bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Donepezil on Nonlinear Arterial Pressure and Pulse Interval Dynamics in Spontaneously Hypertensive Rats (SHR)
Authors: Wall de Almeida Camila , Silva Carlos , Fazan Jr Rubens , Virgilio da Silva Luiz Eduardo , Lataro Renata Maria , Salgado Helio 
Published: May 2024

Objectives: This study aimed to evaluate the effects of donepezil, an anticholinesterase agent that potentiates parasympathetic function, in the nonlinear dynamics of blood pressure (BP) and pulse interval (PI) from spontaneously hypertensive rats (SHR). Entropy-based approaches which quantify the irregularity or unpredictability of time series were employed. Additionally, detrended fluctuation analysis (DFA) was applied to estimate the degree of self-similarity in the time series. We hypothesized that donepezil improves both entropy and DFA indices of BP and PI. Methods: Male SHR or Wistar-Kyoto (WKY) rats (5 weeks old) were implanted with subcutaneous osmotic mini-pumps for donepezil (DON) administration (1.4 mg/kg/day) or vehicle. At the end of the treatment (16 weeks), conscious WKY (N=12) and SHR treated with donepezil (N=8), or vehicle (N=9), had their BP directly recorded during 1h. Time series (15 min) from systolic BP and PI were generated and used to calculate sample (SampEn), fuzzy (FuzzyEn), and dispersion (DispEn) entropy, as well as DFA scale exponents in short (α1; 5≤n≤15), mid (α2; 20≤n≤100) and long (α3; 100≤n≤500) windows. The results are shown as mean ± SD. One-Way ANOVA, followed by Tukey’s post-test, evaluated differences between the WKY, SHR, and SHR+DON groups. Results: The data are displayed in the table. Lower PI DispEn was observed in SHR treated with DON compared to WKY. Entropy values of BP series were found smaller in SHR and SHR+DON compared to WKY rats. For DFA of the PI series, SHR+DON showed higher α1 compared to the WKY. Moreover, SHR displayed higher α3 when compared to the WKY. In the series of BP values, the results showed higher α2 and α3 in SHR compared to WKY. [Formula: see text] Conclusion: These findings showed that SHR exhibited lower BP entropy and higher DFA of BP and IP compared with WKY. However, donepezil did not prevent these changes of non-linear indices from BP and PI variability in SHR. Funding Sources: FAPESP, Process 2020/06043-7. CNPq, Process 306994/2021-6 and 423999/2021-4. FAEPA. CAPES. 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.
Cardiomyocyte Ketone Metabolism Regulates Myocardial Hyperemia
Authors: Gouwens Kara , Chen Ning , Nong Yibing , Collins Helen , Hill Bradford , Nystoriak Matthew 
Published: May 2024

Myocardial perfusion is inextricably coupled to metabolism, with increases in physiologic cardiac demand promoting coronary vasodilation. Despite its wide acceptance, the hypothesis that cardiomyocyte metabolism autoregulates myocardial perfusion lacks mechanistic detail; however, clinical and preclinical studies suggest a signaling role for intermediary metabolites in the vasodilatory response. In particular, the ketone body precursor, β-hydroxybutyrate (3-OHB), enhances myocardial blood flow in humans, but the mechanism by which it does so remains unclear. Here, we determined the extent to which 3-OHB influences myocardial hyperemia in mice. Intravenous 3-OHB infusion (0.5 g/kg) in adult mice (12–24 wks) raised circulating 3-OHB levels (0.5 ± 0.1 to 5.1 ± 0.6 mM; p=0.005) and increased myocardial perfusion (18.6 ± 4.4 to 50.9 ± 10.4 mL/min/g; p=0.024), as measured by myocardial contrast echocardiography. Enhanced perfusion induced by 3-OHB occurred in the absence of changes in cardiac output or systolic performance. Next, to determine if 3-OHB directly dilates the coronary vasculature, we exposed pressurized (80 mmHg), small-diameter (100–260 μm) coronary arteries from mice (C57/Bl6J and 6N) to 3-OHB (0.1–5 mM) but found no significant changes in diameter. Based on these results, we tested whether cardiomyocyte metabolism of 3-OHB is required for the vasodilatory response. We deleted β-hydroxybutyrate dehydrogenase (BDH1) selectively in cardiomyocytes using Bdh1fl/fl mice crossed with tamoxifen-inducible Cre recombinase mice (csBDH1−/−). Although 3-OHB robustly enhanced myocardial perfusion (6.9 ± 1.4 to 21.3 ± 5.6 mL/min/g; p=0.031) at sustained cardiac workloads and peripheral vascular resistance in Cre-negative littermate (control) mice, csBDH1−/− mice completely lacked the 3-OHB-induced hyperemic response (8.0 ± 2.5 to 6.3 ± 2.8 mL/min/g; p>0.999). Together, these data indicate that 3-OHB evokes workload-independent enhancement of myocardial perfusion through a mechanism that requires cardiomyocyte metabolism of 3-OHB. Our results support the general concept that acute changes in metabolic substrate availability may influence oxygen delivery to cardiomyocytes via a cardiomyocyte-vascular signaling nexus. R01HL163818, R01HL142710, R01HL163003, P30GM127607, P30GM127607-05S1, Jewish Heritage Fund for Excellence (JHFE), S10OD025178. 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.
Cerebrovascular Carbon Dioxide Reactivity Is Intact in Chronic Kidney Disease
Authors: Sprick Justin , Sabino-Carvalho Jeann , Mekonnen Elsa , Mcgranahan Melissa , Zanuzzi Matias , DaCosta Dana , Park Jeanie 
Published: May 2024

Introduction: Chronic Kidney Disease (CKD) is associated with a substantially elevated risk of stroke. One factor that might contribute to this heightened risk is an impairment in cerebrovascular carbon dioxide reactivity (CVR), the mechanism through which cerebral vessels dilate and constrict in response to fluctuations in arterial carbon dioxide tension (PaCO2). CVR is known to be impaired in other chronic disease states associated with stroke risk; thus, we aimed to determine if CVR is also impaired in patients with moderate to severe CKD (stages III-IV). We hypothesized that CKD patients would exhibit impaired CVR compared to a control group (CON) matched for age, hypertension, and diabetes status. Methods: 9 CKD participants (age=56 ± 17y, eGFR=39 ± 4 mL/min/1.73m2), and 9 CON participants (age=61 ± 6y) underwent a single experimental protocol in which PaCO2 was manipulated via 2-min of hypercapnia (5% CO2) followed by 2-min hypocapnia (voluntary hyperventilation) while heart rate (via ECG), blood pressure (via finger photoplethysmography), middle cerebral artery blood velocity (MCAv; via transcranial Doppler ultrasonography), and end-tidal carbon dioxide (etCO2) were measured continuously. CVR was quantified as the slope of the linear relationship between breath-by-breath etCO2 and MCAv while accounting for blood pressure as a covariate. Hyper-, hypo- and, integrated (hyper + hypo) CVR was compared between groups via a 2-tailed, unpaired T-test. Results: We observed no differences in CVR between groups. Hypercapnic CVR: CKD = 1.4 ± 1.0 cm/s/mmHg, CON = 1.5 ± 0.8 cm/s/mmHg, Hypocapnic CVR: CKD = 1.5 ± 0.8 cm/s/mmHg, CON = 1.5 ± 0.8 cm/s/mmHg, Integrated CVR: CKD = 1.7 ± 1.2 cm/s/mmHg, CON = 1.7 ± 0.6 cm/s/mmHg, P ≥ 0.90. Conclusions: Contrary to our hypothesis, CVR remains intact in CKD stages III-IV. These findings suggest that other mechanisms contribute to the elevated stroke risk observed in this population. Funding: This work was supported by the American Heart Association (Career Development Award #929040, PI: Sprick), and NIH grants R01HL135183 and R33AT010457. 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.
Low methyl nutrition microenvironment as a key regulator in modulating epigenetic regulation and switching energy metabolism to stimulate hepatocellular carcinoma stemness properties
Authors: Chen Wan-Jing , Huang Kai-Wen 
Published: May 2024

The influence of changes in dietary habits, chemical treatments, variations in the activity of one-carbon enzyme gene modifications, and liver function impairment make hepatocellular carcinoma (HCC) patients prone to marginal methyl nutrient deficiency. Hepatocellular carcinoma has consistently ranked among the top five cancer incidence rates around the world, yet the issue of methyl nutrient deficiency still lacks systematic basic scientific assessment. This study aims to investigate whether the deficiency of methyl nutrients, specifically folate, choline, and betaine, induces the stem cell-like properties of hepatocellular carcinoma cells and promotes malignant progression, as well as to clarify the potential mechanisms involved. We found that human hepatocellular carcinoma cells (HepG2) cultured in a low methyl nutrient environment exhibited the following: (1) Methyl nutrient deficiency induced self-renewal cancer stem cell characteristics in hepatocellular carcinoma cells, forming tumor spheres on the seventh day, with a greater number and larger volume observed in environments with low folate and low choline. Upon isolating the tumor spheres and re-culturing, we found that the sphere cells induced by methyl nutrient deficiency (2) showed increased intracellular NADPH, accompanied by elevated lactate concentration in the microenvironment and changes in energy-related indicators of Warburg metabolism. At the same time, the expression of post-reprogramming related proteins Sirt1 and DNMT1 was altered. In summary, methyl nutrient deficiency may promote the malignant progression of hepatocellular carcinoma through both epigenetic modifications and energy conversion. National Science and Technology Council (NSTC112-2320-B-567-001). 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.
A novel preclinical model of human lung cancer cachexia
Authors: Snoke Deena , Van der velden Jos , Bellefleur Emma , Heininger Skyler , Ather Jennifer , Lenahan Sean , Dearborn Jacob 
Published: May 2024

Most patients with lung cancer are afflicted with cancer cachexia (CC), a syndrome characterized by wasting of muscle and fat tissues, which leads to poor treatment response and increased mortality. Pre-clinical models used to study CC often do not mimic the human condition, which may explain why there are no approved treatments for CC. To overcome this barrier, we sought to develop a model of lung CC that better recapitulates the pathoetiological characteristics of human lung CC using mice with a tamoxifen-inducible, lung epithelial cell (club cell)-specific KrasG12D allele ( G12D mice). We hypothesized that this model would mimic human CC in tumor location and burden, rate of progression, and tumor-driven tissue wasting. Following induction by tamoxifen injection, adenocarcinomas developed in the terminal bronchioles as early as 3.5 weeks post-induction and were accompanied by loss of 15% of animal body weight over a 12-week period. This weight loss began at 6 weeks and yielded a slow rate of CC progression (-1.9%/week) relative to currently available lung CC models (-5-10%/week). Body weight loss resulted from reductions in hindlimb muscle mass (18-30%) and profound depletion of inguinal and gonadal adipose tissue depots (60-70%) compared to age-matched wild-type (WT) littermates. At 6 weeks post-induction, fat tissue was reduced at the tissue and cellular levels while reductions in hindlimb muscle weight and fiber size were not observed. This fat loss corresponded with increased serum glycerol levels at 6 and 12 weeks, a metabolic characteristic that was also found in patients with lung cancer receiving treatment. Lung organoids were developed from G12D and WT mice. G12D organoids exhibited similarities in gene expression to human lung tumors ( RNAseq) and their conditioned medium (CM) elicited glycerol release from cultured 3T3L1 adipocytes compared to CM from WT organoids, suggesting that tumor-derived factors may contribute to early adipose tissue atrophy. Collectively, these findings suggest that G12D mice may be a valuable model, well-suited to identify mechanisms leading to CC and test preventative therapies. NIH R01 AR065826(MJT), NCI R21 CA283492(MJT), T32- HL076122-18(DBS/MEP), R01 CA273238 (YJ-H) and the University of Vermont Cancer Center. Funding support for RNAseq provided by Zymo Impact Initiative Grant (DBS). 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.
Racial Disparity in Microvascular Function in Men with Newly Diagnosed Prostate Cancer
Authors: Simon Abigayle B , Looney Jacob C , Blackburn Marsha , Crandall Reva , Thomas Jeffrey , Guha Avirup , Mukundi Tiffany 
Published: May 2024

BACKGROUND:Cardiovascular disease (CVD) is a leading cause of death in men with prostate cancer. In addition, non-Hispanic Black (NHB) men experience worse CVD-related mortality compared to their non-Hispanic White (NHW) counterparts, although the reason for this racial disparity remains unclear. Notably, vascular endothelial dysfunction often precedes the emergence of overt CVD. Indeed, conduit-vessel dysfunction, micro-vascular dysfunction, and arterial stiffness are independent predictors of CVD risk. Thus, the purpose of this study was to comprehensively assess vascular health in recently diagnosed NHB and NHW men with prostate cancer. Methods: Twenty-eight men (10 NHW, 18 NHB) with a new clinical diagnosis of prostate cancer (within 3 months) participated in this study. Flow-mediated dilation (FMD) was performed to represent conduit-vessel vascular endothelial function. Cutaneous post occlusive reactive hyperemia (PORH) with local thermal heating (LTH) and iontophoresis of acetylcholine were performed to represent various mechanisms regulating microvascular function. Lastly, pulse wave velocity (PWV) and pulse wave analysis (PWA) were performed to assess central and aortic stiffness, respectively. Data are reported as mean ± SD. Results: A 4-year age difference ( p=0.131) was observed between NHB (65±7 years) and NHW (69±6 years) men. No differences in BMI or clinical laboratory values were observed between NHB and NHW patients (all p>0.05). NHB men exhibited significantly lower microvascular function compared to NHW men, including PORH (NHB: 117±44 PU vs NHW: 207±47 PU; p<0.001), LTH (NHB: 180±73 PU vs NHW: 281±65 PU; p=0.003), and iontophoresis (NHB: 67±28 PU vs NHW: 136±38 PU; p<0.001). No differences in FMD ( p=0.596), PWV ( p=0.695), or PWA ( p=0.883) were observed between groups. CONCLUSION: The results of the current study provide compelling evidence that microvascular dysfunction is present in NHB men who are recently diagnosed with prostate cancer compared to their NHW counterparts. Given that NHB men were 4 years younger, these data support that the microvascular dysfunction may accelerate vascular aging and contribute to the racial disparity in CVD following prostate cancer diagnosis. Supported by: AHA SFRN 863621 (RAH). 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.
Hypertension and Ventilatory Ineffciency During Exercise in the Fitness Registry and the Importance of Exercise National Database (FRIEND)
Authors: Watso Joseph , Robinson Austin , Arena Ross , Harber Matthew , Kaminsky Leonard , Myers Jonathan 
Published: May 2024

Background: Ventilatory ineffciency (high minute ventilation/rate of carbon dioxide production [V̇E/V̇CO2] slope) during exercise is more common in patients with metabolic syndrome and cardiovascular disease, and is prognostic of cardiovascular mortality. Interestingly, new data suggest that adults with controlled or untreated, but not uncontrolled, primary hypertension (HTN) have ventilatory ineffciency during exercise. However, the sample sizes were modest (n=~20/group). Therefore, we used a large database to test the hypothesis that adults with controlled or untreated, but not uncontrolled, primary HTN have higher V̇E/V̇CO2 slope than adults with no HTN. Methods: We used American Heart Association guidelines for HTN as systolic blood pressure [BP] ≥130mmHg, diastolic BP ≥80, or anti-HTN medication in the Fitness Registry and the Importance of Exercise National Database (FRIEND). To isolate primary HTN, we excluded those with any disease other than HTN, any medication use other than anti-HTN medication(s), current smoking status, and/or obesity (body mass index [BMI]≥30). The V̇E/V̇CO2 slope was determined from a peak cycling exercise test. We excluded adults with a peak respiratory exchange ratio <1.00 during exercise. All data are presented as median[IQR]. We compared groups using linear regression unadjusted and adjusted for sex, fitness, and age. Results: The sample (n=4,659) characteristics were age: 42[18] years old (range 18-91 years); 52% with HTN; 18% female; BMI: 26.0[4.0] kg/m2; cardiorespiratory fitness: 28.5[11.0] mL O2/kg/min; race/ethnicity: <1% American Indian, 3% Asian, 12% Black, 8% Hispanic, 4% Other, & 73% White. The V̇E/V̇CO2 slope during exercise was higher in adults without HTN (n=2,410; 24.9[3.8]) compared to those with uncontrolled HTN (n=252; 24.7[3.0]; standard error of the estimate[SE]: -0.20, 95% confidence interval[CI]: -0.33 to -0.07, p=0.003), but not controlled HTN (n=132; 24.4[3.4]; SE: -0.14, 95%CI: -0.31 to 0.04, p=0.12) or untreated HTN (n=1,865; 24.7[3.7]; SE: -0.05, 95%CI: -0.11 to 0.009, p=0.09) (model: R2=0.002, F3,4655=3.83, p=0.009). However, no pairwise differences were observed after covariate adjustment (model: R2=0.117, F6,4652=103, p<0.001). Conclusion: In contrast to our hypothesis, these data from the FRIEND indicate that primary HTN is not associated with ventilatory ineffciency (i.e., higher V̇E/V̇CO2 slope). National Institutes of Health K01HL160772 (JCW), American Heart Association 23CDA1037938 (JCW). 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.
Development of an Exercise-based EV Therapy to Improve Skeletal Muscle Recovery After Immobilization
Authors: Fliflet Alexander , Spradlin Ray , Bludgen Tom , Meehan Madeleine , Burger Jayna , Reddy Manasi , Boppart Marni 
Published: May 2024

Introduction: Immobilization is necessary for recovery from illness or bone fractures; however, prolonged immobilization can result in significant loss of muscle mass and function. It is critical to recover muscle mass quickly following immobilization as severe muscle atrophy is correlated with increased likelihood of metabolic disorders, disability, and mortality. Physical rehabilitation can improve outcomes but is not always feasible. The purpose is to determine the extent to which EVs circulating in blood after endurance exercise training (EnVs) act as a safe and effective therapy to recover skeletal muscle mass following disuse. Methods: Donor C57BL/6 mice (n = 8-10, 4-month-old) were provided access to horizontal running wheels in a locked (sedentary) or unlocked (exercise) condition. After 4 weeks of voluntary running, EVs (SedVs or EnVs) were isolated from plasma using size exclusion chromatography according to manufactures guidelines, and concentration confirmed via nanoparticle tracking analysis (NanoSight NS3000). Recipient C57BL6/J mice (n = 5-8, 4-month-old) were subjected to single limb immobilization for 14 days. Upon remobilization, mice received a single intramuscular injection of PBS, SedVs, EnVs, or endurance plasma proteins, and remobilized for 3 and 14 days. Muscle samples were collected after remobilization and assessed for muscle cross-sectional-area (CSA) and capillarization. Results: Upon 3-day remobilization, EnVs did not significantly recover global fiber CSA and fiber-type specific CSA (Type IIa, Type IIx or Type IIb) or capillarization. Upon 14-day remobilization, EnVs did not significantly improve global fiber CSA and fiber-type specific CSA. However, a significant treatment effect was observed for capillary density (P = 0.0445), with increases observed for both SedV (P = 0.034) and EnV (P = 0.0117). Conclusion: EVs isolated from plasma after exercise can significantly improve skeletal muscle vascularization after immobilization, which may represent an important step toward full recovery of skeletal muscle mass. Partially support by NIH (NIAMS R01AR072735). 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.