elizabeth , Soliman Karam 
Published: June 2021

Treatment for Parkinson’s disease (PD) involves the use of drugs that address the loss of dopaminergic function by restoring neurotransmitter homeostasis. However, the current drugs can be limiting, in that they do not address disease progression. A renewed interest in monoamine oxidase B inhibitors (MAObIs) for PD as independent therapeutics has emerged after recent clinical trials has shown efficacy of deprenyl and rasagiline monotherapy for early disease management. However, conventional MAOIs have food and drug counter‐interactions and side effects which limit its use. Previously, we screened 905 natural ethanol plant extracts on the enzymatic activity of recombinant human MAOb. In this study, we confirm and determine selectivity of MAOb / MAOa. The data show that extracts of Glycyrrhiza uralensis root have an IC50 of 0.04 mg/ml and a 266 fold MAOb/MAOa specificity; Phellodendron Amurense an IC50 of 0.02 mg/ml and a MAOb/MAOa specificity 45.29 fold; Psoralea Corylifolia (PC) an IC50 of 0.08 mg/ml and a 18.34 fold MAOb/MAOa specificity; Ferula Assa‐Foetida an IC50 of 0.24 mg/ml and a 30.23 fold MAOb/MAOa specificity. Further studies for PC active ingredients revealed that bakuchiol content within the plant may contribute to MAOI.Grant Funding Source: Supported by NIMHD G12 MD007582 and P20 MD006738
The neuroprotective effects of fluoxetine on rat hippocampus, after chronic and acute 5‐fluorouracil treatment (1143.6)
Authors: Chambers Annabelle , Maqbool Ayesha , Wigmore Peter 
Published: June 2021

5‐Fluorouracil (5FU) an anti cancer therapy, can cause long term cognitive decline. 5FU reduces cell proliferation in hippocampal neurogenesis which is associated with reduced spatial memory in rodents. Prior antidepressant treatment (Fluoxetine (FLX) prevents the behavioural/cellular effects of 5FU. This quantifies neural stem cell (NSC) number and proliferation after drug treatment.Male rats were treated for 19 days with 10mg/kg/day FLX, via drinking water. Rats received 1 (acute) or 5 (chronic) injections of 35mg/kg 5FU or saline i.p., with or without continued FLX dosing. 1 day or 1 week post treatment, Ki67 (proliferation), Sox 2 (NSC’s) positive cells in the sub granular zone were counted.Acute 5FU causes a significant decline in cell proliferation 1 day later while 1 week animals returned to control levels. Pre‐treatment with FLX prevented the decrease caused by 5FU at one day. Chronic 5FU causes prolonged decline in proliferation, also prevented by FLX. Preliminary results indicate that NSC levels are little affected but their proliferative activity is altered.FLX appears to change the proliferative behaviour of NSC under 5FU treatment. NSC location, number and proliferation are influenced by both compound; use of variations in acute/chronic effects aim to deduce specific mechanisms behind FLX’s neuroprotection.Grant Funding Source: Supported by School of Life Sciences, University of Nottingham, and AstraZeneca UK