bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of c‐Kit/sGC signaling axis in vascular reactivity and hypertension
Authors: Hernandez Diana Rosa , Song Lei , Zigmond Zachary M. , Wei Yuntao , Martinez Laisel , Lassance‐Soares Roberta M. , Vazquez‐Padron Roberto I. 
Published: June 2021

A. IntroductionThe receptor tyrosine kinase c‐Kit has been recently found to have a role in vasculoprotection. Genetic deletion of c‐Kit in smooth muscle cells increases aortic plaque accumulation and atherosclerosis burden in conditional hyperlipidemic mice. The present study tests whether a c‐Kit deficiency in mutant mice (KitW/Wv) leads to hypertension and impaired vascular relaxation.B. MethodsFemale and male c‐Kit mutant (KitW/Wv) and littermate (Kit+/+) control mice were commercially available (Jackson lab). Blood pressure was determined in conscious mice using the tail‐cuff method. The first‐order branch of mesenteric artery was mounted into a pressure myograph (DMT, Aarhus, Denmark) to assess endothelium‐dependent and ‐independent vasoreactivity under isobaric conditions. A search for differentially expressed genes between c‐Kit mutant and control SMC was performed using the Mouse MI‐Ready microarray (Ocean Ridge Biosciences).C. ResultsThe deficiency of c‐Kit causes hypertension in mutant mice with respect to their control littermates (mean arterial pressure: 137.5 ± 5.0 vs. 113.06 ± 0.0, p=0.007). Acetylcholine (ACh) induced a concentration‐dependent relaxation of norepinephrine pre‐contracted vessels in both mutant and littermate mice. The Cox inhibitor indomethacin compromised ACh‐induced vasorelaxation only in c‐Kit deficient vessels but not in those from control mice, which highlighted the importance of endothelium‐derived prostaglandins for vasorelaxation in the absence of c‐Kit. Conversely, arteries of mutant mice were poor responders to a NO agonist (SNP). The secondary messenger, cyclic guanosine monophosphate, vasodilated both types of vessels in a similar manner, which indicated that defective NO activity in mutants was due to deficiencies in soluble guanylyl cyclase (sGC) or NO synthesis. A significant downregulation of smooth muscle sGC beta 1 subunit was further found in c‐Kit mutant cells using transcriptomics analysis.D. ConclusionThese results suggest the existence of a novel c‐Kit/sGC signaling axis in SMC that may be relevant for the control of vascular reactivity and hypertension.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Transient ACE‐Inhibitor Treatment Produces Persistent Change in Cardiac Fibroblast Physiology
Authors: Perez Octavio , Garvin Alexandra , Hale Taben 
Published: June 2021

Heart failure is a debilitating illness that is characterized by excessive extracellular matrix (ECM) accumulation. Cardiac fibroblasts maintain homeostasis of collagen production and degradation ‐ a tightly regulated process that is critical for normal heart function. Pathological cardiac fibrosis results from uncontrolled proliferation of fibroblasts and excessive production of ECM proteins including collagens – which may be mediated by reactive oxygen species. The pro‐fibrotic effects are mediated by a differentiated and activated fibroblast phenotype termed a myofibroblast. We have previously shown that angiotensin converting enzyme (ACE) inhibitors induce apoptosis of 30% of cardiac fibroblasts in adult spontaneously hypertensive rats (SHR). In addition, a 10% (p<0.05) reduction in left ventricular mass, compared to untreated control and was accompanied by a 12% (p<0.05) reduction in left ventricular DNA content. Moreover, transient ACE inhibition induces persistent changes that protect against future fibrosis and macrophage infiltration in response to injury. Based on these findings, we hypothesize that cardiac fibroblasts isolated from SHR previously treated with an ACE inhibitor will display a less fibrogenic phenotype than those isolated from control SHR. Adult male SHR were treated for 2 weeks with the ACE inhibitor enalapril (30mg/kg per day, p.o.) or water followed by a 2‐week washout period. Cardiac fibroblast were isolated from left ventricle and cultured to P1. Fibroblasts isolated from SHR previously treated with enalapril secreted significantly higher levels of TGF‐β1 in media (↑30%, p<0.05), and tended to have increased expression of the matricellular protein periostin (↑62%, p=0.052) relative to fibroblasts isolated from untreated SHR. Levels of the pro‐oxidant enzyme NOX2 were not different between treatment groups. Taken together, our data demonstrate that cardiac fibroblasts isolated from SHR that were transiently treated in vivo with an ACE inhibitor are different from those isolated from control SHR hearts. Future studies will further determine the extent to which ECM regulatory proteins differ in cells isolated from ACE inhibitor treated rats, and the response of these cells to an in vitro pro‐fibrotic stimulus. We predict that this altered cell population is primarily responsible for the cardio‐protection that we have shown to persist even after stopping ACE inhibitor treatment.Support or Funding InformationFunding: Springboard Grant, UA College of Medicine – PhoenixThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Helicobacter pylori Infection of the Gastric Epithelium Promotes Programmed Death Ligand 1 Expression and the Formation of Premalignant Lesions
Authors: Holokai Loryn , Chakrabarti Jayati , Chang Julie , Hawkins Jennifer , Sundaram Nambirajan , Mahe Maxime , Helmrath Michael , Zavros Yana 
Published: June 2021

BackgroundHelicobacter pylori (H. pylori) is the number one risk factor for gastric cancer. Currently the 5‐year‐survival rate for gastric cancer is only 29%. Our laboratory has reported that H. pylori infection results in the up‐regulation of the Sonic Hedgehog (SHH) signaling pathway mediated by an increase in the transcriptional activity of NF‐kB. In addition, H. pylori infection induces the expression of programmed death ligand 1 (PD‐L1) on gastric epithelial cells. This expression inhibits T cell proliferation and effector function.HypothesisH. pylori‐induced PD‐L1 expression on the surface of gastric epithelial cells is mediated by the SHH signaling pathway.MethodsHuman‐derived gastric organoids (huFGOs) were generated from sleeve gastrectomies. These huFGOs were then transferred to a collagen‐coated transwell where they readily formed a 2D gastric epithelial cell monolayer (huGEM). The huGEM culture was apically treated with H. pylori. A second experimental group was also infected with H. pylori, but was treated with Vismodegib, a smoothened inhibitor. Gli2 and PD‐L1 expression was analyzed by qRT‐PCR and immunofluorescence. A chromatin immunoprecipitation (ChIP) assay was used to analyze Gli2 binding to the PD‐L1 promoter region. Gli3 was used as a positive control.Results1) HuGEM cultures infected with H. pylori express significantly more PD‐L1: H. pylori infection significantly increased PD‐L1 expression in huGEM cultures 48 hours post‐infection, when compared to uninfected monolayers. This response was blocked by pretreatment with Hedgehog inhibitor vismodegib. 2) Transcriptionally active Gli2 promotes PD‐L1 expression in H. pylori infected huGEM cultures: Transcriptionally active Gli2 was bound to the zinc finger motif of the promoter region of PD‐L1 upon the infection of gastric epithelial monolayers in response to H. pylori infection.ConclusionH. pylori‐induced PD‐L1 expression is mediated by the SHH signaling pathway within the gastric epithelium. Cells infected with H. pylori that express PD‐L1 may freely gain mutations while being protected from the immune response, creating premalignant lesions progressing to gastric cancer.Support or Funding InformationSteven Goldman Memorial Pancreatic Cancer Research Grant (Zavros) 1RO1DK083402This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neuroanatomical Reprogramming Produced By Perinatal Exposure to Indoor Flame Retardants (PBDEs) May Underlie Abnormal Affective/Social Behavior
Authors: Kozlova Elena V. , Anchondo Laura , Krum Julia Megan , Rohac David , Uddin Syed , Huffman Nicole , Huffman Kelly , Curras‐Collazo Margarita C. 
Published: June 2021

Polybrominated diphenyl ethers (PBDEs) are flame retardant pollutants with adverse neurobehavioral effects. In this study, we examined affective and social behaviors in male offspring of pregnant/lactating mothers exposed to a penta‐BDE mixture DE‐71 (low dose (LD) (0.1 mg/Kg/day), high dose (HD) (0.4 mg/Kg/day), corn oil vehicle (control). LD exposure significantly decreased pup litter size which may be associated with changes in dam parameters in gestation. Adult offspring were subjected to behavioral testing that measure social memory, sensorimotor integration/anxiety and depressive like behavior: Social Recognition Task (SRT), SUOK and forced swim tests (FS). HD male offspring showed abnormal SRT ability showing no preference for novel over familiar stimulus mice as compared to control (p<.0001). For SUOK test HD males showed significantly less falls/segments crossed relative to control (p=.024), indicating altered sensorimotor ability. For FS, LD mice spent significantly less time immobile compared to control (p=.002), suggesting that PBDE exposure alters affective behavior and/or promotes hyperactivity. To examine altered neurodevelopment that may underlie behavioral results, we examined intraneocortical connections (INCs) in male offspring at postnatal day 7 (PN7). DiI and DiA fluorescent dyes were injected into the frontal and visual cortices, respectively and dyes were localized to cell layers containing the cells with fibers projecting to dye projection zones (DPZs). DiI and DiA tracing revealed significantly wider normalized DPZs over the visual cortex in LD (p=.04, n=3–8 per group): control 37%, LD 53%, HD 48%. A similar but insignificant change was observed in HD. Frontal association cortex DPZ showed an apparent increase in HD (p=.09, n=3–7 per group): control 47%, LD 53%, HD 57%. The larger dye distribution in LD offspring is not due to gross anatomical differences (cortical length). These results suggest that PBDEs may produce changes in affective behavior in LD male offspring, in part, by altering neurodevelopment of the neocortex.Support or Funding InformationSupported by APS (L.A.), UCMEXUS (E.K.,) UCR Chancellor's Research Fellowship (J.K), DOE HSI‐STEM Fellowship (E.K, N.H ).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Noradrenergic Enhancement of Synaptic Strength in Paraventricular Nucleus Neurons that Innervate the Nucleus Tractus Solitarius
Authors: Brackley Allison Doyle , Toney Glenn M. 
Published: June 2021

Autonomic neurons of the hypothalamic paraventricular nucleus (PVN) integrate synaptic inputs activated by a wide array of internal (homeostatic) and external (perceived stress) stimuli. A well‐recognized yet poorly understood neurochemical modulator of PVN‐driven autonomic function is norepinephrine (NE). Visceral afferent inputs terminate in the brainstem nucleus tractus solitarius (NTS) and strongly modulate local A2 noradrenergic neurons, which densely project to the PVN, and a number of studies report reciprocal connections between the PVN and NTS. To investigate synaptic modulatory actions of NE on NTS‐projecting PVN neurons, retrograde axonal tracing was used to label PVN‐NTS neurons and slice electrophysiology was performed to investigate effects of NE on the strength of glutamatergic synaptic transmission. In whole cell voltage‐clamp recordings during blockade of activity‐dependent synaptic transmission (TTX, 1 μM) and with Vm held at −20 mV, bath application of NE (100 μM) for 5 min increased the frequency and amplitude of 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX)‐sensitive AMPA receptor mediated mEPSCs by 584 ± 141% (n=3) and 143 ± 10% (n=3), respectively. Unlike amplitude, mEPSC frequency remained significantly increased 25 min after NE washout (453 ± 166%, n=3). Holding Vm at −60 mV during NE exposure blunted the increase of mEPSC frequency (222 ± 66%, n=2), but not amplitude (147 ± 26%, n=2. In the absence of depolarization, the NE‐induced increase of mEPSC frequency also recovered more rapidly, returning to baseline with 15–20 min of washout. Blockade of α1‐adrenergic receptors with prazosin (20 μM) prevented the increase of mEPSC frequency (127 ± 21%; P<0.05, n=3) and amplitude (108 ± 8%; P<0.05, n=3) following bath application of NE (100 μM; Vm = −20 mV). Interestingly, effects of NE on mEPSCs were not consistently observed in neurons not retrogradely labelled from the NTS. Although the resting membrane potential (−57.8 ± 0.6 mV, n=9) and membrane capacitance values (−42.9 ± 4.4 pF, n=9) of PVN‐NTS neurons was consistent with PVN parvocellular neurons, the majority (7 of 9) had a membrane input resistance (400–600 MΩ) lower than that typical of parvocellular neurons. These data provide insight into the possible regulation of poorly understood population of autonomic‐regulatory PVN neurons by noradrenergic inputs and indicate that α1‐adrenergic receptors can elicit a large amplitude and prolonged increase of glutamatergic signaling through AMPA (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid) receptors.Support or Funding InformationNIH T32‐HL007446, HL088052 and AHA 25710176 (GMT)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Working memory testing reveals neuroplasticity acutely and longitudinally after mild traumatic brain injury (mTBI)
Authors: Arakaki Xianghong , Lee Ryan , Fonteh Alfred N. , Goldweber Robert T. , Harrington Michael G. 
Published: June 2021

Background and ObjectivesThere are increasing concerns about mild traumatic brain injury (mTBI) because of its effects in later life. However, objective markers that help physicians quantify the injury are still understudied. We aim to investigate the underlying neuroplasticity reflected by working memory processing after mTBI.MethodsWe used cognitive brain challenges to explore neuroplasticity in acute mTBI. Brain activities during the N□back working memory (WM) test was investigated using quantitative electroencephalography (qEEG) in an acute and longitudinal mild traumatic brain injury study. mTBI patients (n=22) and controls (n=9) (trauma patients without head injury), 18–50 years of age, were recruited from the emergency department of Huntington Memorial Hospital in Pasadena, CA. Brain challenges were administered using E‐prime software. Data were collected from 21 recording head sensors at four visits: within 1 week, 14 days, 30 days, and 6–12 months after injury (with some missing visits). Behavioral performance as well as spectral power were analyzed to compare the two groups. Brain WM processing were also evaluated by event‐related potentials (ERPs) P300, and corresponding EEG signal (ir)regularity or “noise” level measured by spectral entropy (SE). High SE means signal is more irregular and “noisier”.Results & DiscussionBehavioral performance during 0‐back challenge was similar between the two groups, though mTBI patients had significantly lower accuracy than controls during 2‐back at the first visit. qEEG analysis revealed altered brain activities in mTBI group during 0‐back: alpha and beta power were lower in mTBI patients than controls at the second and third visit. Further, theta power during 2‐back at second visit were significantly higher (P=0.0099 and 0.0018) in controls (0.73+/−0.37 and 0.96+/−0.46) compared to mTBI (0.21+/−0.41 and 0.09+/−0.55) patients at the left and right temporal regions. When comparing regional theta power from first visit to second visit, controls were increased (p<0.005), indicating a learning mechanism, while mTBIs were not changed (p>0.10). SE analysis of the EEG signals during the P300 time window demonstrated more irregular or noisier brain signals in mTBI patients. These changes indicate neuroplasticity acutely and longitudinally after mTBI, consistent with learning impairment and “noisier” brain after mTBI. The spectral power and SE under WM challenge are sensitive measures of neuroplasticity after injury, and could be potential objective mTBI markers to help diagnosis, prognosis, or treatment management.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Quantitative EEG during memory testing indicates pre‐symptomatic Alzheimer's disease and correlation with MRI
Authors: Arakaki Xianghong , King Kevin S. , Lee Ryan , Wei Ke , Tran Thao , Fonteh Alfred N. , Harrington Michael G. 
Published: June 2021

Background and ObjectivesIncreasing attention for Alzheimer's disease (AD) have been focused on pre‐symptomatic stage for potential effective treatment. We aim to explore the quantitative electroencephalography (qEEG) during memory testing and evaluate qEEG correlations with MRI volumetric data to investigate the underlying events of pre‐symptomatic AD.MethodsWe employed qEEG test to investigate brain activity during working memory processing (N‐back) in a pre‐symptomatic AD study. Study participants, age 60–100 years, with normal cognition were recruited from the local community, consisting of two subdivisions from cerebrospinal fluid proteins: cognitively healthy with normal amyloid/tau ratio (CH‐NAT, n=10) or pathological amyloid/tau ratio (CH‐PAT, n=14). Behavioral performance and spectral power from 21 recording head sensors were collected during testing. EEG signal (ir)regularity or “noise” levels were measured by spectral entropy (SE). To assess brain anatomical structures, MRI was collected from the same individuals. We analyzed the EEG data for all channels, and explored the spectral power correlations with MRI total gray matter and hippocampal volumes.Results & DiscussionThe behavioral performance was similar between the two groups during lower memory load, and CH‐PATs had significantly less accuracy of performance than CH‐NATs during higher memory load. The qEEG from several sensors were significantly different (p<0.01) between CH‐NAT and CH‐PAT groups during the lower load memory testing when behavioral performances did not differ. The CH‐PAT brain signals were “noisier” compared to CH‐NATs. We interpret the altered brain activity in the CH‐PAT group to indicate a compensation mechanism for the CH‐PATs. qEEG measures from specific sensors correlated with total gray matter volume (p<0.001) and hippocampal volumes (p<0.001); these unexpected results suggest neuroplasticity occurs in the pre‐symptomatic AD stage to compensate for reduction in brain regional volumes. We propose that intervention at the pre‐symptomatic phase of AD using strategies that improve cognitive efficiency may attenuate neurodegeneration.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Diet‐Induced Obesity Increases H‐Reflex Excitability in Adult Mice of Both Sexes
Authors: Nguyen Gerard , Putnam Shea , Haile Mulatwa , Wilkinson Katherine A. 
Published: June 2021

Obesity is a metabolic condition characterized by excess adipose tissue and chronic inflammation. It is associated with deficits in balance and motor control leading to an increased risk of falling and fall‐related injuries. These balance deficits may be partially due to alterations in the muscle stretch reflex, which helps correct motor movements and adapt to uncertain terrain. Muscle stretch is sensed by muscle spindle afferents, which then excite alpha motor neurons to cause a reflex contraction. We tested the hypothesis that spinal cord integration of sensory information from muscle spindle afferents is altered in a mouse model of diet‐induced obesity. Changes in spinal cord integration were measured using the Hoffman's or H‐reflex, the electrical analog of the muscle stretch reflex. Following electrical stimulation of the sciatic nerve, two waves of muscle contraction were recorded: the M wave caused by direct excitation of motor neuron axons and the longer latency H wave caused by reflex activation of motor neurons by muscle spindle afferents. Adult mice of both sexes were fed either a control diet (CD, 10% kcal fat; n=16 M, 8 F) or high‐fat diet (HFD, 60% kcal fat; n=15 M, 9 F) for 10 weeks. We measured three properties of the H‐reflex as indicators of excitability: (1) H latency, the time from stimulus to the peak of the H wave; (2) Hmax/Mmax, the percentage of motor neurons recruited from the stimulus of Group Ia afferents; and (3) rate‐dependent depression (RDD), the decrease in H‐reflex amplitude following high‐frequency stimulation (20 stimuli, 5 Hz). After 10 weeks, there were no significant differences in H latency (p=0.558) between groups. However, the 10‐week HFD group showed a significant increase in Hmax/Mmax (p=0.013; sex x diet p=0.570). 10 weeks of high‐fat feeding also decreased the degree of RDD (p=0.001; sex x diet p=0.797). These results suggest that obesity increases spinal cord sensitivity to sensory input from the muscle spindle afferents. A preliminary sample of male mice fed the HFD for 5‐weeks showed similar decreases in RDD (n=6 per group, p=0.033), but no changes in Hmax/Mmax (p=0.485). We are currently increasing this sample size and testing whether more severe increases in excitability are seen following longer exposures to the HFD. Future studies will also determine whether these changes in spinal cord excitability translate into changes in the strength of the muscle stretch reflex and/or balance.Support or Funding InformationThis work was supported by SJSU RSCA funds and NIGMS Grant# 4T34GM008253‐30 (MH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.