bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Metabolic Profiling of Plasma in Lean and Obese Individuals during Oral Glucose Ingestion
Authors: Consitt Leslie , Saxena Gunjan , Law Timothy , Simon Janet , Maschari Dominic 
Published: May 2024

Obesity has long been associated with metabolic inflexibility and insulin resistance. The purpose of this study was to determine 1) if the plasma metabolite/lipid profile was altered during an oral glucose tolerance test (OGTT) with obesity and 2) whether changes in plasma metabolites/lipids were related to insulin sensitivity or metabolic flexibility. Fourteen (7M/7F), young, lean (BMI: 21.9 ± 1.8 kg/m2) and fourteen (7M/7F) young, obese (BMI: 40.6 ± 5.4 kg/m2) individuals underwent a 2-hour OGTT with plasma samples obtained at baseline, 45 min and 120 min. Plasma was immediately stored at -80°C for subsequent targeted metabolomics (Biocrates MxP® Quant 500, Biocrates Life Sciences AG, Innsbruck, Austria). A 2 (body composition group) x 3 (time point) ANOVA was performed for each sex, with the false discovery rate (FDR q-value <0.10) used to account for multiple testing. Of the 73 small molecule metabolites tested, 2 (Glucose and Glutamate) differed between lean and obese females, and 34 metabolites (including 10 amino acids, 9 amino acid related, 5 bile acids, 2 biogenic amines and 2 carboxylic acids) changed with time in females. Of the 427 plasma lipid species tested, 79 (primarily triglycerides, TG) differed between lean and obese females, and 134 (primarily fatty acids and TG) changed with time. In males, 45 metabolites (similar to females) and 5 lipid species (Fatty acids only) changed with time. When examining the change in all plasma metabolites/lipid species from baseline to 120 min, the change in 9 TGs, 1 dihexosylceramide, as well as glycolithocholic acid sulfate (bile acid) were related to insulin sensitivity (Matsuda Index). Metabolic flexibility (change in respiratory exchange ratio from baseline to 120 min) was related to the change in 4 lysophosphatidylcholines, 3 TG, 2 acylcarnitines, 2 diglycerides, 3-Indoleacetic acid and glutamate. American Heart Association Grant: 18AIREA33960404. 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.
Exercise Mitigates Angiotensin II-Mediated Sympathetic Nerve-Macrophage Interaction in Aortic Adventitia Leading to Vascular Remodeling
Authors: Cho Jae Min , Vu Khoa , Zhu Enbo , Roustaei Mehrdad , Nahoul Jonah , Park Seul-Ki , Chapleau Mark W. 
Published: May 2024

Large artery stiffness is a significant risk factor for cardiovascular diseases. Our previous study suggested that angiotensin II (Ang II) stimulates sympathetic innervation in aortic adventitia (AA) leading to elevated mean arterial blood pressure and increased arterial fibrosis, while voluntary wheel-running (VWR) reduces them. The aim of this study is to explore mechanism under Ang II-induced the aortic remodeling through sympathetic nerves and immune cell interactions using transcriptomics. We isolated cells in AA from Ang II (1.5 mg/kg/day) vs. Vehicle (Saline) infused C57BL/6 male mice (n=3 of each group), and we performed single-cell RNA-sequencing (scRNAseq). We profiled 23,419 cells after quality control and filtering steps and annotated 9 cell types in the AA employing a uniform manifold approximation and projection (UMAP) to visualize the remaining cells and the Leiden cluster algorithm. Firstly, we identified the Adrb2 gene for β2-adrenergic receptor (β2-ADR) was predominantly expressed in macrophages/monocytes as compared to other cell types, and significantly more expressed in macrophages vs. monocytes (adjusted p-value, <0.05). We validated the transcriptomic results using immunostaining for β2-ADR and synapsin with CD68 in AA. In addition, Ang II increased AA macrophage proportion which displays M1 phenotype (pro-inflammatory) (adjusted p-value, <0.05). These findings suggest that Ang II promotes M1 like macrophages which interact with sympathetic nerves in AA. Next, we performed Gene Ontology (GO) enrichment test in macrophages and fibroblasts. Ang II Macrophages were enriched in GO terms with inflammation and cytokines, and Ang II fibroblasts were enriched in GO terms involved in extracellular matrix deposition. The GO results indicate that Ang II induced inflammatory macrophages activates fibroblasts to accumulate ECM deposition in AA. Congruent with the scRNAseq results, we found that number of macrophages, ECM accumulation, and vascular stiffness measured by pulse wave velocity were increased with Ang II vs. Vehicle (all, p <0.05), whereas interestingly VWR ameliorated the Ang II effects. This study provides the evidence that Ang II promotes aortic remodeling by interaction between sympathetic nerves and macrophage which results in ECM deposition in AA using transcriptomics approach, while VWR countermeasure to these detrimental effects. 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.
Hepatokine ITIH3 Protects Against Hepatic Steatosis by Downregulating Mitochondrial Bioenergetics and De Novo Lipogenesis
Authors: Kumar Talari Noble , Mattam Ushodaya , Kaminska Dorota , Sotomayor-Rodriguez Irene , Rahman Afra , Péterfy Miklós , Pajukanta Päivi 
Published: May 2024

Accumulating evidence suggest that mitochondrial functions are altered and contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). As a result, research is being conducted to discover targets that alter mitochondrial functions to ameliorate NAFLD, and its progression towards non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Recent studies demonstrate that liver secretory proteins regulate normal development, obesity, simple steatosis to NASH progression. Inter-α-trypsin inhibitors (ITI) are one such proteins secreted by liver, altered in NAFLD, but their functional importance in mitochondrial metabolism is poorly understood. Here, we have identified that ITIH3 is a potential candidate gene that protects against NAFLD by targeting mitochondrial metabolism. We used an integrative multiomics approach using transcriptomic data from approximately 100 different mouse strains called hybrid mouse diversity panel (HMDP) and a cohort of bariatric surgery patients and identified Itih3/ITIH3 expression to be inversely associated with NAFLD/NASH progression and hepatic TG accumulation. Our network enrichment analyses revealed NAFLD-related pathways such as mitochondria, TCA cycle, fatty acid metabolism, cholesterol metabolism, coagulation and fibrinolysis. Next, disease enrichments by ToppGene revealed metabolic syndrome-related disease traits including dyslipidemia, steatosis, NASH and fibrosis. Our in vitro and in vivo studies using loss and gain of function mouse and cell culture models demonstrated that hepatic ITIH3 reduced liver triglyceride accumulation and de novo lipogenesis (DNL). Remarkably, hepatic ITIH3 also lowered mitochondrial respiration and lipid droplet accumulation. This was accompanied by increased STAT1 signaling and Stat3 expression, both of which are known to protect against NAFLD/NASH. Together, we conclude that ITIH3 plays a unique role in regulating the hepatic lipid profile, DNL, and mitochondrial metabolism, all of which have implications for NAFLD treatment. Our findings indicate hepatokine ITIH3 as a potential biomarker and/or treatment for NAFLD. R00DK120875. 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.
Mitochondrial Ca2+-coupled generation of reactive oxygen species causes endothelial dysfunction in Cantú syndrome
Authors: Metwally Elsayed , Yamasaki Evan , Solano Alfredo Sanchez , Thakore Pratish , McClenaghan Conor , Nichols Colin G. , Earley Scott 
Published: May 2024

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits of vascular ATP-sensitive K+ channels (KATP). In this study, we investigated the effects of Cantú syndrome on the vascular endothelium using mutant mice that model the disease. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure and to the adrenergic receptor agonist phenylephrine. We also found that KATP GOF and acute activation of KATP channels with pinacidil increased the amplitude and frequency of wave-like Ca2+ events that were generated in the endothelium in response to the vasodilator agonist carbachol (CCh). Elevated cytosolic Ca2+ signaling activity in arterial endothelial cells from Cantú mice was associated with high mitochondrial [Ca2+], reactive oxygen species (ROS) generation, and peroxynitrite levels. Scavenging intracellular and mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with KATP GOF mutations. We conclude that mitochondrial Ca2+ overload and ROS generation cause endothelial dysfunction in mice with Cantú syndrome. This study was supported by grants from NHLBI (R35HL155008) and NIGMS (P20GM130459) to S.E., and NIH (R35HL140024) to C.G.N., and NIH (R00HL150277) to C.M. The Transgenic Genotyping and Phenotyping Core and the High Spatial and Temporal Resolution Imaging Core at the COBRE Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno is maintained by grants from NIH/NIGMS (P20GM130459). 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.
Autotaxin-Lysophosphatidic Acid Axis: Key Regulator of Blood-Brain Barrier Integrity and Stroke Outcomes during Cerebral Ischemia-Reperfusion
Authors: Panchatcharam Manikandan , Bhattarai Susmita , Manikandan Shrivats , Manikandan Varsha , Miriyala Sumitra 
Published: May 2024

Background: Endothelial hyperpermeability subsequent to ischemic stroke poses severe ramifications for patient outcomes, with the preservation of blood-brain barrier (BBB) integrity being paramount. The pathological role of the autotaxin-lysophosphatidic acid (ATX-LPA) axis in various disorders is established. While LPA's detrimental effects in stroke pathology have been documented, the mechanistic role of its enzymatic precursor, autotaxin (ATX), especially in the context of BBB disruption and mitochondrial dysfunction, necessitates deeper exploration.Objective: Our research aimed to dissect the intricate interplay of the ATX-LPA axis in modulating BBB integrity and mitochondrial bioenergetics during cerebral ischemia-reperfusion injury.Methods: Employing well-characterized murine models, ischemic strokes were meticulously induced, succeeded by reperfusion. A gamut of advanced assays—including the electrical cell-substrate impedance sensor, Seahorse XF24 analyzer, and AR-2 probe fluorescence—were systematically deployed. Moreover, to attain a nuanced understanding, we genetically engineered a mouse model exhibiting endothelial-specific ATX deletion, facilitating a direct interrogation of ATX's endothelial role.Results: Post-ischemic reperfusion culminated in a statistically significant upregulation of ATX mRNA (1.7-fold, p<0.05) and a quadrupled surge in its enzymatic activity (p<0.01). Disturbingly, the I/R cohort manifested augmented LPA concentrations, concomitant with a pronounced mitochondrial bioenergetic collapse, evidenced by metrics such as the oxygen consumption rate and ATP synthesis (both p<0.01). BBB integrity was critically compromised, a derangement that ATX inhibitors ameliorated (p<0.05). Intriguingly, mice with endothelial-specific ATX ablation exhibited remarkably attenuated permeability (p<0.05) and infarct volumetric reductions (p<0.01), while preserving cerebral perfusion (p<0.05).Conclusion: Our findings underscore the ATX-LPA axis as a linchpin in the pathophysiological cascade following ischemic stroke, specifically impinging on BBB and mitochondrial health. Deciphering and subsequently targeting this nexus could herald a paradigm shift in therapeutic strategies for ischemic stroke. This research was supported by National Institutes of Health grants HL141998, HL141998-01S1, AA025744, AA026708, and AA025744-02S1. 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.
Influence of home-based heat therapy on thermal and cardiovascular strain during passive heat exposure in older adults
Authors: Cope Heidi L. , Richey Rauchelle E. , Ruiz Ysabella I. , Moore Amy M. , Olivencia-Yurvati Albert H. , Garfield Tyson C. , Gagnon Daniel 
Published: May 2024

Heat waves are occurring more frequently and with greater intensity. In fact, 2023 marked the hottest summer ever recorded in the Northern Hemisphere. Heat waves increase the risk for heat-related morbidity and mortality, particularly for older adults who have a reduced ability to dissipate heat. Heat acclimation induces physiological adaptations that attenuate thermal and cardiovascular strain during subsequent heat exposures. However, traditional heat acclimation protocols require expensive equipment (e.g., climate chamber) and may be challenging for older adults with limited functional capacity. Home-based heat therapy provides a potentially safe and pragmatic option to induce heat acclimation. The purpose of this pilot study was to test the hypothesis that home-based heat therapy reduces thermal and cardiovascular strain in older adults during acute passive heat exposure. Six older adults (5 women; 67 ± 4 years) performed 8 weeks of home-based heat therapy by immersing their lower legs ~33 cm into a heated (~ 42°C) and circulated water bath 4 days per week, for 45 min per session. Intestinal temperature (telemetric pill) and heart rate were assessed before (pre) and after (post) the intervention during acute heat exposure (45 min lower leg water immersion). In addition, rate pressure product, an estimate of myocardial demand, was calculated as heart rate x systolic blood pressure. Resting intestinal temperature, heart rate, and rate pressure product did not differ from pre to post heat therapy (all P ≥ 0.6). However, the change in intestinal temperature during acute heat exposure was reduced after heat therapy (15 min: pre, Δ0.47 ± 0.17 °C vs. post, Δ0.33 ± 0.14 °C; 30 min: pre, Δ0.84 ± 0.29 °C vs. post, Δ0.72 ± 0.23 °C; 45 min: pre, Δ1.10 ± 0.27 °C vs. post, Δ1.07 ± 0.24 °C; P = 0.03 for main effect of time). Likewise, the change in heart rate was attenuated following the intervention (15 min: pre, Δ14 ± 9 bpm vs. post, Δ10 ± 5 bpm; 30 min: pre, Δ22 ± 13 bpm vs. post, Δ17 ± 6 bpm; 45 min: pre, Δ25 ± 9 bpm vs. post, Δ21 ± 6 bpm; P = 0.02 for main effect of time). Rate pressure product was also reduced following heat therapy (15 min: pre, Δ1280 ± 1636 bpm·mmHg vs. post, Δ322 ± 698 bpm·mmHg; 30 min: pre, Δ1800 ± 1573 bpm·mmHg vs. post, Δ1170 ± 450 bpm·mmHg; 45 min: pre, Δ2145 ± 593 bpm·mmHg vs. post, Δ840 ± 602 bpm·mmHg; P < 0.01 for main effect of time). Our preliminary data suggest that 8 weeks of home-based heat therapy elicits some adaptations that may reflect heat acclimation. However, further work is needed to confirm these initial findings. American Heart Association TPA958179. 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.
Skeletal Muscle Extracellular Vesicles Enhance Mitochondrial Movement and have a Dose-dependent Effect on Increasing Mitochondrial Respiration
Authors: Goebel de Souza Tamiris de Fatima , Seif Samira , O Obi Patience , Ajenkar Anass , Chandrasena Hashini , Tuma Aya , Bydak Benjamin 
Published: May 2024

Chronic exercise leads to systemic health benefits across tissues, including an increase in mitochondrial function in skeletal muscle. One potential mechanism is via the release of extracellular vesicles (EVs), which can transfer functional cargo to recipient cells. Previously, we have shown that using an in vitro model of exercise, chronic contractile activity (CCA)-derived EVs (CCA-EV) increased mitochondrial biogenesis in healthy myoblasts. Here, we hypothesize that CCA-EVs will have a concentration-dependent effect on mitochondrial respiration, and also regulate mitochondrial dynamics in myoblasts. C2C12 myoblasts were differentiated into myotubes, and electrically paced (3hrs/day, 4 days, 14V, C-PACE EM, IonOptix). EVs from control and CCA-stimulated myotubes were isolated from conditioned media using differential ultracentrifugation and biophysically characterized by size and concentration using TRPS (Izon). C2C12 myoblasts were treated daily for 4 days using three different concentrations: 1.0E4; 2.0E4 and 4.0E4 EVs/cell (N=4-5). Basal and maximal oxygen consumption rates (OCR) were measured using the Seahorse XFe24 (Agilent). We used live-cell fluorescence microscopy and Mitometer software to access mitochondrial movement: area/volume, displacement, distance, length, perimeter, speed and velocity. Average size was unchanged between control-EVs (123±10.8 nm) and CCA-EVs (123±11.9 nm) (p=0.9137, N=3), and 2.3-fold more CCA-EVs were released vs. control-EVs (p=0.2072, N=3). Lowest EV concentration (1.0E+4 EVs/cell, N=5) had no effect on basal (p=0.4226) and maximal (p=0.1835) OCR. Intermediate dosage of CCA-EVs (2.0E+4 EVs/cell, N=5) increased basal OCR by 20% (p=0.0037) and maximal OCR by 18% (p=0.0095), while the highest concentration (4.0E+4 EVs/cell, N=4) decreased basal OCR by 9% (p=0.0001) and maximal OCR by 29% (p=0.0009), compared to control-EVs. Mitochondrial motility (N=484-976) in myoblasts treated daily after each day of CCA showed enhanced mitochondrial dynamics with CCA-EVs: increased area/volume (p<0.0001), displacement (p<0.0001), distance (p<0.0001), mean intensity (p<0.0001), perimeter/surface area (p=0.0137) and speed (p<0.0001), compared to control-EVs. In summary, CCA-EVs induced concentration-dependent improvements in mitochondrial respiration in healthy myoblasts, concomitant with enhanced mitochondrial movement. These results open exciting avenues for the therapeutic potential of CCA-EVs in rescuing mitochondrial dysfunction. TFGS is funded by a Research Manitoba Postdoctoral Fellowship. Grants from CHRIM, CHF, DREAM and NSERC to AS funded the research. 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.
Augmented pressor responses to mental stress in females with spontaneous coronary artery dissection
Authors: Zaremba Solomiia , Dillon Gabrielle , Miller Alex , Harvey Ronée , Hayes Sharonne , Baker Sarah , Tweet Marysia 
Published: May 2024

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome or sudden cardiac death due to a separation of arterial wall layers. The majority of patients with SCAD are females (>80%) with few to no traditional cardiovascular risk factors. Though the physiological mechanisms that predispose to SCAD are unknown, common triggers for SCAD events include sympathoexcitatory stimuli, such as mental and emotional stress. Additionally, studies report high prevalence of depression and anxiety among patients with SCAD. Our study aimed to investigate cardiovascular responses to mental stress in patients with SCAD. We hypothesized that patients with SCAD would have exaggerated cardiovascular responses to mental stress compared to healthy controls. Methods: Four female patients with SCAD were age-, and BMI-matched with 4 healthy females. Participants underwent 2 minutes of baseline quiet rest, a 5-minute Stroop Color Word Test to induce mental stress, followed by 2 minutes of recovery. Continuous beat-to-beat blood pressure (BP, finger photoplethysmography) and heart rate (HR, 3-lead ECG) were recorded. Venous occlusion plethysmography was used to measure forearm blood flow (FBF). Forearm vascular conductance (FVC) was calculated as FBF/mean BP×100. Data are presented as change from baseline (Δmean±SD). Group data were compared using independent samples t-tests. Results: Resting hemodynamic parameters (Systolic [SBP], Diastolic [DBP], and Mean BP [MBP], Pulse pressure [PP], and HR) and FVC were similar between groups. Patients with SCAD had greater increases in DBP (Δ12±5 vs. Δ1±5 mmHg, p=0.02) and PP (Δ5±3 vs. Δ-7±8 mmHg, p=0.04) during the last minute of mental stress test compared to controls. Although, there were no differences in the changes of SBP (Δ17±7 vs. Δ-1±13 mmHg, p=0.05), MBP (Δ13±6 vs. Δ3±8 mmHg, p=0.08), HR (Δ8±0 vs. Δ10±2 bpm, p=0.12), or FVC (Δ1.5±1.2 vs. Δ1.8±1.3 ml/min/100 mmHg, p=0.80) between groups. During the last minute of recovery, there were no differences in hemodynamic parameters (SBP: Δ6±9 vs. Δ-4±10 mmHg, p=0.23; DBP: Δ2±7 vs. Δ-3±2 mmHg, p=0.22; MBP: Δ3±7 vs. Δ-3±5 mmHg, p=0.22; PP: Δ4±5 vs. Δ-1±8 mmHg, p= 0.35; HR: Δ-1±3 vs. Δ0±3 bpm, p=0.64), or FVC (Δ1.3±1.7 vs. Δ0.5±0.3 ml/min/100 mmHg, p= 0.35) between groups. Conclusion: These preliminary data suggest that patients with SCAD have greater increases in DBP and PP in response to mental stress compared to healthy controls. These exaggerated pressor responses might have implications for the pathophysiology of SCAD. NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649. 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.