bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redistribution of blood flow during exercise is impaired in heart failure with preserved ejection fraction
Authors: Ramchandra Rohit , Hamilton Charlotte , Shanks Julia , Pachen Mridula , Chang Joshua , Chen Siyi 
Published: May 2023

Exercise intolerance is a cardinal symptom in heart failure with preserved ejection fraction (HFpEF). The underlying pathophysiological mechanisms of HFpEF and their influence on exercise intolerance remains poorly understood. This study investigated the role of re-distribution of blood flow in modulating the increase in hindlimb muscle blood flow during HFpEF.We proposed that exercise intolerance is partially contributed by an impaired ability to divert blood flow from peripheral organs such as the kidney during exercise. We utilised an ovine model of HFpEF in which hypertension was established in aged female sheep. We then examined the mean arterial pressure, heart rate, cardiac output, renal blood flow and hindlimb blood flow response to treadmill exercise in both groups of conscious animals.Animals with HFpEF had elevated left ventricular end diastolic pressures (13 ± 6 vs. 0 ± 1 mmHg, p<0.05) as well as enlarged cardiomyocytes compared to normotensive controls. Exercise in the control animals led to increases in cardiac output and heart rate. These responses were significantly attenuated in HFpEF (increase of 4.5 ± 1 vs. 8 ± 1 L/min, p<0.05) and heart rate (increase of 32 ± 3 vs. 41 ± 4 bpm, p<0.05). In a separate group of instrumented animals, the increase in blood flow to the hindlimb vasculature was attenuated in the HFpEF animals compared to control animals (increase of 2 ± 1 vs. 4 ± 2 L/min, p<0.05). There was a reduction in renal blood flow in the control animals (-150 ± 50 ml/min) and this change was reversed to an increase in the HFpEF animals (+50 ± 20 ml/min).Our results suggest that the exercise intolerance observed in our ovine model of HFpEF may in part be due to an impaired ability to regulate blood flow to the kidney and hindlimb muscles during exercise. RR gratefully acknowledges granting support from the Health Research Council of New Zealand, the University of Auckland Faculty Research Development Fund and the National Heart Foundation of New Zealand. 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.
ChREBP/ ChREBP-beta expression mediates the paradoxical effect of fructose on body weight of fructose-fed rats by brown adipose tissue activation
Authors: Leibowitz Avshalom , Khashab Rawan 
Published: May 2023

Introduction: Western diet fructose content is a neglected nutrition component, with significant devastating metabolic effects like metabolic syndrome (MeS) and obesity. The data suggest that Food-induced thermogenesis is a contributing factor for regulating body weight. Carbohydrate Responsive Element Binding Protein-beta (ChREBPβ) is recognized now as the regulator of fructose metabolism. Brown adipose tissue (AT) which plays essential role as a thermoregulatory organ, is recognized now also as an endocrine tissue that participates in glucose and lipids metabolism. ChREBP expression is associated with activating of BAT and improve metabolic status. On the other hand, increased ChREBPβ seems to have a deleterious metabolic effect on brown AT. Methods: Sprague-Dawley male rats, 8 weeks old were fed High Fructose Diet (HFRD) or match regular chow for 6 weeks (n=8). Body weight (BW) and precise food intake were measured weekly. Brown (peri-aortic and interscapular, PA and IS respectively) and white (mesenteric) AT were collected for further molecular studies. Results: HFrD fed rats gain significantly less weight than the control group (from 236±2 to 397±8 vs. 233±2 to 430±9 gr. P<0.05) despite eating an equal food amount (28±1vs.29±1.5 g/rat/week). The expression of uncoupling 1 (UCP1) mRNA, a BAT activation marker, was significantly higher in BAT than in WAT. Fructose consumption increased UCP1 BAT expression compared to regular chow. However, the expression of ChREBP and ChREBPβ in BAT was significantly lower in HFrD fed rats. Conclusions: In the HFrD rat model of MeS, fructose consumption leads to lesser weight gain for the same caloric intake. This BW difference is accompanied by the activation of BAT in the HFrD group. This paradoxical effect may be regulated by decreased ChREBP/ChREBPβ expression in response to fructose. No disclosure 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.
Greater renal interstitial expansion and inflammation in older male versus older female rats following a four-day simulated heatwave
Authors: Monroe Jacob , Schlader Zachary , Basile David 
Published: May 2023

Acute kidney injury (AKI) is an emerging cause of morbidity during heatwaves worldwide and is associated with negative health outcomes. Older age increases the likelihood of AKI, which is a top cause of hospitalization during heatwaves in older adults. Further, biological sex likely affects the severity of, and prognosis following, AKI. Moreover, recent observations suggest that older women are at greater risk of AKI during heatwaves compared to older men. Whether this observation can be directly attributed to biological sex is unclear. Therefore, we tested the hypothesis that older female rats experience more severe kidney injury during a four-day simulated heatwave, compared to older male rats.To test this hypothesis, older (18-22 month old) male (M) and female (F) Wistar rats were exposed to a 36°C (M: n=5; F: n=8) or a 21°C (M: n=2; F: n=2) environment for three hours over four consecutive days. During, and for five hours following heat exposure, the rats did not have access to food or water, but otherwise were housed in standard housing conditions with free access to food and water. Core temperature (Tc) was continuously monitored and rats were removed from the heat if Tc reached 40.5℃, a safeguard put in place to prevent heatstroke. Data are presented as mean±SD.Male and females did not differ in the amount of time exposed to heat during each day (average duration - M: 39.3±4.0, F: 42.3±5.2 minutes, P=0.86) or body weight loss during heat exposure (average body weight loss - M: -2.0±0.1, F: -2.5±0.1% P=0.93). Serum creatinine concentration did not differ between heat exposed males and females on Day 1 (pre- M: 0.4±0.2, F: 0.4±0.1; post- M: 0.5±0.2, F: 0.4±0.2 mg/dL) or Day 4 (post- M: 0.4±0.1, F:0.3±0.1 mg/dL; P=0.86) Heat exposure resulted in cortical interstitial expansion and immune cell infiltration in aged male, but not female rats (M Heat: 77.2±36.1, F Heat: 12.1±16.5, M Control: 18.2±17.5, F Control: 13.4±19.0 dots per image, P=0.002). Only older male rats displayed greater interstitial immune cell infiltration than older controls in response to heating (P=0.04). Immunohistochemistry demonstrated distinct populations of CD3e+ T cells, CD20+ B cells and CD68+ macrophages within the interstitial immune cell infiltration in the older male rats. Kidney expression of kidney injury molecule 1 (KIM1, P=0.41) and neutrophil gelatinase associated lipocalin (NGAL, P=0.12) did not differ between older male and female rats exposed to heat or control conditions. Compared to older female rats, older male rats display increased cortical interstitial expansion and inflammation following a four-day simulated heatwave. UL1TR002529, T32DK120524 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.
Physiological responses of adults with coronary artery disease during extreme heat exposure
Authors: Bartlett Audrey-Ann 
Published: May 2023

Introduction: Extreme heat is becoming more frequent due to climate change. Different regions experience different forms of heat, such humid or dry heat, a greater risk of morbidity and mortality becomes apparent with higher temperatures. Adults with heart disease are especially vulnerable to the health risks of extreme heat. One possible reason for this greater risk is that adults with heart disease might experience greater physiological heat strain during extreme heat exposure. The objective of this study was to determine if adults with coronary artery disease (CAD) experience greater physiological strain relative to adults without CAD during hot/humid and very hot/dry heat exposures.Methods: 28 adults with stable CAD (2 females/26 males, 66±7 y, 1.96±0.17 m2) and 26 adults without CAD (non-CAD; 13 females/12 males, 69±4 y, 1.86±0.21 m2) rested for 3 hours in hot/humid (HH; 38°C/60% relative humidity; n= 22 CAD and 26 non-CAD) and very hot/dry (VHD; 45°C/15% relative humidity; n=24 CAD and 13 non-CAD) environments on separate days. Participants consumed 3 mL/kg/h of water during each exposure. Core (rectal) and skin temperatures, heart rate, and whole-body sweat loss were measured. Results: During exposure to HH, adults with CAD experienced a greater increase in core (0.58±0.28°C vs. 0.37±0.23°C, p=0.009) and mean skin (5.08±1.11°C vs. 4.06±0.76°C, p=0.0005) temperatures and sweat more (832±252 g vs. 471±244 g, p<0.0001). The increase in heart rate (CAD: 9±7 bpm vs. non-CAD: 9±6 bpm, p=0.914) and percent change in body weight (CAD: +0.12±0.32% vs. non-CAD: +0.25±0.22%, p=0.106) did not differ between groups. During exposure to VHD, adults with CAD experienced a greater increase in mean skin temperature (5.79±1.06°C vs. 4.92±1.23°C, p=0.029), greater sweat loss (1239±171 g vs. 794±159 g, p<0.0001), and greater percent change in body weight (-0.41±0.29% vs. -0.11±0.16%, p=0.001). The change in core temperature (CAD: 0.62±0.37°C vs. healthy: 0.48±0.21°C, p=0.092) and heart rate (CAD: 9±7 bpm vs. healthy: 13±6 bpm, p=0.196) did not differ between groups. Conclusion: During hot/humid heat exposure, adults with CAD experience greater thermal strain and fluid loss, whereas they experience greater fluid loss and dehydration during a very hot/dry heat exposure. The greater physiological heat strain experienced by adults with CAD may reflect the impact of altered cardiovascular function and/or medications on internal distribution and ultimately contribute to a greater risk of heat-related mortality. National Health and Medical Research Council 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.
Click chemistry, FRET-FCS, and expansion microscopy reveal that Na, K-ATPase forms complexes in the plasma membrane
Authors: Brismar Hjalmar , Edwards Steven , Bauer Sebastian , Meineke Birthe , Elsässer Simon , Wennmalm Stefan 
Published: May 2023

In order to study the spatial distribution of Na, K-ATPase alpha and beta subunits in the plasma membrane of epithelial cells we have developed sample preparation protocols based on genetic code expansion, click chemistry and expansion microscopy. HEK 293T cells were transiently transfected with constructs containing the coding sequence for Na, K-ATPase subunits (alpha1 and beta1) carrying a premature amber or ochre stop codon. Two bioorthogonal tRNA and tRNA synthetase pairs were also transfected for stop codon suppression and site-specific insertion of two unnatural amino acids. The unnatural amino acids were then labelled with small organic dyes using CuAAC and SPIEDAC click reactions. Care was taken to keep the transfection and expression levels low.In living cells, we used Fluorescence Correlation Spectroscopy (FCS) and FRET to assess the density of click-labeled and endogenous [SE1] Na, K-ATPase in the plasma membrane. The dyes Alexa488 and Alexa647 were used as a FRET sensor for homo- and heterodimer analysis and, using FRET-FCS, we could detect the oligomerization of alpha and beta in a complex containing two alpha and two beta subunits in a heterodimer.FCS measurements in cells where both the alpha and beta subunits were labeled was used to calculate the absolute density of endogenous and exogenous Na, K-ATPase in the plasma membrane. To detect oligomerization, we used cells where the beta subunit was labeled with a 50/50 mix of Alexa488 and Alexa647. We successfully detected FRET signals and an analysis of the FRET-FCS data revealed a high density of oligomers. FRET-FCS is, compared to conventional cross-correlation FCCS, one to two orders of magnitude more sensitive for the detection of oligomers. FRET-FCS is also inherently insensitive to heterogenous labeling efficiencies, which is a great advantage during live cell measurementsExpansion microscopy was performed using a modified MAP protocol, reaching an isotropic expansion of approximately 4.5-fold. Confocal airyscan microscopy of the expanded cells with <50nm resolution revealed local variations in Na, K-ATPase density and enabled detailed cluster analysis.In conclusion we demonstrate that the density of Na, K-ATPase has large local variations and that the Na, K-ATPase oligomerizes in the plasma membrane. We propose that this oligomerization can have a regulatory function for the net efficiency of Na, K-ATPase in the cell. VR 2020-05347, VR 2019-00217 (Swedish Research Council) 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.
Diesel exhaust particles alter adipose mitochondria bioenergetics
Authors: Warren Cali , Curtiss Katrina , Saito Erin , Reynolds Paul , Bikman Benjamin 
Published: May 2023

Diesel exhaust particles (DEP) constitute a significant quantity of air pollution that infiltrate the bloodstream to drive systemic pathologies. While some pathologies are obvious, such as COPD and heart failure, others are less apparent, such as insulin resistance, diabetes, and even obesity. In every case, a role for the receptor of advanced glycation end-products (RAGE) has been implicated. RAGE are cell surface receptors that are implicated in pathological processes, such as inflammation and diabetic complications. Despite the known connection between DEP and metabolic disorders, the effects of DEP exposure on adipose tissue mitochondrial function is unknown. To understand the potential role of RAGE signaling in the context of adipose tissue DEP exposure, mice were nasally exposed to either room air, nebulized diesel exhaust particles, or nebulized diesel exhaust particles + semi-synthetic glycosaminoglycan ethers (SAGEs, RAGE signaling inhibitors) every weekday for three weeks. Inguinal adipose tissue samples were obtained following exposure, and mitochondrial respiration rates were measured. In mice exposed to DEP or DEP + SAGE, mitochondrial respiration of inguinal adipose tissue was not significantly different compared to the room air control mice with the addition of glutamate and malate or ADP. However, respiration was significantly increased with the addition of succinate and FCCP in the inguinal adipose tissue from mice exposed to DEP. The results of this work indicate that DEP exposure elicits a negative effect on adipose mitochondrial respiration. This work was supported in part by funding from Levels Health (BTB) and the National Institutes of Health (NIH 1R15-HL152257, PRR and BTB). 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.
Zinc Deficiency Drives Renal NFkB Activation
Authors: Wenegieme Tara-Yesomi , Waite Aston , McMichael Kelia , Naraine Meagan , Ume Adaku , Williams Clintoria 
Published: May 2023

Background: Zinc deficiency (ZnD) is comorbid with life-threatening diseases such as diabetes and kidney disease. In these populations, the prevalence of hypertension is elevated. In our published studies, we demonstrated that ZnD alone was sufficient in promoting hypertension in hypertensive-resistant mice. Specifically, our findings revealed that hypertension was a consequence of renal sodium retention. However, the underlying molecular mechanisms driving these effects were undefined. Hypothesis: Since the transcription factor nuclear factor-κB (NFκB) is implicated in the pathogenesis of hypertension, we tested the hypothesis that ZnD drives renal NFκB activation. Experimental Design: To examine the impact of ZnD on renal NFκB, adult male C57Bl/6 mice were fed a zinc deficient or zinc adequate diet for 10 weeks. Both NFκB expression and nuclear translocation were examined by immunofluorescence and Western blot. To directly investigate the role of zinc in NFκB regulation, mouse tubule epithelial cells were exposed to medium containing a zinc chelator (N, N, N', N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine, TPEN) or vehicle for 24 hours. To examine whether ZnD-induced effects on NFκB were reversible, the medium of TPEN-exposed cells were supplemented with zinc. Results: While NFκB expression was undetectable in zinc adequate mice, its expression and nuclear localization were enhanced in zinc deficient mice, as assessed by both immunofluorescence and Western blot. Interestingly, immunofluorescence revealed increased NFκB expression and nuclear localization exclusively in selected tubules. Consistently, our in vitro model demonstrated that TPEN-induced ZnD also promoted NFκB expression and nuclear translocation. Notably, zinc repletion reversed TPEN-induced NFκB upregulation. Conclusions: Collectively, both in vivo and in vitro findings reveal that 1) renal NFκB is a zinc-regulated nuclear transcription factor and 2) ZnD drives NFκB upregulation in selected tubular epithelial cells. Significance: Importantly, this study identifies NFκB as a potential mediator of ZnD-induced renal sodium retention and subsequently hypertension. Funding Source: AHA-16SDG27080009 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.
Electrical stimulation-induced muscle contraction does not reduce intramuscular accumulation of Doxorubicin 24 hours following administration
Authors: McCue Meghan , Rebalka Irena , Hawke Thomas , MacLean David 
Published: May 2023

Background: Doxorubicin (Dox) is a commonly used chemotherapeutic drug. Although an effective anti-cancer agent, it can be profoundly toxic to skeletal muscle (SM). Dox has been demonstrated to accumulate rapidly in SM, leading to tissue damage and cellular dysfunction. Exercise prior to Dox treatment may reduce drug accumulation. However, little is known about the effects of exercise on intramuscular accumulation following Dox administration. Electrical stimulation (stim) could be a low-effort way to exercise SM following Dox administration; however, it has yet to be investigated in this context. Aim: This study aimed to determine if various stim protocols could reduce Dox accumulation in rodent hindlimb muscles 24 hours following drug administration. Hypothesis: Stim-induced muscle contraction will reduce intramuscular accumulation of Dox in a time- and intensity-dependent manner when compared to unstimulated muscles. Methods: Male Sprague-Dawley rats (n=42) were randomly assigned to one of six stim protocols (1 Hz or 3 Hz, for 5, 15, or 30 minutes) or a true control group. Stim groups received a single intraperitoneal dose of Dox (4.5 mg/kg). Twenty-four hours following Dox administration, the assigned stim protocol was carried out on the left sciatic nerve while the right leg served as an intra-individual control. Tissues and plasma were immediately harvested following the stim protocol to determine the acute effects of SM contraction. Drug and metabolite concentrations were assessed in both tissue and plasma using high-performance liquid chromatography. Results: None of the stim protocols investigated led to a reduction in intramuscular accumulation of Dox in the white gastrocnemius [summed data: 3.09±0.76 (stimulated leg) vs. 2.49±0.16 nmol/kg (unstimulated leg), p>0.05] or the soleus [summed data: 1.8±0.27 (stimulated leg) vs.1.5±0.23 nmol/kg (unstimulated leg), p>0.05]. These data are supported by plasma Dox concentrations which were similar in all groups (p>0.05), suggesting minimal uptake or release of Dox by SM. The concentration of Doxorubicinol, a highly toxic metabolite of Dox, also remained unchanged in both muscles and plasma (p>0.05). Conclusion: Electrical stimulation-induced muscle contraction did not reduce intramuscular accumulation of Dox 24 hours following drug administration. While unable to reduce accumulation, stim may still be a valuable tool for maintaining muscle mass and function during Dox treatment. Further investigation is required to characterize and optimize the role of stim during chemotherapy. Funding: This study was funded by a Rene Guilbeault Research Award. 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.