bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improvement of the Adipokines Profile and Insulin Resistance in Metabolic Syndrome Patients Induced by Galantamine Activation of Cholinergic Pathway
Authors: Sangaleti Carine Teles , Costa Fernando Oliveira , Moraes Tercio Lemos , Irigoyen Maria Claudia , Bortolotto Luiz Aparecido Teles , Lopes Heno Ferreira , Pavlov Valentin , Tracey Kevin , Consolim‐Colombo Fernanda Marciano 
Published: November 2023

IntroductionGalantamine, an acetylcholinesterase inhibitor, has been studied showing beneficial effects in preclinical settings of the Metabolic Syndrome (MetS). There is no evidence of clinical investigations addressing to neuroinflammatory modulation with galantamine in MetS.PurposeThe aim of this study was to verify the effects of galantamine treatment on adiponectin and leptin levels and insulin resistance in patients with the MetS.MethodsA prospective, randomized, double‐blind, placebo‐controlled study with 60 patients (30 male), 18–59 years old, that fulfilled the criteria of MetS according to the National Cholesterol Education Program, and met additional inclusion and exclusion criteria was conducted. Patients were randomized in 1:1 ratio to receive placebo or Galantamine capsules at a dose of 8 mg for 4 weeks and 16 mg during 8 additional weeks. Clinical parameters, plasma levels of adiponectin, leptin, insulin and calculation of homeostasis model assessment for insulin resistance (HOMA IR) were performed before randomization (time 0 ‐ T0) and at the end of the study (time 1‐ T1). Two‐way repeated measures ANOVA was used to compare differences between groups and T0 ‐ T1. P<0.05 was considered statically significant.ResultsPrior to treatment with placebo or Galantamine (T0), patients were randomized as follows: age=43±3 vs 41±3 years; body mass index = 34±1 vs 35±1 kg/m2; abdominal circumference = 107±2 vs 108±1 cm; systolic blood pressure =125±2 vs 126±2 mmHg; diastolic blood pressure = 79±2 vs 81±1 mmHg; and heart rate = 70±2 vs 72±1 bpm. No significant alterations in these parameters were observed at T1. At T0 placebo and Galantamine groups had similar levels of adiponectin (8.9±0.2 vs 8.8±3 μg/ml), leptin (32.5±0.3 vs 33.3±0.4 ng/ml) and HOMA IR (3.8±0.3 vs 4.2±0.3). However, plasma adiponectin levels were significantly decreased in placebo group and increased in Galantamine group at T1 (7.0±0.2 vs 9.7±0.4 μg/ml). In contrast, plasma leptin levels and HOMA IR were significantly increased in placebo group and decreased in the Galantamine group at T1 (respectively, 36.9±0.4 vs 25.6±0.3 ng/ml and 6.0±1.2 vs 2.7±0.2).ConclusionOur results indicate a previously unrecognized efficacy of Galantamine in regulating adipokines levels and attenuating insulin resistance in patients with MetSSupport or Funding InformationFundação de Amparo à pesquisa do Estado de São Paulo ‐ FAPESP
Diet‐induced obesity increases hepatic Mig6 expression and attenuates EGFR signaling
Authors: Lutkewitte Andrew J , Fueger Patrick T , Chen Yi‐Chun , Hansen Jeffrey L 
Published: November 2023

Obesity‐induced hepatic steatosis provokes endoplasmic reticulum (ER) stress, which negatively affects cellular processes such as proliferation, survival, and metabolism. Physiologically, the epidermal growth factor receptor (EGFR) is a prominent receptor tyrosine kinase governing hepatocyte proliferation and survival following stress or injury. Unfortunately, EGFR expression and activity, as well as complete hepatic regeneration, are impaired in genetic and diet‐induced obesity (DIO). Therefore, the endogenous feedback inhibitor of EGFR activity, mitogen‐inducible gene 6 (Mig6) could be a novel target for enhancing liver regeneration in DIO‐mediated stress and injury. Thus, we hypothesized DIO‐induced hepatic stress increases Mig6 expression, thereby decreasing EGFR activation. Using primary hepatocytes and cell lines we established that both chemical‐and fatty acid‐induced ER stress decreased EGFR activation and signaling while inducing cell death. Furthermore, Mig6 ablation in hepatocytes restored EGFR signaling and reduced cell death as measured by caspase 3/7 activity. In vivo, C57Bl/6J mice fed a high fat diet (HFD), exhibited increased Mig6 protein expression during DIO and hepatic ER stress. Next, we used Mig6 liver‐specific knockout (LKO) mice fed a HFD to assess the metabolic and hepatic phenotype of Mig6 liver ablation. Mig6 LKO mice had increased liver mass and improved glucose tolerance despite similar hepatic triglyceride content compared to littermate controls. These data suggest Mig6 restricts growth and impairs glucose metabolism regardless of hepatic triglyceride content. We conclude that Mig6 is increased during ER stress from DIO, thereby reducing EGFR activation and bolstering glucose intolerance. The implications are the induction of Mig6 during DIO may attenuate cellular repair and disrupt glucose homeostasis, leading to impaired hepatic function during steatosis.Support or Funding InformationThis work was supported by NIH grant DK099311 (PTF) and American Heart Association Predoctoral Fellowship (AJL)
HSP72 is required for exercise‐induced protection against ventilator‐induced diaphragm dysfunction
Authors: Smuder Ashley J , Morton Aaron B , Hall Stephanie E , Ahn Bumsoo , Wiggs Michael P , Wawrzyniak Nicholas R , Powers Scott K 
Published: November 2023

Mechanical ventilation (MV) is a life‐saving measure for patients in respiratory failure. However, prolonged MV causes significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator‐induced diaphragm dysfunction (VIDD). VIDD occurs as a result of mitochondrial dysfunction, which triggers the production of reactive oxygen species (ROS) and initiates proteolysis. Recent evidence reveals that endurance exercise training is sufficient to prevent MV‐induced mitochondrial dysfunction and avert VIDD. However, the mechanism by which exercise protects the diaphragm against VIDD remains unknown. It is established that exercise promotes numerous cytoprotective adaptations in skeletal muscle fibers, including increased expression of heat shock protein 72 (HSP72). HSP72 plays a key role in numerous cellular functions and overexpression of HSP72 in skeletal muscle can protect against inactivity‐induced muscle atrophy. Therefore, we tested the hypothesis that exercise‐induced HSP72 expression is required to protect against VIDD. Cause and effect was determined by inhibiting the endurance exercise‐induced increase in HSP72 in the diaphragm of exercise trained animals that were subsequently exposed to prolonged MV. Our results confirm that exercise training protects against MV‐induced mitochondrial dysfunction and ROS production, and prevents VIDD. Importantly, inhibition of the exercise‐induced increase in HSP72 in the diaphragm precluded the exercise‐induced protection against VIDD. In addition, prevention of exercise‐induced increases in diaphragm HSP72 attenuated the exercise‐induced reduction in MV‐induced mitochondrial dysfunction, ROS production and protease activation in the diaphragm. We conclude that exercise‐induced protection against VIDD is mediated, in part, by increased abundance of HSP72 in the diaphragm.Support or Funding InformationSupported by NIH R01 AR064189 awarded to SKP
Metabolic Implications of Single‐Unit Avian Intrapulmonary CO2 Chemoreceptor (IPC) Responses to Sustained Anoxia and Normoxia
Authors: Low Trevor Michael , Hempleman Steven Curtis , Molloy Rhett Gordon , Solomon Irene C 
Published: November 2023

Pilarski et al, AJPRegu, 296:1576–1584, 2009 reported that tonic and phasic IPC CO2 transduction are both eliminated by mitochondrial Electron Transport System (ETS) inhibitor rotenone, while ETS uncoupler 2,4‐DNP inhibited only tonic CO2 transduction. They suggested that glycolysis may provide sufficient ATP to power phasic IPC transduction, but not the tonic. To investigate further, we separately ventilated and perfused the R and L lungs of anesthetized mallard ducks, and recorded phasic and tonic L lung IPC responses to CO2 in 6 IPC. Ten (10) min of complete L lung anoxia produced by ligating the L pulmonary artery (LPA) and ventilating L lung with N2 and CO2 reduced average tonic and phasic IPC CO2 responses by 75% (p<0.001). Returning O2 to L lung ventilating gas restored phasic IPC responses to normal but tonic responses remained 50% depressed (p<0.001). Returning blood flow through LPA as well as returning O2 to L lung ventilating gas restored phasic and tonic responses to normal. We suggest tonic IPC responses may need ETS to generate ATP and also blood‐flow to replenish metabolites and ions; whereas phasic IPC responses need ETS mainly to oxidize reduced NADH to allow glycolysis to continue.Support or Funding InformationSupport: NIH R15 HL087269‐02.
Restoration of brain serotonin synthesis in Tph2 knockout (Tph2−/−) rats significantly increases eupneic ventilation during postnatal development
Authors: Massat Benjamin , Martino Paul , Hodges Matt 
Published: November 2023

Sudden Infant Death Syndrome (SIDS) is the leading cause of post‐neonatal mortality in the United States. SIDS victims have been found to have lower levels of brainstem tryptophan hydroxylase 2 (Tph2) and serotonin (5‐HT) but retain 5‐HT‐producing neurons. Tph2 is brain specific enzyme that converts tryptophan into 5‐HTP, which is then converted into 5‐HT by dopa decarboxylase (DDC). Our previous data indicated that rats lacking Tph2 failed to generate brain 5‐HT and had dramatically reduced ventilation at rest from postnatal ages (P) 12–17. This study aimed to determine if the CNS 5‐HT depletion could be restored and if reduced ventilation normalized in Tph2−/− rats given 5‐HTP. Respiratory variables were measured for ~20 minutes with a whole body plethysmograph designed to study young rats breathing continuously supplied with room air. Following an initial study, pups were given a set of three injections of either saline (0.9% NaCl; n=12 WT rats) or 5‐HTP (10 mg/kg; n=9 Tph2−/−rats) at 12‐hour increments and then studied again a minimum of one hour after the third injection. Brain tissue (HPLC) and tail clippings (genotyping) were collected immediately post‐study. We found that 5‐HTP injections in Tph2−/− rats led to detectable levels of 5‐HT in the brain, nearly reaching control levels. Importantly, 5‐HTP treatment did not alter dopamine or norepinephrine levels in the brain. Prior to 5‐HTP treatment, Tph2−/− pups had significantly reduced eupneic VE and breathing frequency (P < 0.05). Saline injections had no effects on VE, breathing frequency, or VT in WT littermates. However, 5‐HTP treatments in DATph2−/− pups significantly increased VE, VT, and f (P < 0.05) from pre‐injection control, where VE (and VT) were greater in 5‐HTP‐treated DATph2−/− pups compared to saline treated WT pups (P < 0.05). These data show that injections of 5‐HTP led to 5‐HT production in Tph2−/− rats, which increased resting minute ventilation, tidal volume, and breathing frequency. Thus, DATph2−/− rats may provide a useful animal model in which CNS 5‐HT levels can be temporally controlled in to more fully understand the roles of 5‐HT during development.Support or Funding InformationFunded by the American Physiological Society Undergraduate Summer Research Fellowship
Developmental changes in trigeminal motoneuron properties in the American bullfrog, Lithobates catesbeianus
Authors: Kinkead Richard , Fournier Stéphanie , Chamberland Simon 
Published: November 2023

In frogs, the neural circuits generating gill and lung ventilation are distinct, yet their activities converge on the same groups of motoneurons located in the brainstem, including the trigeminal, hypoglossal, and vagal motoneurons. Because lung ventilation requires more forceful contractions to “push” air back into the lungs, it is plausible that the basic electrophysiological properties of respiratory motoneurons that activate the buccal musculature change during tadpole development in ways that facilitate lung ventilation; however, this hypothesis remains untested. To address this issue we used an electrophysiological approach to compare the functional properties of trigeminal motoneurons between pre‐metamorphic tadpoles and adult frogs. Retrograde labelling of trigeminal motoneurons was performed with the fluorescent marker DiI at least 14 days prior to experiments. Using a coronal slice preparation, we performed whole‐cell recordings from fluorescently‐tagged cells to measure basic motoneurons properties. Electrophysiological characterization was performed by measuring membrane potential responses to steps of current injections. Unexpectedly, the trigeminal motor pool seemed to be composed of two distinct motoneuron populations based on cell size. Resting membrane potential did not differ between populations or developmental stages (~−54 mV). The smaller cells were generally more excitable than the larger ones as indicated by a lower rheobase (49 ± 7 versus 275 ± 48 pA) and a more hyperpolarized action potential threshold (−43 ± 2 versus −38 ± 2 mV). The density of the hyperpolarization‐activated inward current (Ih) was more than 10 times greater in smaller cells. With regards to development, recordings revealed lower membrane resistance in frogs than tadpoles; this developmental change was more important in the smaller cells. Finally, the amplitude of evoked action potentials was greater in frog motoneurons than tadpoles; the developmental augmentation was more important in the smaller cells. While morphometric assessment of each cell type is underway, the cell heterogeneity observed in the trigeminal motor nucleus raises the possibility that the different cell types are associated with different motor commands (gill versus lung ventilation). Owing to the developmental changes observed in the smaller cells, we propose that this population is associated with the production of air breaths.Support or Funding InformationSupported by Natural Sciences and Engineering Research Council of Canada
Maturational changes in phenotype and electrophysiological properties of Bötzinger Complex post‐inspiratory neurons of rats
Authors: Moraes Davi J.A. , da Silva Melina P. , Varanda Wamberto A. , Machado Benedito H. 
Published: November 2023

Respiratory pattern is determined by chloride‐mediated conductances via GABAergic and glycinergic receptors. GABA and glycine act as inhibitory neurotransmitters in the adult central nervous system, but as excitatory neurotransmitters during postnatal development. In this study, we investigated the respiratory pattern, electrophysiological properties, phenotype and the actions of chloride‐mediated conductances on Bötzinger Complex (BötC) post‐inspiratory (post‐I) neurons on different postnatal days [neonatal, P1–5 (n=25); intermediate, P6–15 (n=39); juvenile, P15–21 (n=45); adult, P22–40 (n=57)] in in situ preparation of rats. Age‐dependent increase in both duration of expiration and post‐inspiration over the first 14 days of life were observed. Regarding the glicinergic and glutamatergic BötC post‐I neurons, burst activity, low threshold spike and calcium current increased with age. Changes in subthreshold responses were also observed, including an increase in input resistance and excitability. Rheobase current, spike frequency adaptation and action potential duration decreased progressively during postnatal development. The transition from excitatory to inhibitory effects of GABA and glycine on BötC post‐I neurons occurred at approximately P6. The age‐dependent changes in the actions of chloride‐mediated conductances are mediated by the development of chloride cotransporters (KCC2, NKCC1 and NKCC2) in BötC post‐I neurons. We conclude that postnatal maturation of the electrophysiological properties of BötC post‐I neurons may explain the development changes in the respiratory pattern and respiratory control of upper airway resistance in rats.Support or Funding InformationFAPESP
Thyroid hormone deficiency disrupts respiratory control development and responses to hypoxia in newborn rat
Authors: Rousseau Jean‐Philippe , Kinkead Richard 
Published: November 2023

The brain is an important target of thyroid hormones (THs) at all stage of life, however, the maximal vulnerability to an imbalance of TH supply occurs during the early development when the developing embryo/foetus is dependent on maternal supply of TH. During this time, any maternal TH deficiency, small or severe, can alter brain structure or function which can become progressively and substantially magnified during subsequent developmental periods to produce long‐lasting or permanent deficits. The earlier in development thyroid hormone deficiency occurs, the more profound effects it will have on the development of an organism and individual organs such as brain. There is an abundant literature on the effects of maternal TH deficiency on development and function of the central nervous system, lungs, neuromuscular junctions and diaphragm; however, little is known about this influence on respiratory control development. Because thyroid hormone receptors (TRs) are expressed in the fetal brain during gestation and they are present in the brainstem, we proposed that TH can influence respiratory control development in the newborn rodent. Specifically, we hypothesised that a perinatal deficiency in thyroid hormones is sufficient to disrupt the development of respiratory circuits in the rodent. Thyroid hormone deficiency in the foetus was recreated by administrating an antithyroid susbstance (Methimazole;MMI) in drinking water of the pregnant dam at concentration of 0,02% (weight per volume; w/v) from the first day of pregnancy (gestational day 1; GD1) to the day of experiment with the newborn. In‐vitro and in‐vivo measurements were performed on Sprague Dawley rats aged of 1 and 4 days (P1–P4). Fictive breathing (in‐vitro) was measured by extracting the brainstem with a part of the spinal cord and placing it in a chamber where it was superfused with an artificial cerebrospinal fluid (aCSF). The output signal from the respiratory network was recorded by a suction electrode placed on the fourth ventral root representing the inspiratory signal sent to the diaphragm via the phrenic nerve. Measurements of ventilatory activity (in‐vivo) in newborn pups were performed using whole‐body, flow‐through plethysmography. Development of the hypoxic chemoreflex was compared between groups in each protocol using a 15 minutes period hypoxia. By comparison with controls, pups from MMI treated dams did show age‐dependent decrease in phrenic burst frequency under normoxic conditions. In 4 days old pups (MMI), phrenic burst depression was not observed during hypoxia. The in‐vivo results from the whole‐body plethysmography reveal a decrease in the basal minute ventilation (VE) in treated 1 day old pups and a blunted hypoxic ventilatory response. We conclude that thyroid deficiency during perinatal period alters the respiratory control development and responsiveness to a hypoxic challenge.Support or Funding InformationSupported by NSERC.
Canonical Transient Receptor Potential 4 Protein Encodes High Frequency Calcium Transients in Severe Pulmonary Arterial Hypertension
Authors: Francis Christopher Michael , Xu Ningyong , Zhou Chun , Stevens Troy 
Published: November 2023

Canonical transient receptor potential 4 protein (TRPC4) comprises an endothelial store‐operated calcium entry channel, and TRPC4 inactivation confers a survival benefit in pulmonary arterial hypertension (PAH). Store‐operated endothelial Ca2+ signals mediated by TRPC4 enhance vascular permeability, but the contribution of TRPC4 to endothelial cytosolic Ca2+ signals and to the regulation of endothelial permeability in the vasculopathy of PAH is poorly understood. Therefore, we tested the hypothesis that TRPC4 increases the frequency of localized endothelial Ca2+ transients and vascular permeability in PAH. We measured permeability in isolated perfused lungs, and found that TRPC4 exaggerated permeability responses to thapsigargin in Sugen/hypoxia treated hypertensive rats. We compared the endothelial Ca2+ activity of wild type and TRPC4 knockout hypertensive rats using confocal microscopy, and evaluated how Ca2+ signals were influenced in response to thapsigargin and sequential treatment with acetylcholine. We found that thapsigargin‐stimulated Ca2+ signals were increased in hypertension, and recovered by TRPC4 inactivation. Store depletion revealed bimodal Ca2+ responses to acetylcholine, with both short (<30 s) and long duration (>30 s) populations. Robust long duration responses to acetylcholine were abolished in PAH. Thus, TRPC4 underlies an exaggerated endothelial permeability response in hypertension. Furthermore, TRPC4 increased the frequency of endothelial Ca2+ transients in severe pulmonary arterial hypertension, suggesting that TRPC4 provides a calcium source associated with endothelial dysfunction in the pathophysiology of PAH.Support or Funding InformationThis work was funded by NIH grants HL60024 and HL66299
Acid Sensing Ion Channel 1 Contributes to Hypoxia‐Induced Proliferation and Hypertrophy in Mouse Pulmonary Arterial Smooth Muscle Cells
Authors: Yellowhair Tracylyn R. , Herbert Lindsay M. , Resta Thomas C. , Jernigan Nikki L. 
Published: November 2023

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD) and results from vasoconstriction and pulmonary arterial remodeling. Our laboratory has shown that acid sensing ion channel 1 (ASIC1) contributes to the arterial remodeling associated with chronic hypoxia‐induced pulmonary hypertension. However, the specific role of ASIC1 in hypoxia‐induced migration, proliferation and hypertrophy of pulmonary arterial smooth muscle cells (PASMC) is currently unknown. We hypothesize that ASIC1 contributes to PASMC proliferation and hypoxia‐induced hypertrophy. To determine involvement of ASIC1 in proliferation, PASMC from wildtype (ASIC1+/+) and ASIC1 knockout (ASIC1−/−) mice were incubated with bromodeoxyuridine (BrdU; 10 μM) for 24, 48, and 72 hrs. PASMC were fixed and labeled with a conjugated Anti‐BrdU FITC antibody to measure BrdU incorporation in newly synthesized DNA by flow cytometric analysis. At 24, 48, and 72 hrs, the total amount of BrdU incorporation was increased in PASMC from ASIC1+/+ mice compared to PASMC from ASIC1−/− mice. To determine the contribution of ASIC1 to hypoxia‐induced hypertrophy, PASMC from ASIC1+/+ and ASIC1−/− mice were exposed to normoxia (21% O2, 5% CO2) or hypoxia (2–4% O2, 5% CO2) for 24, 48, or 72 hrs. Unlabeled fixed cells were processed by flow cytometry using the forward scatter parameter to determine cell size. Exposure to hypoxia increased PASMC size in both groups, however the hypertrophic response was greater in PASMC from ASIC1+/+ mice compared to PASMC from ASIC1−/− mice at 24, 48, and 72 hrs. These data demonstrate that ASIC1 contributes to proliferation and hypoxia‐induced hypertrophy of PASMC and provides an understanding of the mechanism(s) by which ASIC1 contributes to pulmonary arterial remodeling associated with chronic hypoxia‐induced pulmonary hypertension.Support or Funding InformationThis work was supported by National Heart, Lung, and Blood Institute Grants HL‐92598 (to N. L. Jernigan), HL‐111084 (to N. L. Jernigan), and the American Physiological Society STRIDE program (R25 HL115473)