bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calcitriol regulates skeletal muscle primary fibroblast proliferation, transition to myofibroblast, and Smad signaling-associated fibrogenesis
Authors: Srikuea Ratchakrit , Hirunsai Muthita 
Published: May 2023

To repair damaged muscle, extracellular matrix remodeling that relies on function of fibroblasts plays crucial role in skeletal muscle healing and functional recovery. Currently, several lines of evidence suggest skeletal muscle is a vitamin D-target tissue. Nevertheless, non-calcemic action of calcitriol (the active form of vitamin D3) on the regulation of fibrogenesis process involving in fibrosis development after skeletal muscle injury has not been reported. Herein, cultured primary fibroblasts isolated from skeletal muscle of male C57BL/6 mice (age 1-month-old, n=6) were treated with calcitriol and compared its effect with antifibrotic agent suramin. Cell proliferation was evaluated using BrdU incorporation assay. Transition of fibroblast to myofibroblast and TGF-β1/Smad signaling were investigated using immunocytochemistry and western blot analysis. The results revealed that calcitriol and suramin treatment significantly decreased primary fibroblast proliferation via reduction of cell number in the S-phase of cell cycle. However, anti-proliferative effect of calcitriol was diminished after the cells were co-treated with TGF-β1. TGF-β1 treatment induced transition of fibroblast to myofibroblast through significantly increased α-smooth muscle actin (α-SMA) and p-Smad2/3 protein expression along with altered cellular organization of intermediate filament vimentin. Although calcitriol able to suppress α-SMA and p-Smad2/3 protein expression levels in TGF-β1-treated cells, it showed differential effects compared with suramin that significantly suppressed cell proliferation and decreased transcription factor related to fibrogenic determination (TCF4). Altogether, these findings reveal calcitriol action on the regulation of primary fibroblast proliferation, transition of fibroblast to myofibroblast, and Smad signaling-associated fibrogenesis. Additionally, TGF-β1 stimulation directly affects anti-proliferative effect of calcitriol on skeletal muscle fibroblasts that could modulate calcitriol action on fibrogenesis process of skeletal muscle after injury. This research project was supported by Mahidol University under the New Discovery and Frontier Research Grant (NDFR 23/2564 to R.S.) and the CIF and CNI grant, Faculty of Science, Mahidol University (to R.S.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Immune, metabolic, and renal effects of post-wean BPF exposure in BUF/Mna female rats
Authors: Wagner Valerie , Holl Katie , Clark Karen , Reho John , Dwinell Melinda , Solberg Woods Leah , Lehmler Hans-Joachim , Raff Hershel , Grobe Justin , Kwitek Anne 
Published: May 2023

Exposure to endocrine-disrupting chemicals (EDCs) increases the risk of obesity and related cardiometabolic disorders. Bisphenol F (BPF), an EDC that affects the thyroid, reproductive health, and immune cell function, is a common substitute for bisphenol A (BPA) and is used in manufacturing polycarbonates and consumer products. EDC exposure effects likely vary in the population, indicating gene x EDC interactions; however, genetic risk factors interacting with EDCs are unknown. In vivo toxicity studies performed in isogenic or genetically undefined outbred models may obscure or overemphasize exposure outcomes and do not address significant variability in population-level effects. These limitations can be avoided by studying the N/NIH Heterogeneous Stock (HS) rats, an outbred population derived from eight founder inbred strains readily amenable to genetic study. We hypothesize that BPF-induced metabolic disease has underlying genetic risk, which can be identified using HS rats and their founding inbred strains. We previously demonstrated that post-wean BPF exposure increases body growth and adiposity in male HS rats. We evaluated the metabolic impact of post-weaning BPF exposure in BUF/Mna rats, one of the HS-founding inbred strains that has genetic risks for thymic hyperplasia and focal segmental glomerulosclerosis. Weanling littermate pairs of male and female BUF rats were randomly exposed to either vehicle (0.1% EtOH) or 1.125 mg BPF/L in 0.1% EtOH for 10 weeks in drinking water. Metabolic measures, tissues, urine, and feces were taken. Males exposed to BPF did not differ from vehicle control. In females, BPF exposure did not change body composition or body weight gain; however, examination of two metabolic cage time points found that BPF females had decreased energy efficiency (weight gained/calorie absorbed) compared to vehicle control. There was an energy balance disruption in BPF females with increased 24 hr distance traveled and decreased resting metabolic rate compared to vehicle females. Also, BPF females had increased thymus and kidney mass compared to vehicle females. Our preliminary data indicate that post-wean BPF exposure affects immune, metabolic, and renal phenotypes in BUF rats in a sex-specific manner. These results suggest that BPF exacerbates inherent organ dysfunction in a genetically susceptible HS-founding inbred strain. This work supports BPF exposure as a metabolic disease risk factor and indicates that the HS rat will be a useful model for dissecting gene x BPF interactions on metabolic health. NIH T32 GM008629, NIH P30 ES005605, NIH R24 OD024617. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The high ventricular function in the shortfin mako shark (Isurus oxyrinchus)
Authors: Lai N Chin , Head Brian , Lai Yin , Tresguerres Martin , Tang Tong 
Published: May 2023

The shortfin mako sharks ( Isurus oxyrinchus) belongs to the family Lamnidae, which is a group of high performance regional endothermic elasmobranch fishes that has metabolic rates (47.4±8 ml/kg/min) higher than ectothermic elasmobranchs, and also rivals that of mammals. As in all elasmobranchs, the mako sharks do not possess direct cardiac sympathetic innervation to elevate cardiac performance, but it still retains an ancient design of a capacious semi-rigid pericardium (5.4±0.6 ml/kg) likely to accommodate its large atrial diastolic volume. This study test the hypothesis that the increase in cardiac output in the mako is influenced by a strong positive lusitrophic effect that serves to increase stroke volume, which in turn invokes the Frank-Starling’s effects. The objectives is to show differences in the physiology and biochemical properties between mako (Is) and an ectothermic blue shark ( Prioance glauca, Pg), both are oceanic species and share similar life history. Echocardiography showed a higher early to late filling velocity ratio (p=0.036) in the Is (0.92±0.16, [n=15]) than in Pg (0.45±0.04, [9]). The early time velocity integral is also greater in Is (8.8±2.4 cm, [15]) vs Pg (6.8±0.8 cm [9]) indicating a stronger conduit filling imparted by the energy from previous systole in Is. However, basal cAMP (Is: 31±12 [7] vs Pg: 31±1 [3] fmol/min/μg) and stimulated cAMP with isoproterenol+GTPγS (Is: 65±21 [7] vs Pg: 59±7 [3] fmol/min/μg) activity are similar in both groups. This suggests that the differences in ventricular contractility are not through the classic adrenergic signaling pathway involving adenylyl cyclases, but likely through the mechanical stretching of the myofibrils from diastole. Caveolin distribution of the ventricular tissues following sucrose density gradient shows a higher degree of Caveolin-1/3 in the buoyant fraction and little in the in the heavy fraction in both shark species indicating an absence of t-tubules. However, Is shows a remarkably high amount of buoyant Cav-1/3 fraction compared to Pg. We posit that the high fraction abundance of Cav-1/3 provides a gateway for corticotropin-releasing factor, such as urotensin I or possibly an ancestral precursor of urocortin, which has been shown to elevate heart function in mammals. The study is supported by NSF IBN93-16621. No disclosure. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Electrophysiological properties and phenotype of the expiratory lateral parafacial neurons of rats
Authors: Magalhães Karolyne , da Silva Melina , Mecawi Andre , Paton Julian , Machado Benedito , Moraes Davi 
Published: May 2023

Active expiration is essential for increasing pulmonary ventilation during high chemical drive (hypercapnia). Several studies demonstrated that the lateral aspect of the parafacial (pFL) region, which contains expiratory neurons, drives abdominal muscles during active expiration in response to hypercapnia. However, the electrophysiological properties and synaptic mechanisms determining the activity of pFL expiratory neurons and the specific conditions for their emergence are not fully understood. Therefore, using whole-cell electrophysiology and single-cell qRT-PCR techniques, we evaluated the intrinsic electrophysiological properties, the phenotype, and the respiratory-related synaptic inputs to the pFL expiratory neurons, as well as the mechanisms for the expression of their expiratory activity under conditions of hypercapnia induced active expiration in in situ preparations of juvenile rats. We also evaluated whether these neurons possess intrinsic CO2/[H+] sensitivity. All recorded pFL expiratory neurons were glutamatergic. In normocapnia, GABAergic and glycinergic inhibition during inspiration and expiration suppressed the activity of excitatory pFL expiratory neurons. In hypercapnia, these neurons escape glycinergic inhibition and generate burst discharges at the end of expiration. Post-inhibitory rebound, CaV3.2 isoform of T-type Ca2+ channels, and intracellular [Ca2+] contribute to their expiratory activity. Hypercapnia/hypocapnia or acidosis/alkalosis did not affect the activity of pFL expiratory neurons, indicating that these neurons do not possess intrinsic CO2 and pH sensitivity. Additionally, ion channels/receptors (TASK or GPR4) related to CO2/[H+] sensitivity were not expressed by pFL expiratory neurons. In conclusion, the intrinsic electrophysiological properties and post-synaptic disinhibition of glutamatergic neurons both play essential roles in generating the expiratory oscillations in the pFL region during hypercapnia in rats. FAPESP and CNPq This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Gut microbial metabolite delta - valerobetaine (VB) influences energy metabolism by altering fat utilization and satiety-related hormones in mice
Authors: Kim Jiyoung , Naudin Crystal , Liu Ken , Parcha Kim , Dawson Paul , Jones Rheinallt , Neish Andrew 
Published: May 2023

There is mounting evidence that the gut microbiota exerts profound influences on systemic homeostasis and metabolism, including effects on host energy metabolism, fatty acid oxidation, and obesity. However, we know little about how the microbiota mechanistically influences these aspects of host biology. Previously, we used mass spectrometry-based metabolomics platforms to demonstrate remarkable differences in the metabolite composition in the hepatic mitochondria of germ-free (GF) and conventional mice and identified Δ-valerobetaine (VB) as a key discriminative molecule. VB was undetectable in GF mice but present in conventional mice. We showed that VB is produced by specific bacterial species and inhibited mitochondrial fatty acid oxidation by suppression of the carnitine shuttle. VB administration to GF and conventional mice increased visceral fat mass and exacerbated hepatic steatosis with a Western-style diet but not a chow control diet and can thus function as a microbiota-derived obesogen. Here we show that VB impacts the physiological aspects of energy metabolism. VB reduces the Oxygen consumption rate (OCR) in HEPG2 cells and alters mitochondria-related protein markers (PGC1α, AMPKα, TFAM) suggesting changes in VB can alter the function of mitochondria. To evaluate whole animal consequences, we utilized the CLAMS-HC metabolic cage system to measure the respiratory exchange ratio (RER) in conventional mice. We found that western diet-fed animals treated with VB (IP 50mg/kg) for a week significantly increased RER compared to control groups on the same diet, whereas there was no impact of VB on regular chow diet-fed animals. Higher RER indicates the usage of glucose rather than the usage of fat, thus shifting the resources to produce energy and enhancing the accumulation/retention of adipose tissue. We also found a significant increase in food intake among VB-treated animals regardless of diet. We further investigated the impact of VB on energy-regulating hormones from serum and found a significant alteration in leptin and ghrelin levels. These data suggest VB alters energy utilization in a diet-dependent fashion possibly through regulating energy satiety hormones. Manipulation of VB levels by changing the intake of dietary precursors, or with VB-producing bacterial taxa, may provide therapeutic approaches to disorders of energy/lipid metabolism. This project has been funded by U.S. NIH R01 AI64462. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Optogenetic therapy on cardiac vagal dysfunction-related ventricular arrhythmia in type 2 diabetes
Authors: Hu Wenfeng , Tu Huiyin , Wadman Michael , Li Yulong , Zhang Dongze 
Published: May 2023

Withdrawal of cardiac vagal activity is associated with ventricular arrhythmias-related sudden cardiac death and high mortality in T2DM patients. Although vagal nerve stimulation (VNS) has emerged as a promising therapy for ventricular arrhythmias, VNS-induced off-target side effects due to a lack of organ specificity severely limit its prescription in the clinic. To avoid the limitations of the VNS, we employed an optogenetic technique that combines with a miniaturized bio-optoelectronic implant with genetic targeting strategies to achieve cardiac-specific vagal activation in T2DM rats. We hypothesize that optogenetic activation in cardiac vagal postganglionic (CVP) neurons can restore vagal control of cardiac function, and further reduce susceptibility to ventricular arrhythmias in T2DM. Rat T2DM was induced by a high-fat diet plus streptozotocin injection. AAV-channelrhodopsin-2 (ChR2, 2 μl, 5x1012 vg/ml), an excitatory light-sensitive opsin gene, was in vivo transfected into CVP neurons located in the atrioventricular ganglion (AVG). At three weeks after opsin gene (i.e., AAV-ChR2) transfection, continual optogenetic stimulation in CVP neurons was applied twice daily (10 Hz, 50% duty cycle, 5 mW for 1 hour) by illuminating a LED probe that is controlled and powered wirelessly in conscious rats. Our data from immunofluorescence staining showed that microinjection of AAV-ChR2 into the AVG induced expression of ChR2-mcherry in almost all CVP neurons. Optogenetic activation of CVP neurons resulted in a negative inotropic reaction on the left ventricular systolic pressure in a frequency-dependent manner in anesthetized rats. Data from spectral analysis of heart rate variability demonstrated that optogenetic stimulation gradually restored T2DM-reduced high-frequency power (an index of cardiac vagal activation) from one to three days after optogenetic therapy in vivo, whereas it has no effect on low-frequency power (an index of cardiac sympathetic activation). Additionally, data from 24-hour continuous ECG recording in conscious rats demonstrated that optogenetic stimulation in CVP neurons improved the T2DM-impaired heterogeneity of ventricular electrical activity, which was measured by evaluating ventricular arrhythmia-related ECG parameters at three days after optogenetic therapy in vivo. These data suggested that optogenetic activation in CVP neurons might be an effective intervention against cardiac vagal dysfunction-related ventricular arrhythmias in the T2DM state. This study was supported by the Great Plains IDeA-CTR Pilot Grant (to DZ), NIH-NHLBI (R01HL144146 to YLL), and AHA Career Development Award (851929 to DZ). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Downregulation of hepatic lncRNA Gm19619 improves gluconeogenesis and lipogenesis following vertical sleeve gastrectomy in mice
Authors: Fang Zhipeng , Fan Mingjie , Yuan Dongqiang , Jin Lihua , Wang Yangmeng , Xu Senlin , Zhang Eryun , Chen Zhen , Huang Wendong 
Published: May 2023

Long non-coding RNAs (lncRNAs) are emerging important epigenetic regulators in metabolic processes. Whether they contribute to the metabolic effects of vertical sleeve gastrectomy (VSG), one of the most effective treatments for sustainable weight loss and metabolic improvement, is unknown. Herein, we identified a novel hepatic lncRNA Gm19619, which was strongly repressed by VSG but highly up-regulated by diet-induced obesity and overnight-fasting in mice. Forced transcription of Gm19619 in the mouse liver significantly promoted hepatic gluconeogenesis with the elevated expression of G6pc and Pck1. In contrast, AAV-CasRx mediated knockdown of Gm19619 in the HFD-fed mice liver significantly improved hepatic glucose and lipid metabolism. Mechanistically, Gm19619 was enriched along genomic regions encoding leptin receptor (Lepr) and the transcriptional factor Foxo1, as revealed in chromatin isolation by RNA purification (ChIRP) assay. Moreover, Gm19619 was confirmed to promote gluconeogenesis by activating the Foxo1 pathway, facilitate the lipogenesis and repress lipolysis by inhibiting the leptin receptor signaling in the mouse liver. In summary, we have idenfied and characterized a new hepatic lncRNA which may mediate VSG effects to modulate gluconeogenesis and lipid metabolism in the liver. This study was supported partially by the George & Irina Schaeffer, the John Hench, and the Ella Fitzgerald Foundations and the National Institutes of Health grants (R01DK124627 to W.H. R01HL145170 and R01GM141096 to Z.B.C. and COH P30CA33572 to COH). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Neuropeptide Y potentiates T-Lymphocyte inflammation after psychological trauma
Authors: Lauten Tatlock , Reed Emily , Elkhatib Safwan , Moshfegh Cassandra , Clopp Amelia , Case Adam 
Published: May 2023

Post-traumatic stress disorder (PTSD) is a psychiatric disorder characterized by severe behavioral alterations, but also demonstrates elevated levels of systemic inflammation, sympathoexcitation, and a potentiated risk for autoimmune and cardiovascular diseases. These physiological changes suggest perturbations to the immune system, however, the signaling mechanisms linking psychological trauma to the immune system are not well understood. Utilizing a pre-clinical mouse model of PTSD known as repeated social defeat stress (RSDS), we previously demonstrated that psychological trauma causes robust T-lymphocyte-driven inflammation in the spleen as evidenced by increased pro-inflammatory cytokine production (primarily interleukin 17A, IL-17A), inflammatory polarization, and enhanced mitochondrial reactive oxygen species. Moreover, targeted denervation of the spleen was able to completely ablate this T-lymphocyte inflammatory response after psychological trauma, suggesting the signal was autonomic and neural in nature. Given that the splenic nerve possesses only sympathetic neurons (no direct parasympathetic innervation), we hypothesized that psychological trauma mediates splenic T-lymphocyte inflammation via enhanced release of sympathetic neurotransmitters. To test this, we first exposed naïve primary T-lymphocytes to various sympathetic catecholamines, including dopamine, norepinephrine, and epinephrine. Contrary to our original hypothesis, we observed no significant changes in IL-17A expression or mitochondria reactive oxygen species. Next, we assessed the physiological response of naïve T-lymphocytes exposed to neuropeptide Y (NPY) given its role in both sympathoexcitation as well as in PTSD. Interestingly, naïve T-lymphocytes treated with NPY also demonstrated no effect, but when NPY was given in combination of norepinephrine, we observed both an increase in IL-17A gene expression (~2 fold) and intracellular redox (~2 fold). To further investigate this effect, we examined NPY levels in our RSDS mouse model over-time. Circulating NPY levels spiked immediately after only one day of RSDS (~4.5 fold, p=0.0317) but steadily declined over the remaining 10 day psychological trauma induction. Intriguingly, NPY levels were strongly correlated with both circulating IL-17A and T-lymphocyte mitochondrial reactive oxygen species levels after RSDS, supporting our in vitro observations. Overall, these data suggest NPY may be playing a critical role in shaping the inflammatory milieu after psychological trauma, which may enhance the likelihood of inflammatory comorbidities. NIH R01HL158521 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.