bluuebunny/crossref_metadata_2025 huggingface dataset:
The protective effect of Allium Cepa against kidney stones diseases in rat model
Authors: Wahid Reham , Hassan Nancy , Samy Walaa , FaragAllah Eman , El-Malkey Nanees , Talaat Aliaa , Malek Mahmoud
Published: May 2023

Background and aim: Kidney stone disease (KSD) is considered one of the serious medical problems, despite recent management methods for kidney stones, there are many undesired consequences, thus recent literatures highlight the great need for natural compounds for safe, effective and affordable management of KSD. So, we aimed in this study to investigate the protective effect of Allium cepa administration against both stone formation process and its kidney injury effect. Hypothesis: Allium cepa administration has a beneficial role against renal stones formation and subsequent renal injury. Methods: 24 adult male albino rats were assigned into 3 groups; group I: control group; group II: received 0.75% ethylene glycol in the drinking water for 4 weeks; and group III received 0.75% EG in the drinking water plus freshly prepared Allium Cepa extract (ACE) 5ml/kg administration using intragastric tube for 4 weeks. The concentrations of creatinine and BUN in serum were measured, and urine analysis was done to assess creatinine clearance, proteinuria and kidney injury molecule-1 (KIM-1) levels. Tissue oxidative stress markers (SOD and MDA) were assessed, and kidney expression of SIRT-1, Beclin, LC3, osteopontin, and Regucalcin were measured by RT-qPCR. Histopathological assessment using Semi-thin Toluidine Blue Staining was done and immunohistochemistry for Bax, Beclin-1 and TNF-α markers was performed. Results: There was a significant increase of creatinine clearance value (P<0.05) with low serum creatinine and BUN levels in the ACE received group compared to EG group (P<0.001), in addition to decreased proteinuria and urine KIM levels in the ACE received group compared to EG group (P<0.001). The present study showed less stone formation, damage and apoptosis in the ACE received group compared to EG group (P<0.001). Moreover, the ACE received group showed significant lower expression of osteopontin and autophagy genes, but higher expression of regucalcin and SIRT-1 genes compared to the EG group (P<0.001). Regarding oxidative stress and inflammatory markers, MDA, TNF-α and mast cells filtration were significantly lower and SOD was significantly higher in the ACE received group than their levels in EG group (P<0.001). Conclusion: Alium Cepa extract administration has a significant protective effect against formation of renal stones and a great beneficial effect against renal injury in KSD.

There were no external funding sources for this study, it is self-funding

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.
Impact of aging on the response to mechanical ventilation in mice
Authors: Veldhuizen Ruud , Manji Aminmohamed , Troitskaya Alexandra , McCaig Lynda , Pape Cynthia , Gill Sean
Published: May 2023

Mechanical ventilation is a critical, life-saving therapy that can also negatively impact the lung by affecting edema formation, surfactant metabolism and function, and the release of inflammatory mediators. Outcomes in elderly patients requiring ventilation are generally worse than in younger patients; however, the impact that age has on the response to mechanical ventilation has not been explored in detail. We hypothesized that aged mice would have an altered response to mechanical ventilation compared to young mice.To test our hypothesis male mice of 2-3 (young) and 22-23 (aged) months of age were mechanically ventilated at a tidal volume of 20ml/kg for 3 hours. Subsequently, lungs were lavaged and the lavage fluid was analyzed for total protein and IgM to assess edema, surfactant amounts and function, and the concentration of inflammatory mediators. Frozen lung tissue was used for qPCR analysis of inflammatory mediators. Separate cohorts of young and aged mice were used as non-ventilated controls.Our results showed that protein and IgM concentrations in the lavage fluid were significantly higher in aged-ventilated as compared to the young-ventilated group. Although surfactant levels were similar between young and aged mice, the function of the surfactant was significantly impaired in aged-ventilated as compared to the young-ventilated group. The lavage concentrations of pro-inflammatory mediators (IL6, IL1β, CXCL1, CXCL2, and CCL2) were significant lower in aged-ventilated as compared to the young-ventilated mice, with mRNA levels following a similar pattern. Further, the MRNA levels of inflammatory mediators in non-ventilated animals were markedly lower than in ventilated animals.In conclusion, the response to mechanical ventilation is affected by age. Since surfactant impairment and edema formation contribute to the severity of lung injury, the data for these outcomes suggest a more harmful response in the aged animals. Overwhelming inflammation has also been associated with augmented lung injury. The reduced level of inflammation in the aged mice implies altered inflammatory responses; the impact of this on overall outcomes during mechanical ventilation requires further investigation.

Canadian Institute of Health Research; Western University

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.
Insight into the increased risk associated with CRISPR-generated African G6PD variant (N126D) in rat model of sugen-5416-induced pulmonary hypertension
Authors: Signoretti Christina , Matsumura Shun , Fatehi Samuel , Gupte Sachin
Published: May 2023

Pulmonary Hypertension (PH) is a cardiopulmonary disease associated with sustained increase in pulmonary arterial and right ventricular pressures, resulting in smooth muscle cell remodeling and the thickening of vasculature. Glucose-6-phosphate dehydrogenase (G6PD) is the rate limiting enzyme in the pentose phosphate pathway and is often associated with oxidative stress and the pulmonary vascular remodeling mechanism seen in PH. CRISPR-mediated single nucleotide polymorphism modeling was used to generate the African G6PD variant (N126D; G6PDN126D), which is an X-linked gene mutation resulting in a 20% decrease in G6PD activity and subsequent hypothesized increased risk of cardiovascular diseases for sub-Saharan individuals. The goal of this study was to determine the effects of the G6PDN126D variant using the Sugen-5416 (20 mg/kg in DMSO)/Normoxia (SU/NX)-induced PH rat model. Cardiac catheterization determined that the G6PDN126D variant-SU/Nx group had higher (G6PDN126D: 29.3 ± 5.2 vs WT: 19.5 ± 2.2; mmHg; p<0.05) mean right ventricle pressure and pulmonary artery remodeling as compared to the WT-SU/Nx group. Further, G6PDN126D variant-SU/Nx had lower nitric oxide levels (G6PDN126D: 10.6 vs WT: 13.6; mM/mg protein; p<0.05) and higher second messenger IP3 levels (G6PDN126D: 4.00 vs WT: 0.52; ng/mg protein; p<0.05) as compared to the WT-SU/Nx group. The data suggests that the African G6PD (N126D) mutation results in increased PH in rats and may be associated with increased risks of severe PH in the sub-Saharan population. These results imply more studies are required to develop personalized medicine for the treatment of PH.

RO1HL132574 (SAG), RO1HL166546 (SAG), AHA Grant-in-Aid 17GRNT33670454 (SAG)

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.
Using Limulus Amebocyte Lysate (LAL) to discover the presence of endotoxins in the tanks at the Pritzker Marine Biology Research Center
Authors: Haas Sydney
Published: May 2023

Endotoxins are harmful for many organisms, including those that live in the water. Therefore, it is important to identify effective ways in identifying if they are present in water environments. Research has been conducted to show that Limulus amebocyte lysate (LAL) is an effective way to determine if endotoxins are present. In this study, LAL was used as the main reagent to detect if endotoxins were present in the tanks at the Pritzker Marine Biology Research Center. It is believed that LAL will be able to detect the presence of any endotoxins within the tanks at Pritzker. The first part of the procedure to do this was to collect 5mL of water from each tank at Pritzker. After the LAL reagent was dissolved in LAL Reagent Water, the gel-clot assay was then produced. 0.1mL of the reagent was added to each assay tube. 0.1mL of each product sample or control was transferred into each assay tube, beginning with the negative control and ending with the highest endotoxin concentration. The contents of the tubes were mixed and incubated undisturbed in a 37 C heating block for 60 minutes. After incubation, each tube was examined for gelation. A positive test is defined as the formation of a firm gel capable of maintaining its integrity when the assay tube is inverted 180 degrees. A negative test is characterized by the absence of gel or by the formation of a viscous mass which does not hold when the assay tube is inverted. Endotoxins were detected in an average of 13 tanks at the Pritzker. To expand upon these findings, quantifying how many endotoxins are present in the tanks and what types of endotoxins are present in the tanks will be tested.

Biology department funds at the New College of Florida

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.
Effects of cholecalciferol and calcitriol on skeletal muscle proteolysis in angiotensin II-induced atrophy in differentiated C2C12 cells
Authors: Hirunsai Muthita , Srikuea Ratchakrit
Published: May 2023

Vitamin D3 has been proposed as a potential treatment to improve muscle atrophy in sarcopenic patients. Several lines of evidence suggested a possible crosslink between vitamin D and renin-angiotensin system contributing to skeletal muscle atrophy in response to chronic diseases in aging population. Nevertheless, effects of vitamin D and its metabolite on skeletal muscle cells challenged with angiotensin II remain unclear. Therefore, the effects of cholecalciferol (VD3) and calcitriol (1,25VD3) on the ubiquitin-proteasome pathway in angiotensin II-induced skeletal muscle cell atrophy were investigated. Differentiated C2C12 skeletal muscle cells (myotubes) were used as in vitro study model. Myotubes were assigned into vehicle (veh), 1 μM angiotensin II (AII), 1 μM angiotensin II+100 nM cholecalciferol (AII+VD3), 1 μM angiotensin II+1 nM calcitriol (AII+1,25VD3) and 1 μM angiotensin II+10 μM losartan (AII+Lo) groups. Myotubes were applied with angiotensin II on day 4-6, while VD3 and 1,25VD3 were treated on day 5-6 of the differentiation phase. For AII+Lo group, losartan was administered at 2 h before angiotensin II at day 4 of the differentiation period. Cells were harvested at day 7 of differentiation phase for morphological and biochemical analyses. Angiotensin II resulted in significantly decreased myotube diameter and tended to increase protein expression of the transcription factor; FoxO3a and ubiquitin ligases; MURF-1 and atrogin-1, the major muscle protein catabolism pathway when compared with veh-treated group. Treatment of VD3 and losartan could protect angiotensin II-induced myotube atrophy. In contrast, 1,25VD3 accelerated muscle protein breakdown in myotube-challenged with angiotensin II. Protein expression of FoxO3a, MuRF1 and atrogin-1 was significantly up-regulated in AII+1,25VD3 group compared to veh, AII+VD3 and AII+Lo-treated groups. By which these occurs were accompanied with the overexpression of vitamin D receptor in myotube co-treated with angiotensin II and 1,25VD3. Herein, differential effects of VD3 and 1,25VD3 in angiotensin II-induced myotube atrophy were demonstrated. Administration of VD3 resulted in attenuated degree of muscle loss-induced by angiotensin II, while 1,25VD3 possessed the negative impact to skeletal muscle protein metabolism. Collectively, vitamin D3 supplement may be considered as an alternative adjuvant to alleviate muscle atrophy in the patients related to high level of angiotensin II.

This work was financially supported by Office of the Permanent Secretary, Ministry of Higher Education, Science, Research and Innovation (Grant No. RGNS 63-216 to M.H.) and Srinakharinwirot University (to M.H.).

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.
Erythropoiesis-related RNAs biomarkers are sensitive and specific to low-dose erythropoietin treatment at sea level and altitude
Authors: Loria Francesco , Breenfeldt Andersen Andreas , Bejder Jacob , Bonne Thomas , Grabherr Silke , Kuuranne Tiia , Leuenberger Nicolas , Baastrup Nordsborg Nikolai
Published: May 2023

Background: Indirect detection of recombinant human erythropoietin (rhEPO) abuse in Anti-Doping world is done by hematological module of athlete biological passport (ABP). However, actual markers (reticulocytes (%RET) and hemoglobin (HGB)) of this module are not enough specific and have difficulties to distinguish recombinant human erythropoietin (rhEPO) administration from altitude sojourn especially if both condition are merged. Previous study have demonstrated that erythropoiesis-related RNAs, genes 5’-aminolevulinate synthase 2 ( ALAS2) and carbonic anhydrase 1 ( CA1) in capillary dried blood spots (DBS) could be potential biomarkers to increased specificity and sensitivity of the ABP in case of hypoxic conditions. Study design and methods: In the present study, we monitored ALAS2 and CA1 expression in DBS after injection of 20 IU kg bw-1 epoetin alpha at sea level and the effect merged with altitude exposure. For this purpose, DBSs samples collected from 39 volunteers’ males and females were analyzed. Participants were divided in two groups (EPO and placebo) and subjects from both groups sojourned at sea level and at altitude. The purpose was to evaluate the performance of RNAs biomarkers for the detection of rHEPO injection in a longitudinal blinded setting. Results: Our results illustrated a clear significant increase of ALAS2 until to 300% when treated at sea level and at altitude. Regarding CA1 the increase is up to 200% in both conditions. Interestingly, our results suggested no combined effect of altitude and rhEPO injection on ALAS2 and CA1 biomarkers as previously demonstrated with %RET values. In placebo group. Moreover, no effect of altitude on ALAS2 and CA1 was observed in contrast to %RET parameter. Results from blind setting test demonstrated a performance of interpretation of 92% regarding ALAS2 and CA1 monitoring. Conclusion: Erythropoiesis-related RNAs in capillary DBS such as ALAS2 and CA1 were sensitive and specific biomarkers for low-dose rhEPO misuse at sea level and altitude. Interestingly, altitude seemed not to be a confounding factors for ALAS2 and CA1 biomarkers in contrast to %RET. Furthermore, this investigation provide evidence that low-dose of rhEPO injections can be detected in a longitudinal blinded setting with RNA biomarkers in DBS.

World Anti-Doping Agency (WADA)

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.
Conniving of prophetic variables of diagnostic importance and their impending role to develop fibromyalgia
Authors: Tariq Nusrat , Malik Arif
Published: May 2023

OBJECTIVE: Fibromyalgia (FM) is a widespread syndrome that lacks any evident reason and is characterized by the existence of chronic pain of unknown etiology. Various variables of medical importance were previously studied among the patients to determine their specificity and sensitivity involved in the pathogenesis of the disease but still, the well-defined etiology and theranostic approach are deficient. The current study aimed to determine the specificity and sensitivity of serum biomarkers to establish blood-based tests for the diagnosis of fibromyalgia. HYPOTHESIS: As fibromyalgia disease has an undefined etiology so its diagnosis and treatment are a challenge for medical professionals. The hypothesis of the current research work was to assess that the assayed biomarkers may have sensitivity and specificity regarding fibromyalgia which may become valuable theranostic variables to diagnose fibromyalgia. MATERIALS AND METHODS: The study population comprised of hundred fibromyalgia female subjects, diagnosed according to the ACR criteria of fibromyalgia. Hundred healthy female subjects served as control. Serum levels of interleukins (IL-1,2,6,7,8,9,10,17,18,1B,1RA), matrix metalloproteases (MMP-2,7,9), tumor necrosis factor (TNF-α and β) were assayed by their respective commercially available ELISA kits. A contingency table was drawn upon the recorded data to rule out sensitivity, specificity, accuracy, and odds ratio at 95% CI. RESULTS: Analysed data helped state the potential markers involved in the pathogenesis of fibromyalgia. It showed that IL-1, IL-1RA, MMP-2, and TNF-α stand to be the most sensitive (SN) and specific (SP) markers with SN-SP of (73%-95%, 67%-93%, 67%-88%and, 53%-76%) respectively. Moreover, it showed the odds ratio of IL-1,1RA and MMP-2 remained (49, 26.8, and 14) among the patients. CONCLUSION: Findings of the current study entitles the importance of IL-1, IL-1RA, TNF-a, and MMP-2 as they show maximum accuracy along with high sensitivity and specific range in fibromyalgia. Higher values of the odds ratio determine that IL-1, IL-1RA, TNF-a, and MMP-2 are more specific and sensitive for fibromyalgia. Thus, their early detection could have significant importance in ruling out the disease condition. Maximum accuracy and a higher sensitivity range of the said variables may have medical and theranostic importance in treating fibromyalgia.

This research did not receive any special grant from funding agencies in the public, commercial or not-for-profit sectors.

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 Physiology of Migraine and its Prevention by Nutrition
Authors: Stanton Angela
Published: May 2023

Migraine is a genetic condition associated with hypersensitive sensory neurons, more sensory neuronal connections, and different electrical properties than a non-migraine brain[1, 2]. Migraineurs waste 50% more sodium in their urine than typical subjects[3]. The most prominent migraine related genetic variants are associated with critical ionic channels that operate the brain’s electrical functions: action potential, resting potential, the delivery of neurotransmitters, and the resetting of membrane potential[4, 5]. Migraineurs’ brains are very sensitive to electrolyte imbalance as a result of channelopathy[6-8] and because of carbohydrate sensitivity. Migraineurs tend to end up with metabolic syndrome. In this paper I present case studies based on findings in a Facebook migraine group with over thirteen thousand migraine members, who have been able to abort and prevent all of their migraines while also tapering off of all of their migraine medications, by applying only nutritional and hydration changes.1. Ambrosini, A. and J. Schoenen, The electrophysiology of migraine. Curr Opin Neurol, 2003. 16(3): p. 327-31. 2. Tso, A.R., et al., The anterior insula shows heightened interictal intrinsic connectivity in migraine without aura. Neurology, 2015: p. 1043-50. 3. Campbell, D.A., E.M. Tonks, and K.M. Hay, An Investigation of the Salt and Water Balance in Migraine. British Medical Journal, 1951: p. 1424-1429. 4. Science, W.I.o. The Human Gene Database. GeneCards: The Human Gene Database 2017 [cited 2017 1/28/2017]; The Human Genome Database]. Available from: http://www.genecards.org . 5. Liu, H., et al., Resting state brain activity in patients with migraine: a magnetoencephalography study. The Journal of Headache and Pain, 2015. 16(1): p. 42. 6. Lee, J.-Y. and M. Kim, Current Issues in Migraine Genetics. J Clin Neurol, 2005. 1(1): p. 8-13. 7. Catterall, W.A., et al., Inherited Neuronal Ion Channelopathies: New Windows on Complex Neurological Diseases. The Journal of Neuroscience, 2008. 28(46): p. 11768-11777. 8. Longo, D.L., et al., Harrison's Manual of Medicine 18th Edition. 2013, New York: McGraw Hill Medical.

Not funded

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 impact of skipping a meal on perceived stress and mental distress
Authors: Welch Megan , Rosenberg Lexis , Nagorny Katerina , Chowdhury Ushima , Bubis Sabrina , Begdache Lina
Published: May 2023

The prevalence of food insecurity is exceptionally widespread, largely affecting those who do not have access to healthy and consistent food. Skipping a meal due to a lack of money or other resources is one prominent aspect of food insecurity that many must practice to survive. The aim of the study is to assess the impact of skipping a meal on participants’ perceived stress and mental distress. It is hypothesized that skipping a meal is directly related to an increase in perceived stress and mental distress. An anonymous questionnaire was administered through social media outlets, such as GroupMe, Facebook, and Instagram, to individuals over 18. The questionnaire included demographic questions and seven validated scales, including the Brief Resilience Scale, Stress Mindset Measure, Perceived Stress Scale, Food Mood Questionnaire, Food Insecurity Experience Scale, Academic Motivation Scale, Kessler-6, and the Psychological Distress Scale. These scales measured dietary and physical activity, the prevalence of food insecurity, stress, mental distress, resilience, academic motivation, and perceived stress. Data from 1005 individuals were analyzed using Spearman’s Rho correlation in IBM SPSS Version 25.0. Our results indicate that skipping a meal has a positive correlation with symptoms of mental distress, such as lack of confidence, nervousness, lack of energy, and irritability (p<0.01). This could be detrimental to students and older individuals alike, as food insecurities are a rising global issue and can negatively impact day-to-day life. Our study suggests that one aspect of food insecurity, such as skipping meals, may increase feelings of mental distress and negatively impact the quality of life.

Currently applying to Binghamton University Undergraduate Research Center and Harpur Edge

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.
StomachSim: An in-silico simulator of gastric biomechanics with application to pyloroplasty
Authors: Kuhar Sharun , Seo Jung-Hee , Pasricha Pankaj , Mittal Rajat
Published: May 2023

Aim: We have developed StomachSim, an in-silico simulator that is designed to simulate the biomechanics and fluid mechanics of a wide range of gastric conditions as well as gastric surgical procedures. Here we demonstrate its use in quantifying the effects of motility disorders and pyloroplasty on the hydrolysis and emptying of a liquid meal inside the stomach. Methods: A physiologically realistic model of the stomach, including the antral motility, is synthesized based on in-vivo imaging, and the mixing and gastric emptying are simulated using computational fluid dynamics (CFD). The enzymatic biochemistry for protein hydrolysis is also implemented by incorporating the secretion of a proteolytic enzyme from the proximal stomach walls and the subsequent enzymatic reaction with the protein dissolved in the liquid meal. Using this model, we measured the effect of stomach motility and the diameter of the pyloric orifice on the retropulsive and pyloric jets, the rate of hydrolysis in different regions, and the emptying of gastric contents. Results: This study presents a proof-of-concept for the application of StomachSim in gastric disorders and surgeries. The emptying rate of our model for the healthy case agreed with the in-vivo measurements of similar caloric density liquid meals. A stomach with a 50% lower motility amplitude had a 35% lower net emptying rate and a 41% lower emptying rate of the hydrolyzed protein. Furthermore, the emptying rate showed a non-linear variation with respect to the motility of the stomach. For a simulated pyloroplasty procedure where the pyloric orifice diameter is doubled and the orifice stays open permanently, the emptying rate of the lower motility case doubled over its original value. Conclusion: StomachSim offers a novel and potentially effective modality for examining the effect of gastric conditions and gastric surgical procedures on gastric function. Our simulations show that gastroparesis and pyloroplasty not only affect the emptying rate but also alter the mixing of contents thereby changing the rate of hydrolysis. The model helped quantify the changes in the flow of contents in the antro-duodenal region for varying degrees of gastroparesis and pyloroplasty.

The authors acknowledge support from NSF award CBET 2019405 and NIH award 1R21GM139073-01.

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.
Epoxyeicosatrienoic Acid administration or Soluble Epoxide Hydrolase inhibition attenuates renal fibrogenesis in obstructive nephropathy
Authors: Padanilam Babu
Published: May 2023

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites with biological effects, including anti-apoptotic, anti-inflammatory, and anti-fibrotic functions. Soluble epoxide hydrolase (sEH)-mediated hydrolysis of EETs to dihydroxyeicosatrienoic acids (DHET) attenuates these effects. Recent studies have demonstrated inhibition of sEH prevents renal tubulointerstitial fibrosis and inflammation in chronic kidney disease (CKD) model. Given the pathophysiological role of the EET pathway in CKD, we investigated if administration of EETs regioisomers and/or sEH inhibition will promote anti-fibrotic and reno-protective effects in renal fibrosis following UUO. EETs administration abolished tubulointerstitial fibrogenesis, as demonstrated by reduced fibroblast activation and collagen deposition after UUO. Inflammatory response was prevented as demonstrated by decreased neutrophil and macrophage infiltration and expression of cytokines in EETs-administered UUO kidneys. EETs administration and/or sEH inhibition significantly reduced M1 macrophage markers while M2 macrophage markers were highly upregulated. Furthermore, UUO-induced oxidative stress, tubular injury, and apoptosis were all downregulated following EETs administration. Combined EETs administration and sEH inhibition however, had no additive effect in attenuating inflammation and renal interstitial fibrogenesis after UUO. Taken together, our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy, and suggest EETs treatment as a potential therapeutic strategy to treat fibrotic diseases.

NIH DK 116987

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.
Motor neuron loss and neuromuscular transmission failure following chemogenetic inhibition of BDNF/TrkB signaling in adult rats
Authors: Fogarty Matthew , Khurram Obaid , Mantilla Carlos , Sieck Gary
Published: May 2023

Brain derived neurotrophic factor (BDNF) signaling through its high-affinity tropomyosin receptor kinase B (TrkB) is known to have potent effects on motor neuron survival and morphology during development and in neurodegenerative diseases. However, the specific effects of reduced BDNF/TrkB signaling on neuromuscular structure and function in adult mammals are not as well known. In this study, we employed a novel 1NMPP1 sensitive TrkBF616 rat model to evaluate the effect of 14 days inhibition of BDNF/TrkB signaling on the number and morphology of phrenic motor neurons (PhMNs) and diaphragm muscle (DIAm) neurotransmission in adult animals. We hypothesized that reduced BDNF/TrkB signaling results in PhMN loss and impaired DIAm neuromuscular transmission. Adult female and male TrkBF616 rats were divided into 1NMPP1 or vehicle treated groups. Three days prior to treatment, PhMNs in both groups were labeled via intrapleural injection of Alexa-Fluor647 cholera toxin B (CTB). After 11 days of treatment, retrograde axonal transport was assessed by secondary labeling of PhMNs by intrapleural injection of Alexa-Fluor488 CTB. After 14 days of treatment, the spinal cord was excised and 100 μm thick spinal sections containing PhMNs were imaged in 3D using two-channel confocal microscopy. Phrenic nerve and DIAm was excised en bloc, and the extent of neuromuscular transmission failure (NMTF) was assessed by comparing DIAm isometric forces evoked by nerve (40 Hz in 330 ms duration trains repeated each s) compared to direct muscle stimulation (40 Hz 330 ms duration train) superimposed every 15 s. Presynaptic (synaptophysin immunoreactivity) and postsynaptic (α-Bungarotoxin) compartments of neuromuscular junctions (NMJs) were labeled and imaged in 3D by confocal microscopy and the extent of pre- and postsynaptic apposition assessed. 1NMPP1-induced BDNF/TrkB inhibition reduced the total number of PhMNs by ~16%, reduced the mean PhMN somal surface areas by ~25%, reduced PhMN dendritic surface area by ~38%, impaired secondary CTB uptake by 2.5-fold and impaired neuromuscular transmission by ~33%, with no overt evidence of NMJ derangement. We conclude that inhibition of BDNF/TrkB signaling in adult TrkBF616 rats is sufficient to lead to PhMN loss, morphological degeneration, deficits in retrograde axonal transport and impaired DIAm neurotransmission.

Supported by NIH: R01-AG44615 and R01-HL146114

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.
Dose-dependent effects of fentanyl on pulmonary ventilation and arterial blood gases in adult awake goats
Authors: Neumueller Suzanne , Forster Hubert , Grams Kirstyn , Pan Lawrence , Buiter Nicole , Hilbert Grace , Lewis Stephen , Hodges Matthew
Published: May 2023

Synthetic opioids, such as fentanyl, typically suppress breathing frequency (f) and tidal volume (VT) in rodents but decrease and increase f and VT in humans, respectively. In this and the three adjoining posters we present data on the physiologic and behavioral dose-dependent effects of intravenous (IV) fentanyl in adult awake female goats. Here we tested the hypothesis that like humans, goats would show dose-dependent decreases in f and increases in VT and corresponding changes in blood gases and pH. Pulmonary ventilation (VI), f, VT and arterial blood gases were measured for 30 minutes (min) before, during and up to 90 min after IV injection (2 min) of 0, 25, 50, 75, 100, and 125 mcg/kg fentanyl. Ventilatory measures were expressed as a percent of control (room air breathing) in 30 sec intervals for 15 min pre- and post-injection and averaged over longer time intervals (5 or 15 min) thereafter. While we observed no changes in breathing measures over 30 min before and 90 min after saline injection, the responses to IV fentanyl were highly variable and individual- and dose-dependent. However, most goats showed transient decreases in f (20-30%) where the duration of f suppression was dose-dependent (2-10 min), whereas VT increased (25-50%) for 60 min or more without an apparent dose-dependence. As a result, VI was only transiently decreased (2-4 min) and instead was above control for up to 90 min post-injection. Arterial blood was drawn (~3 ml; 30 sec) in duplicate at ~15 and 25 min into the 30 min control period, and then individual samples were obtained continuously during and immediately following the injection and in duplicate at 10, 15, 30, 45, 60, 75 and 90 min post-injection. While some goats showed transient hypoventilation (decreased PaO2/O2 saturation) immediately after fentanyl injection, on average blood gas analyses suggested modest hyperventilation (decreased PaCO2/increased pH) 60-90 min post-injection consistent with the overall effects on VI. The calculated difference in the alveolar to arterial oxygen gradient (A-a gradient) was unaffected with saline or 25 mcg/kg fentanyl, but was increased with higher doses of fentanyl peaking 15-30 min after injection in a dose-dependent manner suggesting increased V/Q mismatch. We conclude that in awake goats, fentanyl has opposite effects on f and VT similar to that in humans. However, individual variation in timing and nature of the ventilatory responses to fentanyl over the dose range tested herein suggests that the compensatory f and VT changes allowed for the maintenance of arterial blood gas and pH status.

NIH DA050571

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.
Cough sensory mechanism -- Multiple sensor theory in airway mechanosensory units
Authors: Yu Jerry
Published: May 2023

Two doctrines: one-sensor theory (OST) and line-labeled theory (LLT) significantly influences our data interpretation in lung sensory field. In OST, one afferent axon connects to a single sensor. In LLT, different sensors send signals to different brain regions to evoke reflex. Thus, lung inflation activates slowly adapting receptors (SARs) and send signals to inhibit breathing (inhibitory line), causing Hering-Breuer reflex. The inflation and deflation stimulate rapidly adapting receptors (RARs) to send signals to stimulate breathing (excitatory line), producing the Hering-Breuer deflation reflex. Our physiological and morphological studies demonstrate numerous sensors up to 4 different types may be housed within a unit, i.e., an axon connects to many heterogeneous sensors (multiple-sensor theory, MST). In addition to SARs and RARs, there are deflation-activated slowly adapting (dSARs) or rapidly adapting receptors (dRARs). They work together to determine the unit behavior. For example, SAR or RAR units may respond to deflation if they house dSARs responsible for the Hering-Breuer deflation reflex. MST requires a conceptual shift because different types of information carried in an afferent axon violates conventional doctrines. Data generated over last eight decades under OST require re-interpretation. For example, based on LLT scientists believe “SARs do not cause cough”: their activation on deep lung inflation does not evoke cough. Similarly, deep inspiration and expiration activate RARs, but not cough. Therefore, SARs and RARs are excluded from the cough initiation mechanism. MST posits discharge pattern and timing dictates reflex response. It follows that, in the mechanosensory afferent pathway, continuous discharge (during sustained inflation) produces apnea and cyclic discharge facilitates respiratory rate. Therefore, there is no reason to exclude punctate-associated irregular surging discharge from cough initiation. Indeed, mechanosensors have highest density in large airways, punctate stimulation activates all four types of sensors and their coactivation significantly enhances afferent input. These thick myelinated afferents have the highest conduction velocity and discharge frequency and connect to inspiratory and expiratory neurons monosynaptically to perform effective cough action. Decades of research data support activation of this system can evoke powerful inspiratory and expiratory muscle responses. Blocking it eliminates cough response. While punctate stimulation also activates C fiber and high threshold Ad fiber sensors and may produce cough, the mechanosensory units are most important for punctate-induced cough.

(Supported by a VA Merit Review Award (PULM-024-17S)

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.
Vasoactive properties of hepatokines using mesenteric resistance arteries in male Wistar rats
Authors: Nielson Andrew , Costa Tiago , Wood Emily , Wenceslau Camilla , McCarthy Cameron
Published: May 2023

Hepatokines, defined as proteins or protein-like substances secreted mainly or exclusively by the liver in an endocrine or paracrine way, play an essential role in modulating the metabolic progress and pathological conditions of the body. While it is well known that hepatokines play a major pro-inflammatory role in the body, it is still unclear as to whether their actions specifically affect vascular function. We hypothesized that some, if not all, hepatokines would play a role in vasoconstriction in mesenteric resistance arteries (MRA) of male Wistar rats (12 weeks old, n=4-17). To test this hypothesis, we isolated and mounted MRA with endothelium in a wire myography. After evaluating vascular viability, arteries were treated with hepatokine (1 μg/mL) or vehicle for 30 minutes. This was done for a total of 15 different hepatokines: ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, Fetuin-A, FGF21, Follistatin, GDF-15, Hepassocin, IGF-1, LECT2, Lipocalin-13, SEPP1, SMOC-1, and Tsukushi. Subsequently, we performed concentration-response curves to phenylephrine (10-9 to 10-4 M) and used maximal response and LogEC50 to compare the contraction response curve of the MRA bathed in hepatokine to the control (vehicle). Interestingly, the hepatokines ANGPTL3 [% KCl 120mM, Vehicle: 132.1±3.2 vs. ANGPTL3: 141.6±3.9, p=0.0540] (figure a), FGF21 [% KCl 120mM, Vehicle: 123.3±5.8 vs. FGF21: 139.7±4.8, p=0.0355] (figure d), and ANGPTL4 [% KCl 120mM, Vehicle: 130.2±3.6 vs. ANGPTL4: 141.7±3.7, p=0.0282] (figure b) increased maximum contraction, while the hepatokines SMOC-1 [LogEC50, Vehicle: -5.7±0.1 vs. SMOC-1: -6.0±0.1, p=0.0134] (figure e) and ANGPTL6 [LogEC50, Vehicle: -5.7±0.1 vs. ANGPTL6: -6.0±0.1, p=0.0103] (figure c) increased the sensitivity of phenylephrine compared to the control. On the other hand, the hepatokines ANGPTL8, Fetuin-A, Follistatin, GDF-15, Hepassocin, IGF-1, LECT2, Lipocalin-13, SEPP1, and Tsukushi did not change vascular function. These data show that the vascular system senses the presence of hepatokines. Based on these findings, we suggest that hepatokines could be novel therapeutic targets in vascular disease.

NHLBI (R00HL151889), NIGMS (1P20GM103641 - Pilot Project), UofSC SOM (Startup funds)

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.
Amylin receptor agonism protects against metabolic side effects of acute olanzapine
Authors: Medak Kyle , Jeromson Stewart , Belluci Annalaura , Arbeau Meagan , Wright David
Published: May 2023

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and several on- and off-label conditions. While effective in reducing psychoses, acute olanzapine treatment causes rapid hyperglycemia, insulin resistance, and dyslipidemia and these perturbations are linked to an increased risk of developing cardiometabolic disease. Increases in glucagon are central to the metabolic side effects of olanzapine. Amylin receptor activation has been shown to reduce circulating glucagon but it is unclear if targeting amylin signaling would be an effective approach to lessen olanzapine-induced hyperglycemia alone or as an adjunct with other glucose lowering medications such as glucagon-like peptide-1 (GLP1) receptor agonist liraglutide. The purpose of this study was to 1) determine if treatment with recombinant amylin or the amylin receptor agonist pramlintide is sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis and 2) if there are synergistic effects of combining pramlintide and liraglutide. We hypothesized that amylin and pramlintide would confer protection against olanzapine-induced perturbations in glucose homeostasis and that these effects would be additive with liraglutide. We found that pramlintide co-treatment lowered olanzapine-induced increases in glucagon:insulin. There was an additive effect of pramlintide and liraglutide in protecting against olanzapine-induced hyperglycemia and a synergistic effect on markers of dyslipidemia. Our findings provide evidence that pramlintide, while moderately protective against some aspects of olanzapine-induced metabolic dysfunction, can be used to enhance other interventions which protect against olanzapine-induced hyperglycemia.

This research was supported by a Project Grant (PJT 159538) from the Canadian Institutes of Health Research to DCW. KDM was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council (NSERC) of Canada.

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.
Renal denervation modulates neurohormonal activity and inflammation in heart failure with preserved ejection fraction
Authors: Pushpakumar Sathnur , Juin Subir Kumar , Smolenkova Irina , Tyagi Suresh , Sen Utpal
Published: May 2023

Heart failure with preserved ejection fraction (HFpEF) accounts for >50% of cases with heart failure (HF) and is often accompanied by derangements in several organs including kidney. Under normal conditions, the heart and kidney functions are reciprocally regulated by several bidirectional pathways that include neurohormonal, hemodynamic, and endocrine signaling, however, the underlying renal mechanisms during HFpEF remains largely unknown. Current evidence postulates that sympathetic nervous system (SNS) hyperactivation and low-grade inflammation play a key role in HFpEF, however, whether these mechanisms are cause or effect of HFpEF remains unknown. The kidney responds to volume overload in HFpEF via modulation of glomerular function, RAAS activation and norepinephrine release. Separately, selective denervation has been shown to reduce immune activation in hypertension, post myocardial infarction, and inflammatory arthritis, Therefore, the purpose of the study was to investigate whether renal denervation (RDN) in HFpEF modulates SNS activity thus RAAS, to reduce stress, and inflammation. Methods: C57BL/6J (WT, 50-52 wks) mice w/o and with HFpEF, and w/o and with RDN were used in the study. Aorto-vena cava fistula (AVF) was created as a model of diastolic dysfunction and serial ECHO was done to denote HFpEF (ejection fraction, EF > 50%). Results: AVF mice showed exercise intolerance, increased plasma catecholamines and low levels of atrial and brain natriuretic peptides (ANP and BNP resp.) but increased C-type natriuretic peptide (CNP) compared to WT groups. RDN improved exercise ability, increased ANP and BNP, and decreased plasma catecholamines in RDN+ AVF group. AVF hearts showed increased inflammatory cell infiltration and cytokine expression; RDN abrogated these changes. Further, RDN attenuated abnormal cardiac indices (Ejection fraction, fractional shortening, E/A ratio, and E/e’ ratio) and SNS activity following AVF. GFR was increased and renal resistive index (RI) decreased in RDN and RDN+AVF mice. In AVF mice, cardiac vasculature showed rarefaction and reduction of septal branches that improved following RDN. Conclusion: Taken together, our results suggest that RDN enhances cardiac regeneration by modulating SNS activity, improving renal function, and reduction of inflammation.

NIH grant: DK116591, AR071789

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 effect of Akt-induced skeletal muscle hypertrophy on the UBR family of E3 ubiquitin ligases
Authors: Hughes David , Baehr Leslie , Sharples Adam , Waddell David , Bodine Sue
Published: May 2023

Introduction: The N-degron pathway contributes to proteolysis by targeting N-terminal residues of destabilized proteins via E3 ligases that contain a UBR-box domain. Emerging evidence suggests this UBR family of E3 ubiquitin ligases are important in the regulation of skeletal muscle mass. We sought to investigate the response of E3 ubiquitin ligases in the UBR family to a hypertrophic stimulus via Akt overexpression in skeletal muscle. Methodology: Male C57BL/6 mice (5 to 6-months old) were subjected to in vivo electroporation with either a wild-type Akt (Akt-WT) or constitutively active Akt (Akt-CA) plasmid (20ug) in the tibialis anterior (TA) muscle with the contralateral leg serving as an empty vector control (EV). After 7 days, TA muscles were collected, weighed, and processed for biochemical and histochemical analyses. Western blotting was performed to determine levels of puromycin incorporation, Akt/mTORC/S6K1 signalling, ubiquitin, and UBR-related E3 ligases (e.g., UBR2, UBR4, and UBR5). RNA was isolated from frozen muscle powder and qPCR performed to assess mRNA expression for UBR2, UBR4, UBR5, UBR7, MuRF1 and MAFbx. Results: Akt overexpression led to significant increases in TA muscle mass for the Akt-WT (+5%) and Akt-CA (+11%) transfected muscles after 7 days. We observed significant increases in puromycin labelling in the Akt-CA transfected muscles, indicative of elevations in nascent polypeptides. UBR4, UBR5 and UBR7 protein was significantly increased with Akt-CA overexpression. Interestingly, mRNA expression for UBR5 did not change across groups, yet UBR2, UBR4 and UBR7 displayed increased expression in Akt-CA transfected muscles. No change was observed for MuRF1 or MAFbx mRNA expression, but we did observe a significant increase in total ubiquitin levels following Akt-CA overexpression. Conclusion: The increased level of UBR E3 ubiquitin ligases in hypertrophied skeletal muscle provides further evidence for a possible important role for this family of E3 ligases in muscle growth. Future studies will seek to understand the translational control of the UBR E3 ubiquitin ligases and their potential role towards protein quality control in skeletal muscle plasticity.

D.C.H. was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number K01AR077684. A.P.S. was supported by The Research Council of Norway (RCN or Norges forskningsrèfâ¥d/NFR) project number: 314157.

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.