bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmadynamic (PD) & pharmacokinetic (PK) properties of AF‐219: first in class, selective, clinical P2X3 antagonist in development for chronic pain and related conditions
Authors: Ford Anthony P , Smith Steven A , Dillon Michael P 
Published: June 2021

P2X3 receptors are ATP‐gated channels with expression somewhat limited to primary afferent populations suspected of chronic sensitization in pain‐related disorders & offering therapeutic potential for antagonists (Ford, 2012, Purinergic Signal. 8:3–26). We describe preclinical PD & PK of AF‐219 (MW 353), a selective P2X3 antagonist optimized from an HTS lead.AF‐219 blocked ATP activation of rat & human P2X3 & P2X2/3 trimers in calcium flux & voltage‐clamp assays: IC50 values 25–200 nM; unlike A‐317491 & TNP‐ATP, allosteric inhibition of ATP was displayed. In homogenate binding studies, AF‐219, but not ATP or TNP‐ATP, displaced specific binding of [3H]AF‐353. At 10 μM no activity was seen at other P2X channels & in a battery of receptors, enzymes & channels.Favorable PK properties were observed for AF‐219 in rat, rabbit, dog & primate: high metabolic stability; oral availability (38–82 %F), elimination half‐life (t½ 1.5–7.6 h) & plasma free‐fraction (55–67% protein‐bound); predominant renal elimination (parent). AF‐219 was dose‐dependently efficacious (1–60 mg/kg, p.o. or s.c.; total plasma range 100–3000 ng/ml) in rodent models of hyperalgesia (neuropathic & inflammatory) or visceral hypersensitivity. The favorable PD, PK, & in vivo activity confirm AF‐219 as an excellent medicinal candidate to establish the role of P2X3 receptors in chronic pain and related conditions.
Delivery of chemotherapeutic paclitaxel by multifunctional nano‐carriers with dual targeting for enhanced anticancer activity
Authors: Dodwadkar Namita Sudhir , Biswas Swati , Torchilin Vladimir 
Published: June 2021

ObjectiveIn our previous studies, we demonstrated efficient mitochondrial targeting of nanocarriers by surface modification with triphenylphosphonium (TPP). Our current objective was to develop a dual functionality nanocarrier with transferrin (Tf) for tumor targeting and TPP for mitochondrial targeting.MethodsLiposomes were prepared using Tf‐PEG‐PE and TPP‐PEG‐PE or PEG‐PE (8 mole %) for TPP‐PEG‐PE modified liposomes (TPP‐L and Dual‐L) or simply PEG‐PE liposomes (PL). Human cervical carcinoma (HeLa), human ovarian carcinoma (A2780) and normal mouse fibroblasts (NIH3T3) were used for cellular studies. Paclitaxel (PTX) was loaded into 150–200 nm liposomes for cytotoxicity analysis.ResultsYellow color indicated significant co‐localization of rhodamine labeled TPP‐L and mitotracker green in mitochondria.ConclusionsTPP‐L were mitochondriotropic. Dual‐L have higher cancer cell‐specific interactions that lead to higher anti‐tumor cell efficacy. This newly developed system suggests a promising treatment strategy for eradication of cancers.*Supported by NIH grants RO1 CA121838 and RO1 CA128486 to V.P.T.
Neural signature of cerebral activity of the fetal cholinergic anti‐inflammatory pathway derived from heart rate variability
Authors: Durosier Lucien Daniel , Xu Alex , Matushewski Brad , Cao Mingju , Herry Christophe , Batkin Izmail , Seely Andrew J.E. , Ross Michael G , Richardson Bryan S , Frasch Martin G 
Published: June 2021

Fetal cholinergic anti‐inflammatory pathway (CAP) activity parallels changes in fetal heart rate variability (fHRV) in response to acidemia or inflammation. We hypothesized that 1) a multi‐domain fHRV measures approach will detect CAP activation early and 2) the degree of CAP activation will reflect the level of cerebral inflammation independent of the type of stimulus ‐ spontaneous hypoxia (n=5, arterial O2sat<50%), LPS (n=6) or control (n=9).Chronically‐instrumented near term fetal sheep underwent increasingly intense umbilical cord occlusions until fetal pH<7.00 (~3–4 h). FHRV measures Skewness, Assymetry Index (AsymI), RMSSD, Sample Entropy (SampEn) and Fuzzy Entropy (FuzEn) were calculated continuously using the automated and standardized Continuous Individualized Multiorgan Variability Analysis, and correlated to microglia (MG) counts in specific brain regions. RMSSD and FuzEn increased and SampEn decreased early. Measures of fHRV symmetry did not change with worsening acidemia but correlated to MG counts, with CA1 MG counts correlating only to AsymI. SampEn correlated most often to MG counts in all regions except the DG, which correlated to FuzEn, Skewness and RMSSD. The spatiotemporal pattern of correlation to fHRV measures of different property domains provides a neural signature of cerebral CAP activity.Funding: Women's Development Council, FRSQ, CIHR, MITACS/NeuroDevNet
Effects of Age and Exercise on Fiber Type and Total Fiber Number in Skeletal Muscle
Authors: Hoffman Marie , Akins Tiffany , Barton Gregory , McKiernan Susan , Aiken Judd , Diffee Gary 
Published: June 2021

There have been varied reports of the effects of age and exercise on fiber type composition in skeletal muscle. To elucidate these discrepancies, we conducted a one year endurance exercise study in male FBN rats, starting with rats age 24 mo and continuing daily until age 36 mo. Rats were divided into 3 groups; high intensity (H), and moderate intensity (M) treadmill exercise, and sedentary (S). M and H animals trained at 13 m/min for 30 min/day, with the H group at 5% incline. At the end of the training protocol the plantaris muscle was removed, frozen and sectioned. Fiber type was determined by IHC using an anti‐type I MHC antibody (BA‐D5s). Total fiber number and number of type I v. type II fibers were determined from high resolution images of muscle cross sections. Total plantaris fiber number declined with age (decrease of 34% in 36 mo compared to 24 mo) but fiber number was not significantly different between the 36 mo exercise groups and the sedentary animals. The proportion of fibers that were type I fibers was 15% in 24 mo, and then 18%, 20% and 18% in S, M, and H respectively. None of these percentages were significantly different from one another, indicating no shift in fiber type with either aging or exercise. These results indicate that total fiber number decreases with age, but this fiber loss may not be preferential to specific fiber types, and also suggest that exercise is unable to minimize fiber loss.Supported by: NIH AG030423
Movement guided learning© as a novel means of musculoskeletal anatomy instruction
Authors: Bentley Danielle Christine 
Published: June 2021

Our bodies can be physically stretched, palpated, and manipulated. These movement opportunities can be used in anatomical instruction, essentially turning a student's body into their own educational tool. This research details the initial development and use of a novel teaching approach, Movement Guided Learning© (MGL). Following prior instruction on both the skeletal system and the muscular system, students participated in a tutorial‐styled learning activity that relied on the MGL teaching approach. The learning activity was exploratory, guiding students through physical movements/stretches, directing students through surface palpation/visualization, and challenging students to collectively brainstorm on the application concepts. Musculoskeletal anatomy knowledge was assessed before and after the MGL activity, with improvements on open‐ended concept questions (t(9) = −3.65, p=.005). The MGL activity was well received by students, with all students indicating they believe it should be used in future classes. MGL as a means of musculoskeletal anatomy instruction provides an opportunity for students to independently construct deeper, more integrated, concept understanding.Grant Funding Source: none
The role of BCL11 transcription factors in mouse craniofacial suture development
Authors: Kyrylkova Kateryna , Iwaniec Urszula T. , Leid Mark 
Published: June 2021

Craniofacial sutures are the fibrous joints that unite the bones of the skull and are the major sites of bone growth during craniofacial development. These joints normally close postnatally, allowing the brain and the skull to reach the proper size and shape. The premature fusion of one or more sutures leads to a condition called craniosynostosis, which represents a congenital defect affecting approximately one in 2000 live births. Craniosynostosis results in craniofacial morphologic abnormalities and increased intracranial pressure, which can lead to severe neurological and cognitive deficits in children. Surgery, with its inherent risks, remains the only therapeutic modality. Therefore, it is important to understand the molecular mechanisms underlying craniosynostosis in order to develop targeted biologically‐based treatment.The transcription factors BCL11A and BCL11B play essential roles in the development of immune, central nervous, and cutaneous systems. We show that ablation of BCL11 transcription factors in mice leads to craniosynostosis, which results in severe midfacial hypoplasia and malocclusion. We conclude that BCL11A and BCL11B are essential for normal development of craniofacial bones and restrict premature suture fusion. The results suggest the possibility of modulation of BCL11 expression for the treatment of craniosynostosis.Grant Funding Source: DE021879 from NIDCR to ML
Pharmacological evaluation of a new series of benzofuran‐2‐ carboxamides as antihyperlipidemic agents in rats
Authors: Al‐Qirim Tariq Musbah , Shattat Ghassan , Sweidan Kamal , Sheikha Ghassan Abu 
Published: June 2021

The aim of this study is to investigate the pharmacological activity of a new series of benzofuran‐2‐carboxamides (3a‐3d and 4a′‐4c′). Compounds (3a, 3b, and 4a′—4c′) were tested in vivo using Triton‐WR‐1339‐induced hyperlipidemic rats as an experimental model. The tested animals were divided into eight groups: control, hyperlipidemic, compounds 3a, 3b, 4a′, 4b′, 4c′, and beza□brate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were signi□cantly reduced in compounds 3b (p<0.0001) and 4c′ (p <0.05) after 12 and 24 h compared to the normal control group. Furthermore, high‐density lipoprotein‐cholesterol levels were remarkably increased in compounds 3b (p<0.001) and 4c′ (p <0.05). Meanwhile, compound 4b′ slightly reduced the TG levels after 12 and 24 h. The present study demonstrated new properties of the novel series benzofuran‐2‐carboxamides 3b and 4c′ as potent lipid‐lowering agents. It is, therefore, reasonable to assume that compounds 3b and 4c′ may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.This research is financially supported by Al‐Zaytoonah University of Jordan
The Impact of Nutrition Education on Food Security Status and Food‐Related Behaviors
Authors: Farrell Jamie Allison , Cordeiro Lorraine , Qian Jing , Anliker Jean , Peterman Jerusha 
Published: June 2021

Low‐income households are at risk of food insecurity and altered food related behaviors. This study examined the relationship between food security status and specific food purchasing practices. Participants in the Massachusetts Expanded Food and Nutrition Education Program (EFNEP) completed a pre‐curriculum survey. Household food security was assessed by the USDA 6‐item food security module. We asked additional questions about how often participants could afford healthy foods, fruits and vegetables, and the same foods throughout the month. In the pre‐EFNEP survey, 41% (n=58) were food insecure and 66% (n=38) had marginal/low/very low food security. Overall, 22% (n=13) that could always or often afford healthy foods, 26% (n=15) that could always or often afford fruit and vegetables, and 24% (n=14) that could always or often afford the same foods all month experienced low/very low/marginal food security. Those with marginal/low/very low food security were less likely than fully food secure to report they could always afford healthy foods, fruits and vegetables, and the same foods all month. Food purchasing behaviors can be affected by the strain of limited resources. Nutrition education can provide skills and knowledge to low‐income, food insecure populations so they may better manage resources to afford foods they need throughout the month.UMass Amherst Office of Faculty Development
Pediatric patients with Prader‐Willi syndrome have lower muscle mass than those with exogenous obesity
Authors: Buraso Chutdanaiphakorn , Wattanasirichaigoon Duangrurdee , Sae‐Chew Pattarana , Phoonlapdacha Phanphen , Dumrongwongsiri Oraporn , Sangcakul Areeporn , Suthutvoravut Umaporn , Chongviriyaphan Nalinee 
Published: June 2021

Patients with Prader‐Willi syndrome (PWS) have morbid obesity and short stature. We conducted this cross‐sectional study to determine body composition in pediatric patients with PWS.We enrolled 3 groups of children aged 2–15 years: 12 diagnosed with PWS, 18 with exogenous obesity, and 18 healthy with normal weight for height as controls. Body composition was determined using bioelectrical impedance analysis (BIA).We found that the PWS group had significantly higher ratio of fat mass to fat‐free mass than the exogenous obesity group and normal controls (1.1, 0.6, and 0.2, respectively; p = 0.001 and less than 0.001, respectively). The median percentage of muscle mass in the PWS group was significantly lower than that in the exogenous group (47 vs. 58%; p = 0.003) and that in the normal control group (47 vs. 80%; p < 0.001).In conclusion, pediatric patients with PWS had higher fat mass and lower muscle mass than those with exogenous obesity. The intervention for this group of patients should include not only controlling weight but also increasing muscle mass.This study was funded by the Nutrition Association of Thailand (Nestle Nutrition Institute Research Award).
Enteric Glial Cells Activate Colon Cancer Stem Cells to Promote Tumorigenesis
Authors: Valès Simon , Biraud Mandy , Marionneau‐Lambot Séverine , Oullier Thibauld , Neunlist Michel , Van Landeghem Laurianne 
Published: June 2021

Colon cancer stem cells (CSCs) are regulated by their cellular microenvironment that delivers paracrine signals crucial to CSC maintenance and tumor growth. Among CSC neighboring cells are enteric glial cells (EGCs) that are potent regulators of intestinal epithelium functions, but whose impact on CSCs has never been studied. We hypothesized that EGCs modulate CSC functions and associated tumorigenesis.In vitro. CSCs were FACS‐isolated from HT29 colon cancer epithelial cells (CD44High/CD133High) and 3D cultured in Matrigel in presence of EGCs seeded on Transwell filters. Impact of EGCs was assessed on numbers and size of tumorspheres grown from CSCs and compared to known EGC‐derived soluble factors. In vivo. CSCs were injected alone vs. concomitantly with EGCs subcutaneously in immunodeficient mice.In vitro EGCs increased numbers and size of tumorspheres grown from CSCs. In vivo concomitant injection of CSCs and EGCs increased tumor load vs. CSCs alone. In vitro EGC‐conditioned medium (CM) did not impact CSCs, but CM of EGCs that had been pre‐incubated with HT29 cells increased tumorsphere numbers, indicating that tumor cells activate EGCs to acquire pro‐tumorigenic abilities. Among all known glial factors tested, only prostaglandin E2 (PGE2) reproduced EGC effects on CSCs. HT29 cells increased expression of mPGES‐1 (enzyme generating PGE2) and PGE2 release in EGCs. CAY10526 (mPGES‐1 inhibitor) abolished pro‐tumorigenic properties induced by HT29 cells in EGCs.These results suggest that tumor cells activate EGCs to acquire pro‐tumorigenic abilities, and that tumor‐activated EGCs stimulate CSC tumorigenicity via PGE2‐dependent pathways.
Enteral Obestatin and Ghrelin Influences on Intestinal Contractility in Piglets ‐ in vitro Studies
Authors: Woliński Jarosław , Słupecka Monika , Ochniewicz Piotr 
Published: June 2021

Ghrelin and Obestatin are peptides encoded by the same ghrelin gene. Substantial amount of both peptides has been found in colostrum and milk. We have investigated the intestinal contractility of suckling piglets (7 days old, n = 10) fed every 75minutes by artificial sow system in laboratory condition enterally treated (3 x per day) with obestatin (10μg/kg b.wt. O), ghrelin (10μg/kg b.wt. G) or saline (C), (n=6 for each group), for 7 days. Duodenal and middle jejunum whole‐thickness preparations from piglets (21days old) were studied in an organ bath, for isometric recording under treatment with acetylocholine (ACh), atropine and tetradotoxin (TTX). The electrical field stimulation (EFS) was performed (90 V, duration 10 sec) at three frequencies: 0.5, 5 and 50Hz with 1 min intervals. Significant decrease in amplitude was observed after treatment with both peptides for EFS–stimulated as well as spontaneous contractile activity in duodenum. No changes were observed in jejunum. In obestatin and ghrelin treated animals injection of atropine did not result in a significant decrease of amplitude of spontaneous contractility of both intestinal segments. In all experimental groups the amplitude of EFS – stimulated and spontaneous contractility was sensitive to treatment with TTX. Our results indicate the importance of peripheral obestatin and ghrelin as regulators of intestinal contractility in piglets during early postnatal period.Project of Polish National Science Centre 2012/05/B/NZ9/00901
GAL‐160 Preferentially Increases Respiratory Motor Drive to the Tongue over the Diaphragm during Unobstructed Breathing and Standardized Obstructive Apneas (OA) in Rats
Authors: Baby S , Mardirosian S , Schemm C , Peng S , Golder F , MacIntyre E 
Published: June 2021

GAL‐160, a carotid body (CB) stimulant, decreases spontaneous OA frequency and OA duration in a rodent model of OSA. Mechanistically, we propose that the effect of GAL‐160 on OA frequency is due to increased upper airway respiratory muscle (RMUA) activity during eupnea, and the effect of GAL‐160 on OA duration is due to an increased response of RMUA to obstruction. We evaluated the effects of GAL‐160 on eupneic respiratory drive to the RMUA by recording hypoglossal (HN) and phrenic (PN) neurograms from urethane anesthetized, mechanically ventilated rats before and during IV infusion of vehicle and GAL‐160 (0.24 mg/kg over 30‐min). Baseline neurograms were standardized between rats by setting baseline PaCO2 at 3 mmHg above each animal's apneic threshold to CO2. To evaluate the effects of GAL‐160 on the RMUA response to obstruction, the EMGGG and EMGDIA responses to standardized 10‐s tracheal obstructions were recorded from anesthetized, spontaneously breathing rats, before and during GAL‐160/vehicle infusions.GAL‐160 increased HN activity (67 ± 23% above baseline) without altering PN activity (‐13 ± 20%) during unobstructed breathing. Bilateral CB denervation abolished this effect. GAL‐160 increased the peak EMGGG response to a 10‐s obstruction (pre‐drug: 214 ± 180%; GAL‐160: 589 ± 358%; p<0.01) without altering the EMGDIA response (pre‐drug: 60 ± 31%; GAL‐160: 78 ± 47%). Vehicle infusion had no effect on the neurograms or EMGs recorded. These data demonstrate that GAL‐160 preferentially increases respiratory drive to the RMUA via the CB and during both eupneic breathing and OA. This mechanism may contribute to the efficacy of GAL‐160 in our rodent model of spontaneous OSA.
Alveolar Overdistension Does Not Occur Even at Very High Airway Pressure
Authors: Jain Sumeet , Kollisch‐Singule Michaela , Gatto Louis , Nieman Gary , Habashi Nader 
Published: June 2021

ObjectiveAcute respiratory distress syndrome (ARDS) is a disease with unacceptably high morbidity and mortality. Improper mechanical ventilation can cause a secondary ventilator induced lung injury (VILI), which significantly increases ARDS mortality and incidence. VILI is thought to occur via two mechanisms: alveolar recruitment‐derecruitment (R/D) and alveolar overdistension. We hypothesize that overdistension does not occur at the alveolar level with high airway pressures in either normal or surfactant deactivated lungs.MethodsSprague‐Dawley rats were anesthetized, instrumented, and ventilated with continuous positive airway pressure (CPAP) ventilation with pressure increased from 5 to 10, 20, 30, 40, and 50 cmH2O. In vivo microscopy was used to photograph subpleural alveoli at each pressure level. Surfactant was deactivated using Tween lavage, and subpleural alveoli photographed at the same airway pressures. Alveolar area/photomicrograph was measured using computer image analysis.image(Alveoli colored in yellow)ResultsAlveolar diameter did not increase significantly between CPAP 30 and 50 cmH2O and never exceeded known normal range (63.2µm maximum average diameter) for rat lung alveoli (range 43‐102µm).ConclusionsSubpleural alveoli do not overdistend even at high airway pressure in normal or surfactant deficient lungs. Thus gross barotrauma must occur in the conducting airways and pulmonary parenchymal injury caused by VILI must be secondary to alveolar R/D.
Chronic‐Binge Alcohol‐Induced Hepatic Injury and Inflammation Were Ameliorated in Mice Deficient for Transient Receptor Potential Vanilloid 1 Gene
Authors: Kirpich Irina , Falkner Keith , Beier Juliane , Arteel Gavin , McClain Craig 
Published: June 2021

IntroductionExperimental alcohol‐induced liver injury is exacerbated by a high polyunsaturated fat diet rich in linoleic acid (LA). The aim of the study was to evaluate the role of bioactive oxidized LA metabolites (OXLAMs) and their signaling through the Transient Receptor Potential Vanilloid 1 (TRPV1) in an experimental animal model of alcoholic liver disease (ALD).MethodsC57BL/6 wild type (WT) and Trpv1 knock out mice were fed a diet containing 5% ethanol for 10 days, followed by a single ethanol gavage. Liver steatosis, injury and inflammation were assessed. In vitro studies using HepG2 cells were performed to evaluate OXLAM/TRPV1 signaling.ResultsChronic‐binge alcohol administration to WT animals resulted in a marked increase in plasma OXLAM levels, specifically 9‐ and 13‐HODEs, in parallel with the up‐regulation of hepatic Trpv1. These effects were associated with hepatic steatosis, inflammation and injury. Genetic depletion of Trpv1 did not blunt hepatic steatosis caused by EtOH, but ameliorated hepatic injury and prevented the increase in pro‐inflammatory cytokine and chemokine expression, including Tnf‐α, IL‐6, Mip‐2, Mcp1, and Pai‐1. Exposure of HepG2 cells to 9‐ and 13‐HODEs resulted in activation of TRPV1 signal transduction with the increased intracellular Ca2+ levels, suggesting that OXLAM/TRPV1/Ca2+ signaling may be a relevant pathway contributing to ALD.ConclusionsTRPV1‐OXLAM interactions appear to play a significant role in ethanol‐induced hepatic inflammation/injury, further supporting an important role for dietary lipids in ALD.