bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Acute Melatonin Supplementation on Cardiovascular Variables During Sympathetic Stimuli in Healthy Young Individuals
Authors: Skillett Sarah , Song Jiwon , Buelow Alexander A. , Matney Jacob E. , Mixon Chris , Akbari Amir , Stanford Matt 
Published: May 2024

Melatonin supplementation has displayed antihypertensive and antioxidant functions in animals and clinical populations. While the exact mechanisms are unknown, animal studies have indicated melatonin may inhibit sympathetic responses by inhibiting vascular α-receptors. However, these effects are untested in humans. PURPOSE: To determine if acute melatonin supplementation alters vascular responses to sympathetic activation caused by mild hypovolemia at rest and during rhythmic exercise in healthy humans. METHODS: 14 healthy young adults (25±1 years, 6 females, tested in days 1-7 of menstrual cycle) participated in a randomized, single blind, crossover protocol. 5 mg of melatonin (MEL) or placebo (PLA) (mint water, mimics flavor of melatonin spray) were given as a sublingual spray 30 minutes before data collection to allow for peak absorption. Forearm blood flow (FBF, doppler ultrasound) and mean arterial pressure (MAP, finger photoplethysmography) were continuously measured during 5 min of supine rest, 2 min of −20mmHg lower body negative pressure (LBNP, causes simulated hypovolemia), 7 minutes of rhythmic handgrip exercise at 20% maximal effort, with minutes 5-7 having LBNP superimposed (Ex+LBNP). Each event was separated by 10 min of quiet rest. Forearm vascular conductance (FVC, FBF/MAPx100mmHg) was calculated. Paired t-tests were performed to compare data between conditions, significance was set as p ≤0.05. RESULTS: Data are presented as Δ% mean ± SD. No significant differences were found with small effect sizes for FBF (PLA:-23.64±22.46 vs. MEL: -34.14±27.17, p=0.33, r=0.18) and FVC (PLA:-22.97±24.16 vs. MEL:-32.98±28.01, p=0.36, r=0.17) from rest to LBNP. There were also no significant differences found, with small effect sizes for FBF (PLA:996.61±1385.63 vs. MEL: 643.24±588.87, p=0.30, r=0.19) and FVC (PLA:770.60±1071.85 vs. MEL:513.45±478.07, p=0.33, r=0.18) from rest to exercise. Lastly, no significant differences were found with small effect sizes for FBF (PLA:4.41±22.48 vs. MEL:4.57±20.08, p=0.98, r=0.01) and FVC (PLA:2.75±21.16 vs MEL:2.93±19.79, p=0.88, r=0.03) from exercise to exercise with LBNP. CONCLUSION: Our data indicates that melatonin does not alter vascular responses with sympathetic stimuli caused by mild hypovolemia, exercise, and combined hypovolemia and exercise. Thus, any vascular effects of melatonin supplementation are not likely caused by inhibition of alpha receptors in healthy humans and the observed improvements in clinical populations are likely attributable to other mechanisms. Non-applicable. 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.
Modulation of Cardiac Ryanodine Receptors by Chloride Intracellular Ion Channel 2
Authors: Sanghvi Shridhar , Sridharan Divya , Bhachu Harmeet , Sayed Nazish , Khan Mahmood , Singh Harpreet 
Published: May 2024

Pathogenic variants of the Chloride intracellular ion channel 2 (CLIC2) are implicated in hypertrophic cardiomyopathy (HCM), a diverse heart condition leading to arrhythmic sudden cardiac death and heart failure. CLIC2 is a unique class of metamorphic protein, related to the enzymatic glutathione s-transferase family and form functional ion channel. Artificial bilayer studies have shown that CLIC2 negatively modulates the activity of cardiac ryanodine receptor 2 (RyR2), implicating the sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ release. However, the subsequent consequences of RyR2 and CLIC2 interaction in cardiac physiology remains unknown. Therefore, we ablated clic2 in human induced pluripotent stem cell (hiPSC) line using the CRISPR-Cas9 system and performed cardiomyocyte differentiation. clic2−/− hiPSC-derived cardiomyocytes (hiPSC-CMs) showed altered electrophysiological properties leading to impaired excitation-contraction coupling. clic2−/− hiPSC-CMs showed an increase in beat rate and field potential duration by 143.49±5.96% and 162.43±5.82%, respectively, whereas conduction velocity and spike amplitude decreased by 43.81±2.22% and 43.32±3.54%, respectively compared to WT hiPSC-CMs. Additionally, action potential duration measurements of clic2−/− hiPSC-CMs showed a decrease in APD30, APD50, and APD90 by 74.42%, 65.19%, and 66.46%, respectively compared to WT hiPSC-CMs. Moreover, clic2−/− hiPSC-CMs showed altered Ca2+ handling, with a decrease in peak amplitude (57.07±2.25%) and duration (38.29±1.30%) compared to the WT hiPSC-CMs. The caffeine induced Ca2+ release in clic2−/− hiPSC-CMs, attributed to the SR/ER Ca2+ overload which decreased by 72.19±3.51% compared to WT hiPSC-CMs. Transcriptomics analysis of clic2−/− hiPSC-CMs revealed 223 transcripts with significant changes in expression levels (89 upregulated and 134 downregulated), implicating CLIC2 in hypertrophy cardiomyopathy, dilated cardiomyopathy, and other heart diseases. Furthermore, the protein expression of CLIC2 increases in end-stage failing human heart samples compared to the non-failing heart. In conclusion, our study sheds light on the novel role of CLIC2 in the regulation of cardiac (patho)physiology. National Institutes of Health (NIH) (HL133050, and HL157453); American Heart Association-Transformational Project Award; National Center for advancing translational sciences (TR004178, understudied proteins and druggable targets) (HS). Presidential Predoctoral Fellowship; Margaret T. Nishikawara Merit Scholarship Endowment in Physiology; Graduate School’s Alumni Grants for Graduate Research and Scholarship Program, The Ohio State University (SS). 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.
Does Zn deficiency promote kidney damage?
Authors: Hasrat Khanzada , Wenegieme Tara-Yesomi , McMichael Kelia , Rockwood Jananie , Waite Aston , Barrett Hannah , Nshuti Adeline 
Published: May 2024

Background: Chronic kidney disease (CKD) impairs the kidneys’ ability to filter blood. End stage renal disease (ERSD), which is characterized by irreversible kidney fibrosis, progresses from CKD. Significant events in kidney fibrosis include the transformation of activated renal cells into myofibroblasts which can be detected by the abundance of ⍺-SMA, and the subsequent deposition of Extracellular Matrix Proteins (ECM). Previous studies have shown CKD patients are zinc deficient which is a critical micronutrient that is responsible for supporting several physiological processes in the body. Based on these findings, we hypothesize that zinc deficiency promotes kidney fibrosis. Experimental Design: To investigate the role of zinc in renal damage, wild type, adult mice (C57BL/6J) were on either a Zn-adequate (ZnA) or a Zn-deficient (ZnD) diet for 10 weeks. To examine the effects of Zn repletion (ZnR), at week 8, a subset of ZnD mice was returned to the ZnA diet. At the end of the study, kidneys were harvested and processed for immunohistochemistry to assess kidney fibrosis. Results: While ZnD mice had greater expression of ⍺-SMA, enhanced ECM deposition was not observed. However, increased ECM deposition was present in ZnR mice. Conclusion: Even though ZnD promotes activation of ECM producing cells, renal fibrosis was absent. Significance: These findings indicate a complicated interplay between Zn homeostasis and kidney fibrosis that warrants further investigation. Funding: R21 DK119879, R01 DK-133698. 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 gut microbiome regulates thermogenic performance in high-altitude deer mice
Authors: Scott Graham R. , Zucker Emma A. , MacPherson Jess , Bucking Carol 
Published: May 2024

High altitude is one of the most extreme environments inhabited by endotherms, where cold temperatures demand high rates of thermogenesis to maintain body temperature (Tb) but hypoxia constrains aerobic metabolism. Recent findings suggest that the gut microbiome contributes to whole-body thermogenesis, but its significance for coping in cold environments remains poorly understood. We hypothesized that the gut microbiome contributes to adaptive increases in thermogenic performance in deer mice native to high altitude. Mice from populations native to high altitude and low altitude were born and raised to adulthood in common lab conditions. Adults from both populations were then acclimated to warm (25°C) normoxia or cold (5°C) hypoxia (12 kPa O2) for 6 weeks, and a subset of mice in each group were treated with antibiotics to disrupt the gut microbiome. Thermogenic endurance was then measured as the duration that Tb could be maintained during acute cold challenge. Antibiotic treatment strongly diminished thermogenic endurance in highlanders, but led to only minor reductions in thermogenic endurance in lowlanders. These differences could not be fully explained by impairments in aerobic heat production by host thermogenic tissues, because antibiotic treatment had only modest effects on cold-induced increases in O2 consumption rate and the abundance of UCP-1 protein and oxidative phosphorylation complexes in brown adipose tissue. Therefore, our findings suggest that the gut microbiome plays an increased role in regulating thermogenesis in high-altitude deer mice, and that changes in host-microbe interactions contribute to high-altitude adaptation. Funded by NSERC of Canada. 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.
Molecular organization of adrenergic and noradrenergic neurons in the mouse ventrolateral medulla
Authors: Stornetta Daniel , Schwalbe Dana , Abraham-Fan Ruei-Jen , Souza George , Jalil Maira , Crook Maisie , Campbell John 
Published: May 2024

Catecholaminergic neurons in the ventrolateral medulla (VLM) regulate many important aspects of physiology, including the sympathetic control of blood pressure, glucose homeostasis, immune function, and the neuroendocrine responses to inflammation and stress. Previous studies have parsed catecholaminergic VLM neurons into distinct sub-populations based on neurochemical content, connectivity, and distinct response to the activation of autonomic reflexes. However, there is no consensus for the molecular organization of catecholaminergic neurons. In this study, we used high-throughput single nuclei RNA sequencing combined with anatomically- and genetically-targeted cell-sorting of spinally-projecting and catecholaminergic neurons to systematically characterize C1 and A1 neurons in the mouse VLM. Our results, based on an analysis of 894 catecholaminergic neurons derived from a dataset of 114,805 single-nuclei transcriptomes, indicate that the VLM contains 7 molecularly distinct subpopulations of catecholaminergic neurons, including 5 adrenergic subtypes and 2 noradrenergic subtypes identified by the expression of enzymes involved in the production of catecholamine ( Th, Dbh) and the vesicular transporters for glutamate ( Slc6a17) and noradrenaline ( Slc6a2). Neurons with projections to the spinal cord were present in 4 of 5 adrenergic cell clusters, and 1 noradrenergic cell cluster. We histologically verified two novel markers of the adrenergic ( Hk2) and noradrenergic ( Eya1) neurons using RNA fluorescent in situ hybridization. Hk2 expression was found primarily in Dbh+ neurons in the rostral VLM, including both bulbospinal and non-bulbospinal neurons, as well as majority of Pnmt+ neurons in the rostral VLM and C2/C3 regions. Eya1 co-localized with Dbh and Slc6a2 consistently in the caudal VLM, aligning with the location of the A1 neurons, whereas Eya1 signal was diffuse in the rostral VLM. Collectively, this shows that Hk2 expression is enriched in adrenergic neurons as judged by conventional criteria irrespective of the cell's location in the medulla, whereas Eya1 is enriched in brainstem noradrenergic neurons and provides a marker for A1 neurons. These data show molecularly distinct adrenergic and noradrenergic neurons are spatially intermixed in the VLM, and provides novel gene markers for distinct subtypes of catecholaminergic neurons that can be used to dissect the function in future studies. This work was supported by National Institute of Health (NIH) R01 HL148004 to SBGA; and R01 HL153916, Pathway to Stop Diabetes Initiator Award 1-18-INI-14, and UVA 3Cavaliers grant to JNC. 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.
Muscle Sympathetic Action Potential Firing Patterns Following Intranasal Insulin Administration in Healthy Adults
Authors: McMillan Neil J. , Jacob Dain , Shariff Brian , Harper Jennifer , Gonsalves Anna , E. Foster Glen , Manrique-Acevedo Camila 
Published: May 2024

Objective: Systemic insulin increases muscle sympathetic nervous system activity (MSNA) in healthy adults by augmenting firing frequency of medium-sized sympathetic action potentials (AP) and recruiting previously latent, larger axons. Whether these neural coding patterns are due to central or peripheral effects of insulin is unclear. We examined the impact of elevated central insulin on AP firing patterns in healthy adults. We hypothesized intranasal insulin administration, which increases central insulin levels, would increase MSNA via elevated firing frequency of APs and recruitment of previously latent, larger axons. Methods: Ten participants were assigned to time control [TC, n=6 (3M/3F)] or 160 IU of intranasal insulin [n=4 (3M/1F)] administered over 5 min. MSNA (fibular microneurography) was assessed at baseline and for 30 min following insulin administration. Sympathetic APs were identified using a matched mother wavelet and continuous wavelet transform. APs were divided into the proportion of those firing in small, medium, or large amplitude clusters. AP firing frequency, percent of APs firing within an MSNA burst (synchronous), and the probability of clusters firing more than once within an MSNA burst were identified. Data are reported as median (interquartile range). Results: MSNA burst frequency increased 15 min after intranasal insulin administration [24(20) to 31(23) bursts/min, p=0.03]. At this time, the percent of synchronous APs [72(27) to 90(24)%, p=0.02] and the probability of medium-sized AP clusters firing more than once within an MSNA burst [13(14) to 19(17)%, p=0.03] increased. No changes in MSNA burst frequency [23(14) to 25(13) bursts/min, p=0.27], percent of synchronous APs [74(15) to 75(34), p=0.48], nor firing probability of medium-sized AP clusters [6(12) to 8(7)%, p=0.97] occurred in TC. The total number of detected clusters did not change in either group (p>0.05). Conclusions: Intranasal insulin increases MSNA burst frequency due to a higher percent of synchronous APs, particularly medium-sized AP clusters; however, we did not observe recruitment of latent, larger axons. These exploratory data highlight potential differences in the sympathetic response to central versus peripheral insulin exposure in healthy adults. CAFNR Joy of Discovery (JKL, JP). 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.
β-Adrenergic Receptor Blockade Augments Sympathetically Mediated Vasoconstriction during Hypoxia in Healthy Young Adults
Authors: Jacob Dain , Shariff Brian , Bond Braden , Boyes Natasha , Harper Jennifer , Bostick Brian , Limberg Jacqueline 
Published: May 2024

Objective: Vascular tone is dictated by the net balance of vasodilatory and vasoconstrictor influences. During hypoxia, systemic sympathetic vasoconstrictor activity is increased but peripheral vasodilation prevails — suggesting vasodilatory factors outweigh sympathetically-mediated vasoconstrictor influences in the healthy state. Given vascular β-adrenergic receptors contribute to hypoxic vasodilation, we hypothesized pharmacological blockade of β-adrenergic receptors would augment the vasoconstrictor response to acute sympathetic activation during hypoxia. Methods: Thirteen young healthy participants (5F/8M, 27±7 yr, 25±3 kg/m2) completed two study visits randomized and blinded to oral placebo or propranolol (1mg/kg, NCT05256069). On each visit, participants completed two trials: 1) 10-min normoxia (0.21 FiO2, 98±0% SpO2) followed by sympathetic activation via a 2-min normoxic cold pressor test (CPT); 2) 5-min steady-state hypoxia (0.10±0.01 FiO2, 81±1% SpO2) followed by a 2-min hypoxic CPT. Forearm blood flow (FBF, venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were assessed. FBF was normalized for mean BP (forearm vascular conductance, FVC). A change in FVC from steady-state to the last 1-min of CPT was calculated (ΔFVC = CPT − steady-state) and expressed as a percent change (%FVC = ΔFVC/steady-state x 100). Results: The vascular response to sympathetic activation (CPT) was unaffected by hypoxia under placebo conditions (normoxia: -34±21%; hypoxia: -29±32%, p=0.33). In contrast, following β-adrenergic blockade with oral propranolol, sympathetically-mediated vasoconstriction was augmented during hypoxia (normoxia: -29±30%; hypoxia: -40±27%, p=0.04). Conclusion: β-adrenergic receptor blockade augments the vasoconstrictor response to acute sympathetic activation during hypoxia in a mixed-sex cohort. These preliminary data indicate functional β-adrenergic receptors are required to restrain sympathetically-mediated vasoconstriction during hypoxia. Based on data supporting sex-related differences in adrenergic control of vascular tone, future work will seek to stratify results by sex. Funding: AHA 909014 (DWJ), APS-SURF (BJB), HL153523 (JKL). 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.
Impact of Peripheral Versus Central Insulin on Cerebrovascular Compliance in Healthy Young Adults
Authors: Shariff Brian , Shoemaker Leena , Pipkins Aubrey , McMillan Neil J. , Jacob Dain , Gonsalves Anna , Harper Jennifer 
Published: May 2024

Objective: Vascular compliance is an essential component of cerebral blood flow regulation. Prior work has shown cerebral vasodilation (elicited by hypercapnia) reduces cerebrovascular compliance (Ci); however, this work has yet to be translated to other vasoactive compounds. Insulin has important vasodilatory effects in the peripheral circulation, but less is known about the role of insulin in cerebrovascular control. Herein, we hypothesized both peripheral (intravenous) and central (intranasal) insulin administration would increase indices of cerebral blood flow and reduce Ci in healthy young adults. Methods: Twenty-five healthy young adults (8 female; 26±7 yrs, 25±3 kg/m2) were assigned to two separate protocols (NCT05244694, NCT05153395). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound) was measured at baseline and under two study conditions: 1) at the end of a 60 min hyperinsulinemic euglycemic infusion, and 2) 60 min following 160 IU of intranasal insulin. Indices of Ci were calculated using a modified Windkessel model applied to blood pressure (finger photoplethysmography) and corresponding MCAv waveforms collected over a 5-min period (10 waveforms) at baseline and during the aforementioned insulin conditions. Results: Blood glucose remained unchanged throughout both protocols (both p>0.05). MCAv was maintained over time under both insulin conditions (protocol 1: 60±13 to 62±17 cm/s, p=0.635; protocol 2: 58±9 to 53±14 cm/s, p=0.146). In contrast, Ci decreased (0.00028±0.00010 to 0.00021±0.00007 cm/s/mmHg, p=0.010) from baseline during peripheral (intravenous) insulin administration. No change in Ci (0.00049±0.00025 to 0.00040±0.00018 cm/s/mmHg, p=0.189) were observed following intranasal insulin administration. Conclusions: Contrary to our hypothesis, there was no effect of peripheral or central insulin administration on resting MCAv in healthy young adults. However, intravenous (but not intranasal) insulin reduced Ci by approximately 25% from baseline values. These findings advance our understanding of cerebrovascular control mechanisms during insulin exposure and provide the opportunity to extend this work to diseased states characterized by insulin resistance, including diabetes. CAFNR Joy of Discovery (JKL, JP). 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.
Reprogramming cardiac macrophages with circular RNAs to attenuate post-MI adverse remodeling
Authors: Jung Mira , Schmidt Arne , Sansonetti Marida , Al Soodi Bashar , Thum Thomas 
Published: May 2024

Cardiac macrophages (cMφ) play a critical role in cardiac remodeling following myocardial infarction (MI). Reprogramming cMφ towards a favorable wound-healing phenotype is emerging as a promising therapeutic strategy for MI patients. Circular RNAs (circRNAs) are a unique class of non-coding RNAs with high stability and abundance, making them attractive therapeutic targets. However, the role of circRNAs in cMφ physiology during heart failure (HF) progression is poorly understood. To identify circRNAs as key regulators of cMφ dynamics, we performed RNA sequencing and bioinformatics analysis on heart biopsies from healthy donors and patients with ischemic HF. We identified a promising circRNA, circMJ1, as a regulator of Mφ polarization and inflammatory response. CircMJ1 was highly expressed in cMφ and its expression was associated with cMφ polarization. Knockdown of circMJ1 significantly inhibited inflammatory signaling pathways in cMφ and reduced the secretion of pro-inflammatory cytokines. The secretome from circMJ1-silenced cMφ (circMJ1-KD cMφ) also significantly suppressed the migration of cardiac fibroblasts and apoptosis of cardiomyocytes. To further assess the therapeutic effcacy of circMJ1-KD Mφ in cardiac remodeling in the context of MI, we employed a novel multicellular 3D ex vivo model, called living myocardial slices (LMS). We applied circMJ1-KD Mφ to both rat LMS subjected to cryo-injury mimicking MI and HF patient-derived LMS. Interestingly, co-culture with circMJ1-KD Mφ demonstrated a remarkable reduction in inflammation and fibrosis, alongside notable improvement in cardiac function in both cryo-injured rat LMS and HF patient-derived LMS. Overall, our findings reveal circMJ1 as a crucial "switch" for Mφ dynamics and suggest the therapeutic potential of engineered circMJ1-silenced Mφ to improve post-MI healing. Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) –465131031. 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.