bluuebunny/crossref_metadata_2025_split huggingface dataset:
Luminal flow-stimulated superoxide participates in connecting tubule-glomerular feedback
Authors: Romero Cesar , Wang Hong , Ortiz Pablo 
Published: May 2024

Increasing NaCl concentration in the connecting tubule (CNT) dilates the afferent arteriole (Af-Art) through the connecting tubule-glomerular feedback (CNTGF). CNTGF is mediated by Na+ transport via epithelial Na+ channels (ENaC) in the CNT. It is unknown if CNTGF is mainly activated by NaCl concentration or sodium delivery or if there is an independent luminal flow effect. Previous studies showed that luminal flow stimulates superoxide (O2−), and O2− can activate ENaC. Thus we hypothesized that increasing luminal flow in the CNT induces CNTGF via O2− generation and ENaC activation. Rabbit Af-Arts with the adjacent CNTs were microdissected and perfused in vitro. Protocols consist of two consecutive dose-response curves to flow rate in the same preparation. When the CNT was perfused with 5mM NaCl, increasing flow rates from 5 to 10, 20, and 40 nL/min caused flow rate-dependent Af-Art dilatation (p<0.01). Adding an ENaC blocker benzamil to the perfusate blocked flow-induced Af-Art dilatation, indicating a CNTGF response. Using mathematical modeling, an increased tubular flow controlled by NaCl delivery into the CNT independently increases CNTGF vasodilation. However, when CNT was perfused with 0 mM NaCl, increasing the flow rate did not induce CNTGF vasodilation. The O2− dismutase mimetic tempol reduced flow-induced CNTGF. In the presence of L-NAME (NOS inhibitor), the reduced CNTGF mediated by tempol was unaffected. We concluded that increasing luminal flow in CNT induces CNTGF activation via ENaC, partly due to flow-stimulated O2− production and independently of NOS. 1K01HL155235. This is the full abstract presented at the American Physiology Summit 2024 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.
Colostrum Supplementation to Rescue Antibiotic-Induced Dysbiosis and Reduce Long-Term Obesity Risk
Authors: Antunes Karen , Leathem Cameron , Mims Tahliyah , Willis Nathaniel , Pierre Joseph 
Published: May 2024

The prevalence of metabolic disease in the United States has increased from 30.4% to 41.9% in the past decades, with rising rates among children. Emerging evidence implicates intestinal microbiome function as contributing to metabolic disease risk, with dysbiosis being associated with overweight and obese status. While sometimes lifesaving, antibioticssuch as azithromycin cause microbiota ecological instability and are significantly associated with a greater risk ofmetabolic disease and obesity in children. Since antibiotics are often necessary, the identification of nutritional interventions to restore microbial membership and function has a high potential value for millions of patients. Colostrum is the first milk produced by mammals immediately after birth and shapes intestinal colonization patterns, specifically enriching Bifidobacterium, Lactobacillus, and limiting the colonization of Proteobacteria. Bovine colostrum containsimmunomodulators, lactoferrin, oligosaccharides, bioactive compounds, and macronutrients. The compounds are similar across mammalian species. Considering the impact of colostrum in the sterile early-life gut, we hypothesized that bovine colostrum provided as a supplemental nutraceutical therapy would augment gut microbial recolonization following antibiotic exposures and mitigate long-term metabolic consequences. Specific pathogen-free (SPF) C57BL/6 mice (male, three weeks old, Jackson Laboratory) were housed under standard laboratory conditions with a 45% high-fat diet. Tylosintartrate antibiotic (ABX) was administered to some mice in drinking water 3 days/week over three weeks, with four days washout/week. To examine colostrum, some animals were provided colostrum gavage during or immediately following ABX exposures. After intervention, body composition and metabolic phenotypes were monitored for 16 weeks.Compared with ABX alone, colostrum following ABX maintained similar body composition and glucose tolerance as controls, while colostrum during ABX appeared similar to ABX alone. Examination of the gut microbiome showed unique enrichment of Akkermansia and Sutterella with decreased Enterobacteriaceae in mice treated with ABX followed by colostrum. Analysis of the gut mucosa demonstrated ABX decreased goblet cell numbers per villi (7.2/villus) compared with control (9.8/villus), and colostrum following ABX elevated goblet cells (8.6/villus). These data suggest colostrum may stimulate epithelial responses that foster host-microbial symbiosis at the mucosal surface and play a role in intestinal recolonization to benefit long-term homeostasis. Dairy Innovation Hub, UW-Madison. This is the full abstract presented at the American Physiology Summit 2024 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.
Novel role of dual oxidase 2 as a mediator of podocyte injury in the diabetic environment
Authors: Ybarra Seleste , Marsh Megan , Hecker Jacqueline , Castro Aracely , Ford Bridget 
Published: May 2024

Glomerular injury is a prominent pathological feature of diabetic nephropathy (DN). In glomerular epithelial cells, or podocytes, hyperglycemia alters slit diaphragm proteins and causes foot process effacement, apoptosis and cell detachment. Oxidative stress has emerged as an important pathogenic mechanism in the development of glomerular injury in DN. However, the mechanisms by which these factors exert their action remain poorly understood. We provide evidence that the NADPH oxidase of the Nox family, Dual oxidase 2 (Duox2), is present in cultured glomerular cells, including podocytes. Exposure of cultured podocytes to high concentrations of glucose (HG) elicited a rapid upregulation of Duox2 protein expression. Inhibition of Duox2 with specific siRNA prevented the HG-induced increase in intracellular reactive oxygen species (ROS) generation and hydrogen peroxide (H2O2) production in cultured podocytes. In additional experiments, we established a functional link between Duox2-derived ROS generation and podocyte injury in response to HG. Impairment of Duox2 function nearly abolished HG-mediated DNA fragmentation, apoptosis and decrease in/reorganization of slit diaphragm protein expression in podocytes, indicating that Duox2 is required for the deleterious effects of glucose in podocytes. Our study demonstrates, for the first time, that Duox2 is responsible for increased ROS generation and subsequent alteration of podocyte function in response to HG. Our work serves as proof of concept to demonstrate the utility of targeting Duox2 as a future therapeutic intervention to reduce diabetes-mediated glomerular lesions. Research reported in this poster was supported by the University of the Incarnate Word Offce of Research and Graduate Studies and the National Institute of General Medical Sciences of the National Institutes of Health under Award Number SC2GM136569. The content is solely the responsibility of the authors and does not necessarily represent the offcial views of the National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2024 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.
Beta-Adrenergic Signaling Induces Arrhythmias and Cardiac Dysfunction in Paclitaxel-Treated Mice
Authors: Gaul-Muller Kelli , Thomas Andrew , Contreras Jorge 
Published: May 2024

In the past two decades, chemotherapy-related cardiac dysfunction (CRCD) has emerged as a dangerous complication in cancer survivors. Despite recent advancements, the mechanisms underlying the development and progression of CRCD remain poorly understood. Paclitaxel (PTX), an antimicrotubular agent, is known to produce dysrhythmia in 29% of patients when used as monotherapy. Since cardiac stress via β-adrenergic signaling is known to exacerbate arrhythmias, here we examine the action of a single isoproterenol (ISO) injection in wild-type mice treated with low and high therapeutic doses of PTX (8mg/kg and 12.5mg/kg, respectively). Male mice were treated with 4 intraperitoneal (IP) injections of PTX or vehicle (1:1:4 ratio of ethanol: Kolliphor: saline) per week for 4 weeks and a remote telemetry device was surgically implanted. Following treatment, mice were challenged with one IP injection of 5mg/kg ISO and ambulatory electrocardiography was performed. Over the course of PTX treatment, low- and high-dose PTX-treated mice displayed significant weight loss compared to vehicle-treated mice (-9.65% vs -0.52%, p=0.0018 and -10.99% vs 0.93%, p=0.0016, respectively). While low-dose PTX-treated mice did not show statistically significant differences in heart weight to body weight ratio compared to vehicle-treated mice (5.56mg/g vs 5.16mg/g, p=0.14), high-dose PTX-treated males showed increased cardiac hypertrophy compared to vehicle-treated mice (5.20mg/g vs 4.89mg/g, p=0.081). Prior to ISO challenge, there was no difference in arrhythmia severity between groups (0.0 vs 0.0, p=0.45 and 0.0 vs 1.0, p=0.99). One hour following ISO challenge, all mice treated with either a low or high dose of PTX showed higher arrhythmia severity than vehicle-treated mice (4.0 vs 2.5, p=0.0087 and 4.0 vs 3.0, p=0.0079, respectively). Additionally, low and high-dose PTX-treated mice experienced more atrioventricular block than vehicle-treated mice in the first hour following ISO challenge (9.17 vs 0.67, p=0.01 and 4.0 vs 1.0, p=0.06, respectively). After 24-hours, differences in arrhythmia severity returned to baseline (0.5 vs 1.0, p=0.99 and 1.0 vs 0.0, p=0.4). Our data indicates that chronic treatment of male mice with therapeutic levels of PTX predisposes to cardiac stress-induced atrial arrhythmias. This finding might have important implications for the treatment of CRCD. This is the full abstract presented at the American Physiology Summit 2024 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.
Fasting identifies SLIT2 as a novel driver of doxorubicin cardiotoxicity
Authors: Ozcan Mualla , Valenzuela Ripoll Carla , Lotfinaghsh Aynaz , Guo Zhen , Diab Ahmed , Ataran Anahita , Hajirezaei Hamid 
Published: May 2024

Intermittent fasting strategies, including alternate day fasting (ADF), may attenuate aging phenotypes and reduce cardiovascular risk in part by stimulating brown adipogenesis. However, in the setting of cardiotoxic doxorubicin (Dox) chemotherapy, we recently described a novel toxicity of sustained ADF, which stimulated cachexia and cardiac atrophy in mice. Presently, we tested the effect of fasting initiated after Dox chemotherapy and found that fasting caused a decline in lean body mass and left ventricular mass index, but increased body fat content, liver weight, and brown adipose tissue (BAT) weight index vs Dox-treated mice. Dox + ADF induced SLIT2, which regulates thermogenesis and metabolic function in BAT. Dox plus recombinant SLIT2 decreased left ventricular ejection fraction vs Dox alone. Plasma proteomics from patients showed that SLIT2 was the top protein associated with Dox cardiomyopathy vs other non-ischemic cardiomyopathy. This study suggests that SLIT2, an activator of brown adipogenesis, is a novel driver of Dox cardiotoxicity. This research was supported by NIH (R01HL155344, K08HL138262, P30DK056341, P30DK020579), Children's Discovery Institute of Washington University and St. Louis Children's Hospital (MC-FR-2020-919), and Longer Life Foundation. This is the full abstract presented at the American Physiology Summit 2024 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.
Our undergraduate program for physiology research, UPRIME (Undergraduate Physiology In Medicine and Education) will continue and further encourage and foster our majors in Human Physiology to enter careers in the health professions and physiology research
Authors: Wu Steven , Barnett Vincent , Anderson Lisa 
Published: May 2024

We previously announced and reported on our undergraduate summer research program, UPRIME, funded by an American Heart Association Grant with departmental support, has been successful in the fostering of junior and senior undergraduates (UPRIME Scholars) for the health professions and research. UPRIME is a 13-week summer program that provides opportunities for biomedical research, educational support and career advising. Our hope is that this holistic approach builds a space for inclusive excellence in which UPRIME scholars can acquire the tools needed for success. During the past three years, we have selected UPRIME Scholars based on the strength of their applications. We have matched the research interests of the students with our departmental strengths and met with the scholars weekly to foster a peer-based community and augment their research efforts with scientific seminars and discussions. Additionally, our UPRIME Scholars were supported to present their work at local and national level meetings. Our companion program, INPUT (INtegrative Biology & Physiology Undergraduate Training) which is designed for freshmen and sophomores with strong interest in physiology, is also part of our department’s commitment to inclusive excellence. Here, we are updating the statuses of previous and current UPRIME Scholars. Previous UPRIME Scholars have graduated and entered either professional schools (including medical and dental) or continue to work in our research labs. In addition, our most recent 2023 UPRIME Scholars that will graduate between 2023 and 2024 are currently still working in their mentors’ labs. Our department will continue to support UPRIME. In addition, we are committed to expanding our program to the regional and national levels. We seek highly motivated applicants from around the nation to apply to UPRIME for the opportunity to gain meaningful experiences in physiology research. American Heart Association. This is the full abstract presented at the American Physiology Summit 2024 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.
Placental IL-1β inhibits PKM2 and leads to endothelial barrier injury in preeclampsia
Authors: Li Qinghua , Su Hang , Liu Xinlu , Huang Haiqin , Lv Xin , Yang Weiwei 
Published: May 2024

Preeclampsia, a life-threatening hypertensive disorder of pregnancy, continues to be a major global health concern. Maternal endothelial dysfunction induced by components from the impaired placenta is a key hallmark of preeclampsia (PE). Increased levels of IL-1β have been observed in preeclamptic placentas, but its association with endothelial dysfunction has remained uncertain. Our hypothesis was that IL-1β released from the placenta links the placental abnormalities with maternal endothelial dysfunction in PE. Our investigation revealed elevated levels of IL-1β in preeclampsia placentas, which were negatively correlated with reduced VE-Cadherin expression in endothelial cells, indicating consistent endothelial dysfunction. Moreover, we identified the glycolytic enzyme pyruvate kinase 2 (PKM2) as a key regulator of glycolysis involved in the regulation of junctional VE-Cadherin in endothelial cells. Rescue assays further demonstrated that the overexpression of PKM2 was necessary to ameliorate endothelial barrier injury induced by IL-1β. Our study provides novel insights into the molecular mechanisms driving preeclampsia, highlighting the regulatory roles of IL-1β, PKM2, and VE-Cadherin in endothelial cells. These identified interactions may play a crucial role in the pathogenesis of preeclampsia, offering potential targets for therapeutic interventions to preserve endothelial integrity and alleviate the condition. This project was funded by Natural Science Foundation of Shandong (ZR2022MH195 and ZR2023MH211), and the Graduate Student Research Grant from Weifang Medical University. This is the full abstract presented at the American Physiology Summit 2024 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.
Knock out of ELAVL1 affects steroid synthesis in adrenocortical carcinoma cell line NCI-H295R and leads to a less malignant phenotype
Authors: Brandau Max , Chernyakov Dmitry , Sbiera Silviu , Landwehr Laura-Sophie , Edemir Bayram 
Published: May 2024

Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal gland. With a 5-year-survival rate below 50% and no curative treatment options in advanced stages new therapeutic options in ACC are needed. Analyzing the ACC cohort of the cancer genome atlas we found a significant negative correlation of the expression level of a gene called Embryonic Lethal Abnormal Vision Like 1 (ELAVL1) and ACC patient survival. ELAVL1 has been described to be unfavorable in a lot of different tumor entities, but its function in ACC progression is still unknown. Methods: To evaluate the function of ELAVL1 in ACC progression we performed a CRISPR/Cas9 mediated knock out (KO) of the ELAVL1 gene in the ACC cell line NCI-H295R. The KO was confirmed on DNA level via Sanger sequencing and on protein level via immunofluorescence and western blot. Transcriptome changes were analyzed by next generation RNA sequencing (NGS). To characterize changes in cell function we performed soft agar colony forming assays and evaluated changes in steroid production via mass spectrometry. Results: Via CRISPR/Cas9 we knocked out ELAVL1 in NCI-H295R cells. NGS data showed 6926 significantly deregulated genes in ELAVL1-KO cells compared to control cells. There was an upregulation of 3468 genes, while 3458 genes showed a lower expression in ELAVL1 KO cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed a significant upregulation of 29 genes associated with aldosterone synthesis and a significant downregulation of 87 genes associated with pathways in cancer. Analyzing cell function via soft agar colony forming assays an impaired colony forming ability in ELAVL1 KO cells was seen. Furthermore, we could prove significant changes in steroid production. ELAVL1 KO led to an inhibition of androgen and glucocorticoid synthesis and an enhancement in mineralocorticoid synthesis. These changes could not only be proven by measuring steroid concentrations in cell culture supernatants, but also by NGS showing a downregulation of the genes CYP17A1 and CYP11B1 and an upregulation of CYP21A2 and CYP11B2. Conclusion: Our study showed that ELAVL1 affects the regulation of around 7000 genes in the ACC cell line NCI-H295R. Especially the inhibition of glucocorticoid synthesis shows that ELAVL1 may be a new target for therapeutic approaches in ACC treatment since hypercortisolism is one of the main symptoms in ACC and a negative prognostic factor for patient survival. The authors have nothing to disclose. This is the full abstract presented at the American Physiology Summit 2024 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 role of pituitary adenylate cyclase-activating polypeptide neurons in the hypothalamic ventromedial nucleus and the cognate PAC1 receptor in the regulation of hedonic feeding
Authors: Sayers Sarah , Le Nikki , Wagner Edward 
Published: May 2024

We explored the role of pituitary adenylate cyclase-activating polypeptide (PACAP) neurons in the hypothalamic ventromedial nucleus (VMN) in regulating hedonic feeding. We hypothesized that VMN PACAP neurons would inhibit reward-encoding mesolimbic (A10) dopamine neurons and thereby suppress impulsive consumption brought on by intermittent exposure to highly palatable food. Visualized whole-cell patch clamp recordings coupled with in vivo behavioral experiments were utilized in wildtype, PACAP- cre, TH- cre and TH- cre/PAC1 receptor-floxed mice. We found that optogenetic stimulation of VMN PACAP neurons inhibited postsynaptic targets in the ventral tegmental area (VTA), an effect replicated by bath application of exogenous PACAP during recordings from preidentified A10 dopamine neurons. These inhibitory actions were abrogated by the PAC1/VPAC2 receptor antagonist PACAP6-38, the KATP channel blocker tolbutamide, and by selective knockdown of the PAC1 receptor in A10 dopamine neurons. PACAP delivered directly into the VTA decreases binge feeding accompanied by reduced meal size and duration. These effects are negated by PACAP6-38, PAC1 receptor knockdown in A10 dopamine neurons, and apoptotic ablation of VMN PACAP neurons. These findings demonstrate that VMN PACAP neurons blunt impulsive, binge feeding behavior by activating PAC1 receptors and KATP channels to inhibit A10 dopamine neurons. As such, they impart impactful insight into potential treatment strategies for conditions such as obesity and food addiction. Work funded by PHS grant DA024314. Work funded by PHS grant DA024314. This is the full abstract presented at the American Physiology Summit 2024 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.