bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tight junction integrity diminished by hypoxia, indomethacin, and hydrocortisone in Caco2 cell line (650.5)
Authors: Barnes Rachel , Carr Nick , King Jonathan 
Published: June 2021

Background: Inflammation, hypoxia and loss of barrier function hallmark inflammatory bowel disease. Tight junctions play a vital role in the regulation of intestinal epithelial permeability. Indomethacin and hydrocortisone are used clinically as first line agents for inflammatory bowel disease.Objective: To examine the effects of indomethacin and hydrocortisone, concurrent with hypoxia, pro‐inflammatory cytokines, on tight junctional integrity and cell viability.Methods: A Caco‐2 cell line was utilized in the setting of normoxia (160 torr) and hypoxia (20 torr) under varying conditions of pro‐inflammatory agents TNF (10ng/mL), IFN‐gamma (10ng/mL)) and anti‐inflammatory agents of indomethacin (50uM) and hydrocortisone (50ng/mL). Epithelial barrier integrity assessed using solute flux assays, tight junction expression and localization analysis. Cell survivability evaluated by LDH quantification and cytotoxicity assays.Results: Epithelial barrier integrity was impaired under exposure of hypoxia alone; these effects compounded with exposure to pro‐inflammatory agents leading to increased cytotoxicity. Addition of anti‐inflammatory agents demonstrated improved cell survivability without improvement in barrier function as demonstrated by solute flux, confocal imaging, and cytotoxicity assays.Conclusions: Anti‐inflammatory agents may alter the regulation of intestinal epithelium cytotoxicity without improvement in barrier function. These findings indicate the possible role of indomethacin, hydrocortisone in altering cell survival mechanisms leading to cellular necrosis vs. apoptosis under hypoxic, pro‐inflammatory environments.Grant Funding Source: Supported in part by NSF‐MRI #1229702
FGF and Notch signaling hierarchy in sensory neurogenesis (651.18)
Authors: Voelkel Jacob , Harvey Jamison , Adams Jason , Lassiter Rhonda , Stark Michael , Molteni Agostino 
Published: June 2021

The purpose of this study was to determine the regulatory relationship of sensory neurogenesis in the trigeminal placode between the Fibroblast Growth Factor (FGF) and Notch signaling pathways. To do this, FGF signaling was blocked cell autonomously or globally while simultaneously downregulating Notch signaling in 10‐12 somite stage Gallus gallus chick embryos. Cell autonomous FGF inhibition with global Notch downregulation significantly reduced the number of proneural cells contributing the future trigeminal ganglion (p=0.0002). A similar reduction was found with concurrent global inhibition of FGF and Notch (p<0.0001). Remarkably, blocking FGF either cell autonomously or globally with simultaneous Notch downregulation reversed the effects of robust neurogenesis seen with Notch downregulation alone (p<0.0001). Further, Notch downregulation for 4 or 12 hours showed no difference in the level of FGF‐receptor 4 mRNA expression when compared to controls. It did however result in a highly fragmented basal lamina, which was reversed when blocking FGF signaling. From these data, we invalidate the FGF downregulates Notch in sensory neurogenesis model and propose a mechanism for parallel regulation of FGF and Notch leading to basement membrane fragmentation and subsequent delamination of differentiating opV placode cells.Grant Funding Source: Supported by NIH/NICHD ‐ R01 HD046475
Psychosocial status of patients with acne (651.23)
Authors: Batpenova Gulnar , Tarkina Tatiyana , Kotlyarova Tatiyana , Sadykova Gulnaz 
Published: June 2021

The goal: a comparative assessment of the psychological status of various group contingents, including patients with acne. The study included 60 people aged 18‐25 years. Of these patients with varying severity of acne ‐ 20 people; patients with severe infectious dermatoses ‐ 20 people; healthy ‐ 20 people. The psychosocial status of patients was assessed by the index for the psychological and social impact of acne on the personality APSEA (Assessment of Psychological and Social Effect of Acne), the maximum number of 144 points.Results: the value of the index ARSEA in acne patients group was 47.9 points; the group of patients with acute infectious dermatoses ‐ 30.8 points; in a group of healthy ‐ 23.7 points. It is indicates to a possible negative impact on the scope of the patient's psychosocial disorders with significant cosmetic defect that is characteristic of acne.The frequency of selecting an adverse additional colors on the test Lusher, all groups were as follows: patients with acne ‐ 70%; acute infectious dermatoses ‐ 50%; healthy‐45%. Within the group of patients with acne selected violet in 25%; gray‐30 %; black‐15%. Of the 70% of patients with acne in 10% for first position two depressive colors. 60% of the patients selected one color. Of the 50% of patients with acute infectious dermatoses in 10% of cases selected two depressed colors. In the healthy group, 45% selected to first position one depressivecolor.
Altered cerebrospinal fluid lipids in preclinical Alzheimer’s disease (651.6)
Authors: Fonteh Alfred , Chiang Jiarong , Cipolla Matthew , Harrington Michael 
Published: June 2021

Background and Objective: Although lipids constitute a major portion of the brain, preclinical changes in lipid metabolism in cerebrospinal fluids (CSF) have not been determined in sporadic Alzheimer’s disease (AD). Our objective is to test the hypothesis that altered brain lipid metabolism precedes AD clinical symptoms.Methods: We fractionated CSF into a 200,000 g supernatant fluid (SF) and nanoparticles (NP) fractions and used liquid chromatography tandem mass spectrometry to determine the glycerophospholipid (GP) and sphingolipid (SP) composition of these fractions from cognitively healthy (CH) subjects. We further analyzed lipids in subgroups of CH participants with normal beta amyloid to total Tau (Aβ/Tau) (CH_NAT) or with preclinical AD‐like Aβ/Tau pathology (CH_PAT), and in AD study participants.Results: Levels of some GP classes and species are higher in the SF fraction from CH_PAT compared with CH_NAT. In contrast, levels of some SP classes and species are higher in the NP fractions from CH_PAT compared with CH_NAT. Activity of metabolic enzymes, PLA2 and acid SMase are significantly altered in AD compared with both CH subgroups.Conclusions: Differences between CH_NAT and CH_PAT suggest increased turnover or remodeling of GP in brain interstitial fluid and SP in brain membrane‐derived lipids in preclinical AD. Means of regulating these lipid metabolic pathways may be beneficial in AD prevention.Grant Funding Source: L.K. Whittier and the Helen Posthuma Foundations
Cerebrospinal fluid fatty acid composition changes in Alzheimer’s disease (651.7)
Authors: Cipolla Matthew , Harrington Michael , Fonteh Alfred 
Published: June 2021

Objectives: To test the hypothesis that levels of saturated fatty acids (SAFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) that are structural components of neuronal membranes or are precursors of signaling molecules change in Alzheimer’s disease (AD).Methods: We recruited and collected cerebrospinal fluid (CSF) from cognitively healthy (CH), mild cognitively impairment (MCI), and AD study participants. After fractionation of CSF into a 200,000 g supernatant fluid (SF) and nanoparticle (NP) fractions, we used gas chromatography‐ negative ion chemical ionization/mass spectrometry to determine the total fatty acid composition of these fractions.Results: Levels of some SAFA, MUFA, and PUFA differed between the SF and NP fractions. Docosahexaenoic acid [DHA, (C22:6, n‐6)] levels were lower in AD compared with CH while alpha linoleic acid [α‐LNA, (C18:3, n‐3)] levels were lower in MCI compared with CH in the SF fraction. In the NP fraction, levels of SAFAs (C15:0, C16:0) and a MUFA (C15:1) differentiated CH from MCI while levels of MUFAs (C15:1, C19:1) and PUFAs (C20:2, C20:3, C22:4, C22:5) were altered in AD compared with CH.Conclusions: Fatty acid metabolism is compartmentalized in CSF fractions and differences between clinical groups suggest that energy metabolism or oxidative pathways are important in AD pathophysiology. Some fatty acids in CSF fractions may be biomarkers of AD. Thus, dietary or pharmacological approaches to regulate brain fatty acid levels and measurement of fatty acid in CSF fractions may be helpful in prevention or monitoring AD.Grant Funding Source: L.K. Whittier and the Helen Posthuma Foundations
Blood‐brain barrier function and it’s relation to dementia development (651.8)
Authors: Andersson Mats , Skoog Ingmar 
Published: June 2021

Our aim was to further investigate the relation to BBB and the developing of dementia.We investigated blood‐brain barrier (BBB) function by measuring cerebrospinal fluid (CSF,) mg/l, in relation to serum albumin (g/L) ratio (CSF/S‐albumin x 10‐3) in a population‐based sample of 85‐year‐olds. Sixty‐five underwent a lumbar punctured (LP) at the age of 85‐year, measuring CSF‐albumin, ‐β ‐amyloid and ‐Tau. Fifty‐three of them also underwent a Computed Tomography CT. The participants were then followed up until death. Repeated studies (e.g. at age 88, 90, 95, 97, 100 and for survivors, in cases possible, every year until death) were conducted in search of dementia signs.Several previous CSF studies (1,2, 3, 4), but not all (5, 6, 7), reported a BBB dysfunction in AD. Decreased mitochondrial content and increased pinocytotic vesicles in capillary endothelium of AD patients (8) support that BBB dysfunction may be involved in the pathogenesis of AD (9, 10, 11, 12, 13). BBB dysfunction may also be secondary to AD. β‐amyloid has been reported toxic to blood vessles, thus stimulation atherosclerosis (14). BBB dysfunction may thus be both involved in the pathogenesis and a consequence of AD.LP was performed at baseline, 25 participants were demented and showed highest mean of CSF/S‐albumin ratio; 8.743. Out of the non‐demented 12 participants developed dementia before they died, mean ratio; 7.433 in CSF/S‐albumin ratio. The 30 participants that did not develop dementia had the lowest ratio of CSF/S‐albumin; 6.652. There were no significant difference between the three groups (p = 0.312), although the samples were small.Further analyses are presently conducted in relation to BBB, different dementia subtypes, β‐amyloid and Tau. Also Computed Tomography findings (atrophy, White‐matter lesions and multiple cerebral infarcts) will also be analyzed in relation to BBB function.
Chronic β1‐blockade impairs ischemic tolerance and preconditioning in murine myocardium (652.2)
Authors: See Hoe Louise , Headrick John , Peart Jason 
Published: June 2021

β‐adrenoceptor (β‐AR) antagonists are commonly applied in ischemic heart disease (IHD) patients, yet may impact negatively upon signaling and efficacies of experimental ‘cardioprotective’ interventions. We assessed the effects of chronic β1‐AR antagonism on myocardial resistance to ischemia‐reperfusion (IR), and on the ability of ischemic preconditioning (IPC) and sustained ligand‐activated preconditioning (SLP) to reduce IR injury in murine hearts.Male C57/Bl6 mice were administered the β1‐AR‐blocker atenolol for 4 weeks (0.5 g/L in drinking water) before subcutaneous implantation of morphine (SLP) or placebo pellets 5 days prior to analysis of ischemic outcomes ex vivo.Post‐ischemic contractile function was substantially impaired in control (placebo) hearts, with ~50% recovery of ventricular force, significant diastolic dysfunction and cellular lactate dehydrogenase (LDH) release. Chronic ß‐AR blockade with atenolol significantly worsened contractile dysfunction and LDH release. Contractile dysfunction and LDH loss were reduced 50% or more with IPC, however protection was negated by ß‐AR treatment. SLP significantly improved post‐ischemic outcomes irrespective of ß‐AR blockade.Data indicate that chronic β1‐AR blockade impacts negatively on both intrinsic ischemic tolerance and preconditioning responses whereas novel SLAP retains protective efficacy.
δ Opioid receptor agonist, DPDPE, enhances neuronal excitability in mouse enteric nervous system (653.4)
Authors: Hashimoto Atsushi , Dewey William , Akbarali Hamid 
Published: June 2021

μ‐opioid agonists are known to inhibit gastrointestinal motility and cause constipation. But a role for the δ opioid receptor activation in propulsive motility is controversial. Previously, it was shown that μ opioid receptor agonist, morphine, decreases enteric neuron excitability via inhibition of sodium channels. Here we examined electophysiological properties by patch clamp techniques and determined the mechanism for δ opioid receptor agonist DPDPE‐induced increase in neuronal excitability in mouse single isolated enteric neurons. DPDPE (5μM) evoked spontaneous action potentials and depolarized the resting membrane potentials from ‐61.3 ± 1.3 mV to ‐52.3 ± 2.8 mV (n=3). DPDPE‐induced action potentials were reversed by ICI 174864, a δ receptor antagonist. In the presence of DPDPE, sodium channels were activated at lower membrane potentials, indicated by a leftward shift of sodium channel voltage‐dependent steady‐state activation curve. The V0.5 significantly increased from ‐28.2 ± 1.4 mV in the absence of drug to ‐37.2 ± 2.3 mV in the presence of DPDPE (n=4). We hypothesize that δ opioid receptor agonist enhances neuronal excitability by increasing sodium channel activity in mouse enteric neurons.Grant Funding Source: Supported by NIH DA024009
Intrathecal nociceptin displaces a PET ligand for its receptor in the brain at analgesic doses in rhesus monkeys (658.1)
Authors: Saccone Phillip , Shao Xia , Sherman Phillip , Quesada Carole , Woods James , Winger Gail , Kilbourn Michael , Scott Peter 
Published: June 2021

The nociceptin receptor (NOP) has been investigated as a potential therapeutic target for pain control. Nociceptin, the endogenous ligand for NOP, produces analgesia in rodents and primates when given intrathecally (i.t.) (Ko et al. 2006, Xu et al. 1996). Recently NOP radiotracers have been developed for use with Positron Emission Tomography (PET) (Kimura et al. 2011, Hostetler et al. 2013). Although behavioral studies have shown that NOP agonists may be therapeutically useful, it is unknown whether nociceptin given i.t. binds to receptors supraspinally, and if so, which areas in the brain display the greatest ligand‐target interaction. The purpose of this study was to measure the amount of radiotracer displacement in the brain at NOP following an analgesic dose of nociceptin. Two female rhesus monkeys were anesthetized, and underwent PET scans with the NOP radiotracer 11C NOP‐1A. Eight minutes following tracer delivery, the monkey was injected i.t. with either saline or 100 nM nociceptin. Preliminary data show that 100 nM nociceptin delivered into the spinal canal displaces the radiotracer 11C NOP‐1A in a variety of brain nuclei. Prominent regions of displacement include the cortex, striatum, and thalamus. These data suggest that analgesia with NOP agonists can be produced with relatively low receptor occupancy and further supports NOP as a novel drug target for analgesia.Grant Funding Source: Supported by: The Michigan Memorial Pheonix Project and NIDA Traning Grant T32‐DA007281
Differential effects of lipopolysaccharide and cigarette smoke exposure on genes associated with contractile agonist responsiveness in mouse lungs (660.2)
Authors: Donovan Chantal , Seow Huei Jiunn , Royce Simon , Vlahos Ross , Bourke Jane 
Published: June 2021

Introduction: Inflammation is a key driver of many lung diseases, including asthma and chronic obstructive pulmonary disease. Exposure to lipopolysaccharide (LPS) and cigarette smoke (CS) are two mouse models that induce inflammation, however studies assessing changes in expression of contractile receptors in these models are limited.Methods: Female Balb/C mice were exposed to inhaled LPS once a day for 4 days or PBS. Male Balb/C mice were exposed to 9 cigarettes 3 times a day for 4 days and sham mice were exposed to air. On day 5, mice were euthanized, bronchoalveolar lavage fluid (BALF) was taken and lungs were harvested for PCR.Results: Inflammation was confirmed in both LPS and CS models by an increase in total cell number in the BALF. In both groups, there were no changes in gene expression levels of serotonin 2A, bradykinin, or muscarinic M3 receptors. There were no changes in G‐protein expression or downstream inositol trisphosphate receptor expression. In the LPS‐treated mice, there was an upregulation of muscarinic M2 receptors and ryanodine isoform 2 receptors (RyR2). In contrast, these receptors were down regulated in CS mice.Discussion: Despite both LPS and CS inducing inflammation, these stimuli have opposite effects on expression of M2 and RyR2 receptors. The influence of these changes on responsiveness to muscarinic and other contractile agonists remain to be determined.Grant Funding Source: Supported by NHMRC
The effect of a novel TRPA1 antagonist JNJ‐41477670 on models of airway hyperactivity and inflammation in rats (660.6)
Authors: Bhattacharya Anindya , Eckert William , Ao Hong , Lebsack Alec , Rech Jason , Wickenden Alan 
Published: June 2021

TRPA1 activation by respiratory irritants and pungent foods causes neurogenic inflammation, possibly contributing to wheezing, cough and dyspnea in humans. In this study we characterized JNJ‐41477670 as a TRPA1 antagonist and tested the efficacy in an allergen challenged model of airway inflammation and hyperreactivity in rats.The potency of JNJ‐41477670 in blocking AITC induced calcium flux at the recombinant rat TRPA1 was 7.2 ± 0.1. JNJ‐41477670 produced a pharmacodynamic effect of mustard oil‐induced in‐vivo CGRP release and nocifensive behavior at an oral dose of 60 mg/kg. In the airways hyperreactivity study, exposure of rats to allergen caused a statistically significant increase airway resistance (RL) following administration of adenosine indicative of the development of airways hyperreactivity. JNJ舉41477670 (60 mg/kg) had no effect on the airways hyperreactivity to adenosine. In the pulmonary leucocyte accumulation study, exposure of sensitised rats to allergen caused a significant increase in pulmonary leucocyte accumulation. JNJ‐41477670, tended to reduce eosinophil accumulation in recovered BAL fluid; however, this reduction was not statistically significant when data were compared to vehicle treated animals. Our data indicates a pharmacodynamic effect of JNJ‐41477670 in mustard‐oil nocifensive model without any efficacy in the airway model of inflammation and hyperreactivity.
Differential generalization among nicotinic acetylcholine receptor agonists in nicotine, varenicline, and epibatidine drug discriminations in mice (661.11)
Authors: Moura Fernando , McMahon Lance 
Published: June 2021

In addition to a nicotine discrimination assay, two novel nicotinic acetylcholine receptor (nAChR) agonist discriminations were established to examine the relative contribution of nAChR agonist efficacy to behavioral effects. Male C57Bl/6J mice were trained to discriminate nicotine (1 mg/kg), the low efficacy nAChR agonist varenicline (3.2 mg/kg), or the high efficacy nAChR agonist epibatidine (0.0056 mg/kg) from saline. Nicotine produced a maximum effect of 86% and 82% drug‐appropriate responding in the nicotine and varenicline discriminations, respectively. In mice trained to discriminate epibatidine, nicotine produced 84% drug‐appropriate responding, but at a dose that reduced the rate of responding to 19% of control. Varenicline produced 95% drug‐appropriate responding in the varenicline discrimination, but only a maximum of 46% and 70% drug‐appropriate responding in the nicotine and epibatidine discriminations, respectively. A t‐test showed that the maximum effect for varenicline was significantly lower (p<0.05) in the nicotine discrimination than in the varenicline discrimination. Epibatidine produced no less than 90% drug‐appropriate responding in all three discriminations. These data suggest that the discriminative stimulus effects of nAChR agonists vary as a function of the efficacy of the training drug. That nicotine only substituted for epibatidine at a dose of nicotine that markedly decreased response rate might suggest that epibatidine and nicotine have overlapping, but not identical, in vivo effects.Grant Funding Source: USPHS DA25267
Running‐wheel access decreases ±3,4‐methylenedioxymethampetamine self‐administration in rats (661.6)
Authors: Aarde Shawn , Vandewater Sophia , Creehan Kevin , Taffe Michael 
Published: June 2021

Running wheel access has been demonstrated to decrease the intravenous self‐administration (IVSA) of methamphetamine (MA). However, the acute effects of MA on running wheel activity and IVSA differ qualitatively from those of ±3,4‐methylenedioxymethampetamine (MDMA). The dose‐response curve for acute, non‐contingent administration of MA on wheel activity is bi‐phasic while MDMA causes monotonic decreases in running as dose increases. To determine the generalizability of wheel access to decrease the IVSA of amphetamines, we trained Wistar rats to self‐administer MDMA (1.0 mg/kg/inf; 2 hr/session M‐F) while vivarium wheel access (7 days/wk) was manipulated between groups. The IVSA of MDMA in the group with wheel access was less than that of the no‐wheel‐access group by the end of the 20‐session acquisition period. Additionally, a smaller percentage of rats within the wheel‐access group showed a clear dose‐response curve as determined over 10 dose‐manipulation sessions that immediately followed the acquisition period. These data indicate that the suppressive effect of running‐wheel access on amphetamine IVSA generalizes across drugs within the amphetamine class despite differences in their acute effects on wheel activity and IVSA.Grant Funding Source: Supported by NIH Grant DA024105 and DA024705
Development of Gs‐biased modulators of the β2‐adrenergic receptor (662.1)
Authors: Carr Richard , Panettieri Reynold , Benovic Jeffrey 
Published: June 2021

Asthma is a complex disease that is manifested by enhanced airway inflammation that leads to airway smooth muscle (ASM) contraction and airway constriction. While β‐agonists serve as a major asthma therapeutic, these drugs may also increase the risk of having a severe asthmatic attack that can result in death. Since several lines of evidence suggest that β2AR interaction with β‐arrestins may play a role in these adverse effects, biased ligands that selectively promote β2AR interaction with Gs may serve as an effective way of treating asthma. While an orthosteric Gs‐biased agonist for the β2AR has yet to be identified, another strategy to stabilize the conformation of a G protein‐coupled receptor (GPCR) is to target the intracellular surface of the receptor using pepducins. Pepducins are lipidated peptides derived from the intracellular domains of a GPCR. A library of β2AR pepducins was synthesized and screened for cAMP production and β‐arrestin recruitment and identified two classes of Gs‐biased pepducins: receptor‐dependent and receptor‐independent. The Gs‐biased pepducins exhibit minimal functional desensitization in cells and do not induce GPCR kinase (GRK) phosphorylation or internalization of the β2AR, although PKA‐mediated phosphorylation was observed. The receptor‐independent pepducins appear to directly activate Gs while the receptor‐dependent pepducins promote cAMP production that is sensitive to the inverse agonist ICI 118,551, suggesting that the pepducin is stabilizing a Gs‐biased conformation of the β2AR. These pepducins represent the first reported Gs‐biased modulators and offer a potential new class of asthma therapeutics.Grant Funding Source: Supported by P01HL114471 (NHLBI) and T32GM100836 (NIGMS)