bluuebunny/crossref_metadata_2025_split huggingface dataset:
Steroid Treatment Impairs Intestinal Stem Cell (ISC) Activation and Contributes to Delayed Ulcer Healing in Inflammatory Bowel Disease (IBD)
Authors: Lynch Evan Brady , Goretsky Tatiana , Bradford Emily , Barrett Terrence 
Published: November 2023

In cases of moderate to severe inflammatory bowel disease (IBD), exogenous glucocorticoid steroids (GC) are the preferred treatment due to their safety and efficacy in alleviating symptoms. Despite the clinical benefits, endoscopic data show that GCs delay ulcer healing through mechanisms that are poorly understood. Intestinal stem cells (ISC) require Wnt/β‐catenin signaling for maintenance of the crypt proliferative compartment, and Wnt responsiveness is an important component of a functional mucosal healing response. The objective of our study was to determine whether GCs impair ISC activation in ulcer re‐epithelialization. Specifically, we hypothesized that that steroids impair canonical Wnt/β‐catenin signaling required for ISC activation needed for mucosal repair.MethodsWe examined the effects of dexamethasone, a GC steroid, on cell signaling pathways involved in Wnt/β‐catenin, PI3 Kinase, and NFkB signaling. We utilized NCM460 (NCM) cells, a normal human colonic intestinal epithelial cell (IEC) line, mouse epithelial cells isolated after DSS‐mediated colitis induction, and epithelial isolations from patient biopsies obtained from University of Kentucky and VA Lexington Hospitals. IEC from untreated and steroid‐treated (7 days) UC patients with equivalent levels of colitis were compared.ResultsIn steroid‐treated NCMs, we saw a significant decrease in transcript levels of Wnt target gene Axin2, a marker of Wnt‐responsive multipotent IECs that participate directly in ulcer healing, and the β‐catenin transcriptional co‐activator CREB Binding Protein (CBP). After transfecting NCM460s with lentivirus containing a TCF/LEF luciferase construct (a marker of Wnt transcriptional activation), we saw that steroid treatment diminished TNF‐mediated increase in TCF/LEF signaling back to control levels. In both murine and IECs isolated from patient biopsies, GC inhibited colitis‐induced Axin2, p‐LRP6 (marker of Wnt signaling) and nuclear β‐catenin protein levels. Together, these data indicate strongly that GCs impair Wnt signaling.DiscussionOur results indicate that GCs impair Wnt/β‐catenin signaling during ulcer healing in in vitro and in vivo models of colitis. While steroids play a significant role in regulating the basal immune response to IBD, our data suggest steroids inhibit epithelial signaling required for ulcer healing. Given the recent data implicating NFkB in Wnt signaling activation, our studies suggest a potential explanation for GC‐induced impairment of stem cell activation needed for mucosal repair in IBD.Support or Funding Information1I01CX001353‐01A1 VA Merit 5TL1TR000115‐05 TL1 Pre‐doctoral CTSA Funding
Infection with the tapeworm parasite Hymenolepis diminuta in early life protects against experimental colitis in mice
Authors: Arai Toshio , Lopes Fernando , Wang Arthur , McKay Derek 
Published: November 2023

BackgroundThe hygiene hypothesis asserts that lack of exposure to infectious disease in childhood contributes to the development of auto‐inflammatory disease. We showed that infection with the rat tapeworm Hymenolepis diminuta evoked a Th2 response, including IL‐10, in adult mice and protected the mice from di‐nitrobenzene‐sulfonic acid (DNBS) induced colitis. Within North America there has been a startling increase in pediatric (early)‐onset inflammatory bowel disease. We tested the hypothesis that infection of mice immediately post‐weaning with H. diminuta would protect them from colitis.AimTo determine if three‐week old mice effectively expel H. diminuta and receive protection from chemically‐induced colitis by infection with this helminth parasite.MethodsFirst, helminth infectivity was compared in three‐ and eight‐week old Balb/c mice (bred at Univ. Calgary). Second, three‐week old Balb/c mice were infected with 5 cysticercoids of H. diminuta by oral gavage and 8 or 10 days later received 1.5 mg of DNBS intra‐rectally. Colitis was assessed 72h post‐DNBS by: 1) loss of body weight, 2) colon length, 3) disease activity score, 4) histopathology, and 5) concanavalin‐A stimulated cytokine production from spleen cells. Third, the ability of re‐challenge with H. diminuta antigen to protect mice from DNBS‐induced colitis in later life was tested.ResultsJuvenile mice expelled H. diminuta although this was delayed by ~2–3 days compared to infected adult mice. Mice infected with H. diminuta 8 days DNBS were not protected against colitis, whereas those infected 10‐days prior to ir. DNBS displayed substantially severe colitis The anti‐colitic effect in the infected mice was paralleled by increased splenic production of IL‐4 and IL‐10, and increased mRNA IL‐4, IL‐10 and FOXP3 mRNA in extracts of colon. Infection also lead to immunological memory in the young mice allowing triggering of an anti‐colitic effect by systemic delivery of worm antigen to previously infected mice.ConclusionsJuvenile mice expel H. diminuta (indicating a functional immune response) and infected mice can be protected from DNBS‐induced colitis. We provide these preliminary data in support of the consideration of helminth therapy in early‐onset of IBD and speculate that exploiting immunological memory for H. diminuta could be a new anSupport or Funding InformationSupported by Yamanashi Scholarship and NSERC CREATE Host‐Parasite Interactions scholarship to TA and NSERC operating grant to DMM.
Emu Oil Reduces Colonic Damage Severity in a Mouse Model of Chronic Ulcerative Colitis
Authors: Safaeian Romina , Howarth Gordon S , Lawrance Ian C , Trinder Debbie , Mashtoub Suzanne 
Published: November 2023

Background/AimsUlcerative colitis (UC) is characterised by large intestinal inflammation and ulceration. Previously, Emu Oil (EO) has been reported to protect the intestine in models of NSAID‐enteropathy, mucositis and acute UC. It was hypothesized that EO would reduce disease and colonic damage severity in a mouse model of dextran sulphate sodium (DSS)‐induced chronic UC.MethodsMice (n=10/group) were gavaged with water or EO (80microL [low dose] or 160microL [high dose]) thrice weekly. Mice were subjected to two cycles each consisting of water or DSS (2% w/v) ad libitum for one week and two weeks water recovery. Mice were euthanized two days after a third week of DSS. Disease activity index (DAI), burrowing activity and histologically‐assessed damage were quantified. Data were statistically analysed using ANOVA with LSD and Kruskal Wallis with Mann Whitney U tests. P<0.05 was considered significant.ResultsDAI was significantly greater in DSS controls compared to controls (P<0.05). EO‐low dose (days 6–9, 26–35) and EO‐high dose (days 6–16, 25–26, 33–35, 45) reduced DAI compared to DSS controls (P<0.05). DSS reduced burrowing activity in mice compared to controls; an effect significantly improved by both doses of EO (days 27, 40; P<0.05). In DSS‐treated mice, colonic damage severity increased compared to controls (P<0.001). Importantly, both doses of EO significantly decreased damage severity in the distal colon compared to DSS controls (P<0.001).ConclusionsEmu Oil reduced colonic damage severity and disease activity and increased burrowing activity in experimentally‐induced chronic UC, suggesting potential as a treatment adjunct for UC.Support or Funding InformationN/A
Novel G protein‐coupled receptors in Pancreatic Beta cells
Authors: Saunders Fiona , Iyinikkel Jean , Lima Maria , Thompson Dawn , Delibegovic Mirela , Docherty Kevin , Murray Fiona 
Published: November 2023

Type 2 diabetes is a widespread metabolic disorder that is on the rise worldwide. Type 2 diabetes is a significant economic burden and increases the frequency of other diseases, such as hypertension and stroke. Reduced secretion of the hormone insulin by pancreatic beta cells, and resistance of the body to insulin contribute to the development of the disease. Insulin secretion can be influenced by circulating mediators, such as hormones, many of which act though G protein‐coupled receptors (GPCR). GPCRs are the largest receptor family in the human genome and are the targets for >30% of approved drugs. GPR75, an orphan GPCR, has been proposed to regulate insulin secretion, thus we aimed to determine its expression in pancreatic beta cells and changes with type 2 diabetes. Using real‐time PCR we found GPR75 is expressed in primary human pancreatic beta cells and the pancreas from control C57Bl/6 mice. Immunofluorescence staining of MIN‐6 cells (a pancreatic beta cell line) showed GPR75 expression on the cell membrane and punctate intracellular staining (indicative of constitutive activity). We found GPR75 to be upregulated in diabetic mice, either with a spontaneous knock‐out of the leptin gene or in LDL receptor knock‐out mice. Our data show expression of GPR75 in pancreatic beta cells and increased expression with diabetes. Uncovering the function of GPR75 in pancreatic beta cells may advance the understanding of type 2 diabetes and even uncover novel treatments for the disease.Support or Funding InformationWellcome Trust
Erythropoietin impacts the stress‐related respiratory dysfunction in mice: neonatal maternal separation and sex dimorphism
Authors: Elliot‐Portal Elizabeth , Kinkead Richard , Soliz Jorge 
Published: November 2023

Neonatal maternal separation (NMS) is an established model of early life adversity that mimics stressful conditions experienced by newborn and infants. NMS disrupts brain development and as adults, individuals show sex‐dependent abnormal neuroendocrine response, predisposing them to physiological/psychological disorders. Concerning the neural control of respiration, studies in rats revealed that NMS causes respiratory instability and increased levels of corticosterone that remained during adulthood. Moreover, increased ventilatory response to hypoxia (HVR) but decreased to hypercapnia (HcVR) was observed in male animals, while decreased HVR but increased HcVR was observed in female rats.Although it is primarily recognized for its capacity to stimulate erythrocyte production, erythropoietin (Epo) is a cytokine that is also produced in the brain (by neurons and astrocytes), and plays role in development, maintenance, protection and repair of the nervous system. Studies from our lab demonstrated that cerebral Epo is a potent and sex‐specific respiratory stimulant that enhances the ability to tolerate hypoxic conditions at neonatal and adult ages. As cerebral Epo also attenuates the activation of the hypothalamic‐pituitary‐adrenal (HPA) axis, here we hypothesized that Epo protects against the stress‐induced cardio‐respiratory dysfunction produced by NMS. To test this hypothesis, circulating corticosterone level of adult (3 months) male and female Tg21 mice, was increased by subcutaneous implantation of beeswax pellets. 14 days later basal ventilation, HVR (10%O2 in N2) and HcVR (5% CO2, 21%O2 in N2) was evaluated by whole‐body plethysmography. Our preliminary results showed that corticosterone does not alter basal ventilation nor HVR in female and male Tg21 mice. However, corticosterone decreased HcVR in female Tg21 mice, meanwhile males showed an increased HcVR. These results suggest that Epo modulates the cortiscosterone‐induced cardiorespiratory dysfunctions.Support or Funding InformationCanadian Institutes of HealthResearch (MOP 130258), the Star Foundation for Children's HealthResearch. The salary of Jorge Soliz is supported by the “Fonds de recherche du Quebec‐Santé” (FRQ‐S).
Ventilatory and Neurochemical Effects of Microdialysis of a μ‐opioid Receptor Agonist (DAMGO) into the hypoglossal nucleus of awake and sleeping goats
Authors: Langer Thomas M , Neumueller Suzanne , Burgraff Nicholas James , Pan Lawrence , Hodges Matthew R , Forster Hubert V 
Published: November 2023

Unilateral dialysis of [D‐Ala2, N‐MePhe4, Gly‐ol]‐enkephalin (DAMGO) into the ventral respiratory column (VRC) of awake and sleeping goats causes a decrease in breathing. This observed decrease is transient, perhaps because of a concomitant local increase in GABA. However, data of others suggest opioids acting on the hypoglossal nucleus (HN) may contribute to opioid induced respiratory depression (ORD) (J Physiol. 2009 Jun 1; 587(Pt 11): 2677–2692). These data suggest neuromodulator compensation may not occur in motor nuclei such as the HN. Accordingly, herein we chronically implanted unilateral microtubules into the HN of adult goats. We then dialyzed DAMGO during both awake and NREM sleep states. We found that dialysis of DAMGO decreased tidal volume and pulmonary ventilation in a majority of goats during both awake and NREM sleep states. In contrast to findings in the VRC, DAMGO dialysis into the HN does not change GABA or any other neuromodulator measured herein in the effluent dialysate. Accordingly, findings to date do not support the concept of neuromodulatory compensation occurring in the HN.Support or Funding InformationNational Heart, Lung, and Blood Institute grants HL‐25739, HL‐112996, HL‐007852, and by the Department of Veterans Affairs
Exposure to chronic intermittent hypoxia does not elicit aberrant respiratory plasticity in adult guinea pig
Authors: O'Connor Karen M. , Lucking Eric F. , Burns David P. , O'Halloran Ken D. 
Published: November 2023

Chronic intermittent hypoxia (CIH), a major pathological feature of obstructive sleep apnoea, enhances carotid body (CB) chemosensory responses to hypoxia producing enhanced basal breathing and ventilatory responsiveness to hypoxia, increased respiratory instability, autonomic dysfunction, cardiac arrhythmias, and hypertension. CIH may also affect metabolic rate. We sought to explore if CIH induces ventilatory and/or metabolic changes in guinea‐pigs, a species that presents with hypoxia insensitive carotid bodies.Duncan Hartley adult male guinea pigs were exposed to repeated 5 minute cycles consisting of 90s hypoxia (FiO2=0.05 nadir) and 210s normoxia (FiO2 = 0.21) for 8 hours per day for 2 weeks (CIH, n=8). Sham animals (n=8) were subjected to the same environmental cues but were constantly exposed to room air. Guinea pigs had free access to food and water throughout the exposure. Using whole‐body plethysmography, ventilation and metabolism were measured during air breathing (FiO2 = 0.21), hypoxia (FiO2 = 0.10) and hypercapnia (FiCO2 = 0.05) in unanesthetised, unrestrained animals at quiet rest. Data are presented as mean±SD and were analysed using unpaired Student t tests or Mann‐Whitney U tests.Baseline ventilation and metabolism in normoxia were unaffected by exposure to CIH. As such, the ventilatory equivalent (VE/VCO2) was similar in CIH exposed and sham animals: 41.2±10.7 versus 35.6±5.2 (p=0.201; sham versus CIH). Exposure to acute hypoxia (FiO2 = 0.10 for 10 mins) did not alter VE, tidal volume (VT) or respiratory frequency (f), both in sham (47±4ml/min/100g; 0.5±0.04ml/100g and 103±9bpm, respectively) and CIH exposed animals (45±5ml/min/100g; 0.5±0.006ml/100g and 98±5bpm, respectively) compared with respective baseline values. Metabolism (VCO2) during acute hypoxia was not significantly different between the two groups (1.01±0.09 versus 1.16±0.2ml/min/100g). Nonetheless, VE/VCO2 was significantly decreased in CIH exposed animals compared with sham (46.6±2.9 versus 39.5±2.5; p=0.0001). In response to hypercapnia, CIH exposed animals had a significantly blunted tidal volume response compared with sham animals (1.1±0.01ml/100g versus 0.84±0.01ml/100g; sham versus CIH). However, VE/VCO2 during acute hypercapnia was not different between the two groups.Our data reveals that CIH exposure does not affect basal breathing, nor does it enhance hypoxic ventilatory responsiveness, which has been described in rats and mice with hypoxia sensitive carotid bodies. Our study employing a species with hypoxia insensitive carotid bodies suggests a critical role for CIH‐induced plasticity in peripheral oxygen sensing mechanisms within the carotid body in the manifestation of aberrant respiratory control.Support or Funding InformationDepartment of Physiology, School of Medicine, University College Cork
Aerobic Fitness Influences Autonomic Support of Blood Pressure in Premenopausal, but not Postmenopausal Women
Authors: Baker Sarah E , Limberg Jacqueline K , Nicholson Wayne T , Curry Timothy B , Barnes Jill N , Joyner Michael J 
Published: November 2023

BackgroundThe risk of hypertension increases as women reach menopause. Our group has recently reported that autonomic support of blood pressure (BP) is increased in post‐menopausal women. Given regular exercise is known to decrease the risk of developing hypertension, we investigated the role of aerobic fitness on autonomic support of BP in women. We hypothesized that trained premenopausal, but not postmenopausal, women would have less autonomic support of BP than age‐matched untrained women.MethodsTwelve healthy, young premenopausal (27±1yrs) and 10 older postmenopausal (56±1yrs) women completed VO2max tests on cycle ergometers. The participants were then stratified by fitness level based on VO2max percentiles from the American College of Sports Medicine's Guidelines (≤50th percentile = untrained; >50th percentile = trained; premenopausal: 7 untrained, 5 trained; postmenopausal: 5 untrained, 5 trained). On a separate day muscle sympathetic nerve activity (MSNA, microneurography, peroneal nerve), heart rate (electrocardiography), and blood pressure (brachial arterial catheter) were recorded before and during ganglionic blockade using trimethaphan camsylate (dose:1.5–7mg/min). Stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were calculated from the blood pressure waveform (WinCPRS).ResultsMuscle sympathetic nerve activity was higher in trained young women than in untrained young women (burst incidence: 35±11 vs. 12±2 bursts/100 heart beats, p=0.03). Young trained women had a smaller reduction in mean arterial pressure (MAP) with trimethaphan than young untrained women (ΔMAP:−5±3 vs. −15±4mmHg, p=0.01), despite a larger reduction in total peripheral resistance (ΔTPR: −6±1 vs. −2±1mmHg*min/L, p=0.02). The trained young women were able to maintain their MAP due to a greater increase in cardiac output (ΔCO: 1.4±0.4 vs. −0.3±0.3L/min, p= 0.01). In older postmenopausal women, MSNA and the fall in BP, CO, and TPR with trimethaphan were not different between trained and untrained individuals (p= 0.81, 0.16, 0.52 and 0.09, respectively).ConclusionBaseline MSNA was higher in trained premenopausal women when compared to untrained premenopausal women; however, aerobic fitness did not influence baseline MSNA in postmenopausal women. In young trained women, the fall in MAP following ganglionic blockade was only one‐third of the response seen in young untrained women. Baseline MSNA and the change in MAP, CO, and TPR with ganglionic blockade were not different between trained and untrained postmenopausal women. These data suggest aerobic fitness reduces autonomic support of blood pressure in young trained women, but not in trained postmenopausal women.Support or Funding InformationSupport: HL83947 (MJJ); HL131151 (SEB), DK 7352‐37 (SEB), HL118154 (JNB)
Central Hemodynamic Response to Acute Sympathetic Activation via Cold Pressor Test in Healthy Aging
Authors: Pearson James , Borner Anastasiya , Murray Kyle 
Published: November 2023

The incidence of cardiovascular related events, such as myocardial infarction and stroke, increase in aged individuals. This cardiovascular risk is elevated further during the winter months when environmental temperatures decrease. Increased sympathetic nerve activity accompanies decreases skin surface temperature. This increase in sympathetic nerve activity may have implications for the control of central hemodynamics and arterial stiffness. We aimed to investigate the influence of acute sympathetic activation via cold pressor test upon central hemodynamics and arterial stiffness in young and healthy aged individuals.Eleven young (Young: 7 males, 27±7yrs, 175±9cm, 77.4±13.8 kg) and eleven healthy aged individuals (Aged: 6 males, 57±12 yrs, 172±8 cm, 75.8±23 kg) completed a cold pressor test (CPT) where the left hand was immersed up to the wrist in 2–4°C water for 3 minutes while supine. All participants were free of cardiovascular acting medications and disease. Central hemodynamics and arterial stiffness, including subendocardial viability ratio (SEVR %), were estimated via radial tonometry linked to software with a generalized transfer function (SphygmoCor®, AtCor Medical). Aortic pulse wave reflection was referenced to a heart rate of 75 bpm (augmentation index; Aix75; %). Aortic pulse wave velocity (aPWV; m/s) was estimated using an automated sphygmomanometer (Mobil‐O‐Graph®; I.E.M). Mean arterial pressure (MAP; mmHg) and heart rate (HR; bpm) were estimated using photoplethysmography (NexFin®, BMEYE). Measurements were obtained at baseline prior to, during and at the end of the cold pressor test.Baseline MAP was not different between Young and Aged (90±10 vs. 91±10 mmHg, P > 0.05). Baseline AIx75 and aPWV were both different between Young and Aged (AIx75: −2±16 vs. 15±9% and aPWV: 5.4±0.6 vs.7.9±1.4 m/s, both P < 0.01). At the end of CPT, MAP increased relative to baseline in both Young and Aged (106±8 and 106±11 mmHg; both P < 0.01) but was not different between groups (P > 0.05). At the end of CPT AIx75 increased relative to baseline in both Young (+18±13% to 15±14%, P = 0.0003) and Aged (+12±6% to 26±7%; P = 0.0001). AIx75 was higher in the aged individuals at the end of the cold pressor test (P = 0.027). Relative to baseline SEVR was unchanged at the end of CPT in Young (150±35 to 155±42%; P > 0.05) but decreased in Aged (157±26 to 135±36%; P = 0.0055).Acute sympathetic activation via cold pressor test resulted in a greater aortic pulse wave reflection and reduced subendocardial viability ratio in healthy aged relative to young individuals. This suggests that acute sympathetic activation increases myocardial strain and may help explain the increased incidence of myocardial infarction in aged individuals during winter months.