bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Neurons Derived from a Human Induced Pluripotent Stem Cell Line Using Patch‐Clamp Electrophysiology
Authors: Metz Kathleen , Cao William , Coyne Leanne , Halliwell Robert 
Published: June 2021

Neuropharmacological studies using animal‐derived tissues are not always directly translatable to humans, and the occurrence of discrepancies can be difficult to predict. Sources of human neurons have been limited in the past, but developments in stem cell science are now providing new opportunities to generate human neurons from stem cells. iCell neurons are derived from a human induced pluripotent stem cell (hIPSC) line and may have the potential to replace animal neurons in neuropharmacological studies. Here, we have explored the neurophysiological and neuropharmacological properties of iCell neurons using immunocytochemistry and single‐cell patch‐clamp techniques.Whole cell recordings were obtained from iCell neurons cultured for up to 4 months in vitro. Functional expression of voltage‐gated sodium and potassium ion channels, as well as ligand‐gated GABAA, glutamate, NMDA, AMPA, kainate and glycine receptors was determined. Spontaneous and evoked action potentials were inhibited by the sodium channel blocker tetrodotoxin, and spontaneous activity levels increased over time in culture. Immunocytochemical analysis revealed a corresponding increase in neurite density over time. iCell neurons therefore appear to have several important functional properties consistent with human neurons and might be a viable alternative to animal neurons in drug studies.Research support was provided by Cellular Dynamics International and the Department of Physiology and Pharmacology at the University of the Pacific.
Perforating Corneal Injury in Rat and Pentadecapeptide BPC 157
Authors: Masnec Sanja , Kokot Antonio , Zlatar Mirna , Kalauz Miro , Radic Bozo , Klicek Robert , Drmic Domagoj , Lazic Ratimir , Seiwerth Sven , Sikiric Predrag 
Published: June 2021

Based on its healing effects in various tissues, we hypothesized that the stable gastric pentadecapeptide BPC 157 heals corneal ulcerations in rats and effects corneal transparency.A penetrant linear 2‐mm incision was made in the paralimbal region of the left cornea at the 5 o'clock position with a 20‐gauge MVR incision knife (Bausch & Lomb) at 45° under an operating microscope. Medication, comprising BPC 157 that was dissolved in distilled water at 2 pg/mL, 2 ng/mL, 2 µg/mL, 2 eye drops in the left eye per rat, was begun immediately after induction of the injury and continued every 8 h up to 120 h; controls received an equal volume of distilled water. In contrast to the poor healing response in controls, BPC 157 significantly accelerated the healing process in 2 µg and 2 ng BPC 157‐treated eyes, starting 24 h after the injury, and the fluorescein and Seidel tests became negative. The epithelial defects were completely healed at 72 h after the injury in the 2 µg BPC 157‐treated group and at 96 h after injury in the 2 ng BPC 157‐treated group. Aqueous cells were absent at 96 h and 120 h after injury in either 2 µg or 2 ng BPC 157‐treated groups, respectively.In conclusion, BPC 157 effects the rapid regaining of corneal transparency. Whereas controls developed new vessels that grew from the limbus to the penetrated area, BPC 157‐treated rats generally had no new vessels, and those that did form in the limbus did not make contact with the penetrated area. Thus, BPC 157 eye drops successfully close perforating corneal incisions in rats. Supported by Grant 108‐1083570‐3635, Croatia
Unacylated Ghrelin Protects Hearts of Mice Subjected to Myocardial Ischemia/Reperfusion
Authors: Huynh David , Bessi Valerie , Ménard Liliane , Noll Christophe , Carpentier Andre , Ong Huy , Marleau Sylvie 
Published: June 2021

ObjectiveGhrelin can be found in the circulation under two different forms: acylated ghrelin (AG) and unacylated ghrelin (UAG). UAG, while being the predominant ghrelin isoform in circulation, is devoid of endocrine activity. Despite its inability to activate the classical ghrelin receptor, some studies have shown that UAG possesses cardiotropic properties. Our aim is to investigate the cardioprotective effects of UAG against myocardial ischemia‐reperfusion (MI/R) injury.MethodsC57BL/6 mice were pretreated twice a day for 14 days with either AG or UAG at 200 nmol/kg/day. Myocardial ischemia was induced by the ligature of left anterior descending coronary artery for 30 min, followed by reperfusion for 6 or 48 h.ResultsInfarct sizes were reduced by 68 and 60% (P<0.001) in AG‐ (n=6) and UAG‐treated mice (n=5), respectively. Unlike the UAG‐treated group, mice treated with AG showed increased fractional uptake rate (Ki) and net (Km) uptake of free fatty acids (FFA), by 46% (P<0.01) and 44% (P<0.05), respectively, using micropositron emission tomography. Plasma FFA concentrations and glycemia, however, were not significantly different between groups.ConclusionOur results show that both AG and UAG are cardioprotective against MI/R, but exert different cardiometabolic effects, with UAG protecting against the early increased FA uptake following reperfusion of ischemic hearts. Our study suggests that UAG could be a promising therapy to reduce myocardial ischemia/reperfusion injury.Supported by the Heart and Stroke Foundation of Quebec and the Canadian Institutes of Health Research.
The Macrophages as the Stimulators of B‐cells Proliferation in the Pancreas
Authors: Danilova Irina , Bulavintseva Tatiana , Gette Irina , Medvedeva Svetlana , Abidov Mussa 
Published: June 2021

The main reason for the development of type 1 diabetes is decrease of the absolute number of B‐cells and their functional activity. The goal of our study was to investigate the regulation of B‐cells regeneration and function.The model of alloxan diabetes was simulated on male Wistar rats according the author's modified method. The treatment of animals responded EC Directive 2010/63/EU. The content of macrophages was determined by the immunohistochemical study of the pancreatic sections (MAC387) (Abcam), and the number of proliferating B cells was detected with double immunohistochemical staining (insulin antibodies (clone E11D7, Millipore) and Ki67 (BD)). The number and size of pancreatic islets were counted. The derivatives of aminoftalhydrozide were used as the modulators of macrophage activity (patent). The density of B‐cells, their proliferative and secretory activity were significantly decreased of the pancreas of diabetic animals, the average size of islets was also decreased. The number of macrophages in the pancreas islets of diabetic animals was drastically increased. This was reduced by half after immunomodulation. The result of immunomodulation was the increase of islets' size, B‐cells' content and their secretory activity. Consequently, a significant decrease of glucose and Hb1c concentration and an increase of the level of insulin were observed in blood.These results afford to use the modulation of macrophage as a promising strategy in the stimulation of reparative processes in the pancreas.
Vitamin D Attenuates TNFα‐induced Chemokine Production in Developing Human Airway Smooth Muscle Cells
Authors: Britt Rodney , Faksh Arij , Vogel Elizabeth , Thompson Michael , Pandya Hitesh , Amrani Yassine , Pabelick Christina , Prakash YS 
Published: June 2021

Introduction: Children with low Vitamin D levels are at increased risk of developing asthma. In the present study, we tested the hypothesis that the Vitamin D receptor (VDR) agonist, calcitriol, will reduce tumor necrosis factor‐α (TNF‐α)‐induced expression of chemokines in human fetal airway smooth muscle cells (fASM).Methods and ResultsHuman fASM cells were dissociated from canalicular stage (18‐22 weeks gestation) lung tissue (de‐identified samples, in vitro use only and considered exempt by Mayo Institutional Review Board). Fetal ASM cells were pre‐treated with vehicle (0.001% DMSO) or 100 nM calcitriol for 1 h, and then exposed to 10 ng/mL TNFα for 6 or 24 h. Expression of CCL5 and CCL11 were measured by quantitative real time PCR and ELISA. Cells were transfected with VDR siRNA. Treatment with TNFα for 6 h increased mRNA expression and secretion of CCL5 and CCL11. While pre‐treatment with calcitriol reduced CCL5 and CCL11 expression in the presence of TNFα. Knockdown of the VDR expression demonstrated that calcitriol's effects are mediated through VDR.ConclusionsThese novel data demonstrate that calcitriol modulates cytokine enhancement of chemokines in developing ASM. Vitamin D may be a new therapeutic target in reducing inflammation in the immature airway.Supported by NIH F32 HL123075 (Britt), T32 HL105355 (Vogel), and R01s HL088029 and HL056470 (Prakash), and the Mayo Clinic Department of Anesthesiology (Pabelick, Prakash).
Hypercontractile Airway Smooth Muscle is a Potential Driver of Respiratory Pathophysiology in Congenital Muscular Dystrophy 1A
Authors: Pate Jessica , Kumar Ajay , Girgenrath Mahasweta , Morgan Kathleen 
Published: June 2021

Merosin deficient congenital muscular dystrophy (MDC1A) is a fatal, autosomal recessive disease caused by laminin α2 chain deficiency, preventing formation of the extracellular matrix protein laminin 211. Afflicted children experience profound muscle weakness and degeneration and often die prematurely from failure to thrive or acute respiratory failure resulting from weak respiratory muscles and progressive scoliosis. While diseased skeletal muscle has been well characterized, airway smooth muscle (ASM) has not been investigated and respiratory failure has been attributed solely to diaphragmatic weakness. Therefore, as a first step we investigated the contractile properties of ASM isolated from DyW mice, an animal model of MDC1A.Primary bronchial rings from 7wk WT and DyW mice were harvested and cleaned. Rings were mounted on wire triangles in a bath with oxygenated Krebs solution and connected to a force transducer to measure contractile responses to depolarizing 51mM KCl Krebs solution and 10‐5 M carbachol to activate G‐protein coupled muscarinic receptors. Rings were quick frozen and saved for histological analysis. Transverse sections (7 µm thick) were stained with Gomori Trichrome to differentiate ASM. Bronchial ASM cross sectional area (CSA) was calculated using NIS Basic Research software. Contractile forces were normalized to ASM CSA to determine ASM stress.The stress responses of DyW bronchi are significantly higher than WT in response to both 51 mM KCl (nWT=7, nDyW=3, p<0.002) and 10‐5 M carbachol (nWT =8, nDyW =4, p<0.006). These data indicate that ASM isolated from DyW mice are significantly hypercontractile compared to their WT counterpart, and could potentially contribute to respiratory insufficiency in MDC1A.
Role of PGE2/EP4 Receptor Signaling on The Effects of Hyperoxia on Airway Smooth Muscle
Authors: Jakupaj Muharrem , Sopi Ramadan , Dreshaj Ismail , Mladenov Mitko , Temaj Gazmend , Cenaj Asllan , Neziri Burim , Beqiri Qëndresa , Krasniqi Avdyl 
Published: June 2021

It was shown that neonatal hyperoxic‐exposure associates with airway hyperresponsiveness and impaired nonadrenergic noncholinergic relaxation. It was demonstrated that reduced relaxant responses were associated with an impairment of prostaglandin E2 (PGE2) release from airway smooth muscle (ASM). In this study we tested the hypothesis that supplementation of PGE2 or EP4 agonists to ASM restore relaxant responses. Tracheal cylinders were obtained from 12 days rat pups exposed to hyperoxia or room air for seven days. These cylinders were used to study contractile and relaxant responses. In hyperoxic trachea the contractile responses to bethanechol were enhanced as compared to room air controls. These enhanced contractile responses were attenuated by pre‐incubation of tissues with PGE2 (1µM). Similar effect showed an EP4 agonist. This effect of PGE2 and EP4 agonist was reversed by an EP4 antagonist. PGE2 and EP4 induced dose response relaxations of ASM, which were reduced by an EP4 antagonist.We conclude that PGE2 induces relaxation of airways via EP4 receptors, and the use of EP4 agonists may serve as a therapeutic approach to overcome the adverse effects of neonatal hyperoxia on relaxant responses of ASM.Supported by MEST
Oscillating wildly: Turning the evolution of respiratory rhythm generation on its head
Authors: Baghdadwala Mufaddal , Trask William , Wilson Richard 
Published: June 2021

How the neuronal control of air breathing evolved is unknown. Brainstem circuits controlling breathing have only been investigated in a small handful of extant vertebrates. This makes an evolutionary analysis challenging.In the frog, we have found evidence for three areas involved in respiratory rhythm generation, each with distinct pharmacologies: the buccal area in rhombomere 7 as well as both lung burst priming and lung burst power stroke regions situated in rhombomeres 4‐5. We have long assumed that circuits generating air breathing in mammals and frogs are homologous, evolving from a common ancestry. However, there are some inconsistencies with this assumption. The primary inspiratory oscillator in mammals, the PreBötzinger Complex (PreBötC), is located in rhombomere 7‐‐the same rhombomere as the frog buccal area‐‐and the rhythms produced by buccal and PreBötC are stubbornly independent of CO2. In comparison, like pre‐inspiratory/expiratory activity in mammals, the lung bursts in the frog are highly CO2 sensitive, and both originate in rhombomere 4‐5.These data suggest that we may have to turn our previous hypothesis that the frog lung area and PreBötC are homologous on its head and consider the possibility that the mammalian PreBötC evolved from a fish oscillator used for water‐breathing. Until more studies on non‐mammalian vertebrates are performed any hypothesis on the evolution of air breathing is but a work in progress, and with so little data currently available, further oscillations are likely.This work was funded by NSERC.
PET Radiopharmaceuticals for the Diagnosis of Cancer
Authors: Lewis Jason 
Published: June 2021

The use of Positron Emission Tomography (PET) for cancer imaging is a well‐established and widely used molecular imaging modality both in clinical and research settings. PET offers the ability to quantitatively measure biological and receptor‐based processes using a wide spectrum of specifically designed radiopharmaceuticals exploiting small molecule‐, peptide‐, antibody‐ and nanoparticle‐based platforms. One novel avenue of application is the PET and molecular imaging of serum biomarkers. One prominent shortcoming in oncology is a high frequency of false positive indications for malignant disease in upfront diagnosis. Because one common cause of false positivism is biomarker production from benign disorders in unrelated host tissues, we hypothesized that probing the site(s) of biomarker secretion with an imaging tool could be a broadly useful strategy to deconvolute the meaning of foreboding but inconclusive circulating biomarker levels. Recent approaches with antibody‐based platforms to image biomarkers will be discussed.
Temperature Effects on the Chick Embryonic Heart Function
Authors: Vostarek Frantisek , Svatunkova Jarmila , Sedmera David 
Published: June 2021

The function of the embryonic heart is strongly affected by temperature. Changes in the kinetics of ion channels are crucial for generation and propagation of electricity. We set to analyze in detail the effects of temperature changes on electrical activity of the embryonic chick heart using in vitro high‐speed calcium imaging and in ovo video microscopy.In embryonic day 4 hearts we found that a decrease in temperature from 37 °C to 34 °C lead in vitro to a 22 % drop of the intrinsic heart rate and unchanged amplitude of Ca2+ transients, compared to a 25% deceleration between 37 °C and 34 °C in ovo. Increase in temperature from 37 °C to 40 °C lead in vivo to 23% and in ovo to 20 % acceleration of the intrinsic heart rate, and a significant decrease in amplitude of Ca2+ transients (atrium ‐35%, ventricle ‐38%). Hyperthermia in vitro increased the incidence of complete atrioventricular (AV) blocks, while no complete AV block was observed in hypothermia. Similar situation was recorded in ovo. Electrical stimulation experiments in ovo suggested that the AV blocks were caused by hypoxia a not by the tachycardia per se. Activation maps placed the location of the AV block at the inner curvature and the AV canal‐ventricular boundary along the outer curvature.Temperature is thus an important epigenetic factor influencing the function of the developing cardiac conduction system. Increased temperature augments the metabolic requirements of the myocardium, resulting in a relative hypoxia and AV conduction disturbances.Supported by GACR P302/11/1308 (DS) and GAUK 716214 (FV).
Compound H Increases Anti‐aging Protein Klotho Expression and Attenuates Arterial Stiffening and Hypertension
Authors: Chen Kai , Chen Jianglei , Sun Zhongjie 
Published: June 2021

Background & ObjectiveThe prevalence of arterial stiffness and hypertension increases with age while the klotho level decreases with age. Compound H stimulates klotho mRNA and protein expression in cell cultures and mouse kidneys. The objective of this study is to asses if compound H affects arterial stiffening and hypertension in aged mice.Methods & Results– Aged mice (24‐30 months) were treated with or without compound H (15 mg/kg, IP daily) for 2 weeks, and adult mice without treatments were used as controls (12 months). Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Compound H reversed aging‐related increases in PWV and BP within 2 weeks of treatment. Compound H effectively increased secreted klotho levels in both kidney and serum. Aging‐related arterial stiffness was associated with increased collagen and decreased elastin contents in the media of aortas. In addition, the expression of MMP2, MM9, and TGFb1 was increased in aortas of aged mice. These changes were attenuated by compound H.ConclusionAging‐related arterial stiffening and hypertension are attributed, at least in part, to klotho deficiency. Compound H increases klotho expression and attenuates arterial stiffening and hypertension in aged mice.
Angiotensin II‐Induced Erectile Dysfunction Prevented By Bradykinin B1 Receptor Antagonism
Authors: McCormick Brittney , Huot‐Marchand Julie‐Emilie , Carrol Chad , Carrier Serge , deBlois Denis , Hale Taben 
Published: June 2021

Chronic angiotensin II (AngII) treatment induces erectile dysfunction in rats. In penile erectile tissue, AngII stimulates smooth muscle contraction leading to detumescence, while bradykinin promotes relaxation to facilitate erection. AngII has been shown to increase bradykinin B1 receptor (B1R) expression in aorta however; an interaction between these systems has not been examined in erectile tissue. This study investigated the impact of bradykinin B1R antagonism on AngII‐induced erectile dysfunction. Sprague‐Dawley rats were treated with vehicle or AngII in the presence or absence of the B1R antagonist R‐954. After 4weeks, arterial pressure (MAP) and erectile function were assessed in anesthetized rats. AngII increased MAP and left ventricular mass, and significantly impaired erectile function relative to control. While concomitant B1R antagonism had no impact on AngII‐induced hypertension, it prevented the cardiac hypertrophy and erectile dysfunction. Impaired erectile responses were not associated with changes in cavernosal collagen content, ROS production, or endothelial NOS or SMAD2/3 expression. This study reveals for the first time that bradykinin B1R blockade can offset AngII‐induced erectile dysfunction independent of hypertension and unrelated to cavernosal tissue remodeling. Future studies will investigate mechanisms underlying this effect and provide insight into the inter‐regulation of the RAS and kallikrein kinin system in erectile function.Funding: APS STRIDE program (NHLBI; 1 R25 HL115473‐01), CMSHC
Chronic heart failure and nitrate supplementation: Impact on skeletal muscle vascular control in exercising rats
Authors: Ferguson Scott , Holdsworth Clark , Wright Jennifer , Hageman Karen , Musch Timothy , Poole David 
Published: June 2021

Chronic heart failure (CHF) results in central and peripheral derangements that ultimately reduce skeletal muscle O2 delivery and impair exercise tolerance. Dietary nitrate (NO3‐) supplementation improves skeletal muscle vascular function and improves tolerance to exercise. We tested the hypothesis that NO3‐ supplementation would elevate exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats. Myocardial infarction (MI) was induced (coronary artery ligation) in young‐adult male rats. After 21‐days of recovery, rats randomly received NO3‐ rich beetroot juice (CHF+BR, n=10) or a placebo (CHF, n=10). Mean arterial pressure (MAP, carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) was measured during treadmill exercise (20 m/min, 5% grade). CHF parameters (MI size, CHF: 29 ± 3, CHF+BR: 33 ± 4%, LVEDP, CHF: 18 ± 2, CHF+BR: 18 ± 2 mmHg) and exercising MAP (CHF: 131 ± 3, CHF +BR: 128 ± 4 mmHg) were not different (P<0.05) between groups. Total hindlimb skeletal muscle BF (CHF: 95 ± 5, CHF+BR: 116 ± 9 ml/min/100g) and VC (CHF: 0.75 ± 0.05, CHF+BR: 0.90 ± 0.05) were greater (P<0.05) in BR supplemented rats. The increases in BF and VC (P<0.05) were found preferentially in muscles and muscle parts containing 蠅70% type IIb + d/x muscle fibers which resulted in a ~22% increase in total skeletal muscle BF and a 20% increase in total VC during exercise. These results provide strong evidence that dietary NO3‐ supplementation improves skeletal muscle vascular function during exercise in rats with CHF and suggest that BR may provide a novel therapeutic modality for the treatment of CHF. NIH HL‐108328
Extended Daily Exercise is the Key to Blood Pressure and BMI Reductions in High School Students
Authors: Hayes Shawn , Irvin Erica 
Published: June 2021

ObjectiveDemonstrate if combining physical education (PE) and health classes into an extended daily single class model will result in decreases in blood pressure and BMI in overweight and obese students.MethodsAt a high school in Portland, OR, HealthCorps and school staff developed and implemented the Fit2Live and Learn (F2LL) program, an integrative approach to health and PE. This was an adjunct to the wellness program run by HealthCorps in the school. The prior PE program was changed from a class that met every other day to a class that met daily for 90 minutes, covering two class periods. Students received credits for both Health and Physical Education courses. The program combined its traditional Health and PE classes into an experiential integrative approach to health concepts. The F2LL program was a school‐year long practice of optimal exercise, healthy eating and mental strength habits for students. We measured BMI, blood pressure, heart rate and percent body fat as measured by bioelectric impedance analysis.ResultsIn a group of 43 students, systolic blood pressure was reduced from 121 to 111 mm Hg (p<0.05) over the course of four visits (eight months). In a subset of those students who were either overweight or obese (n=14), systolic BP decreased from 128 to 117 mm Hg (p<0.05). Diastolic blood pressure and heart rate did not change significantly in any group. BMI was reduced in overweight and obese freshman (BMI>25) from 33.1 to 32.2 kg/m2 and in obese freshman (BMI>30) 37.8 to 37.2 kg/m2. There was a concomitant decrease in percent body fat by 1.4%.ConclusionThe F2LL program combined with HealthCorps' program emphasizing nutrition, mental resilience and physical activity, resulted in significant decreases in blood pressure and BMI in the freshman PE class at one Portland public high school.