bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary analysis of the THRIVE clinical trial on the effect of resistance exercise on skeletal muscle bioenergetics, strength and body composition in breast cancer survivors
Authors: Arentson-Lantz Emily , Sanchez Noah , Clarke Geoffrey , Moon Chrisann , Patel Darpan 
Published: May 2024

Objective: Breast cancer survivors (BCS) are at high risk for loss in skeletal muscle mass, which can be exacerbated by cancer treatment and tumor related factors. While resistance exercise has been shown to be effective in improving strength and physical function in BCS, little is known as to how exercise modulates skeletal muscle bioenergetics in oncology populations. Uncovering these factors are critical for explaining adaptations to exercise among cancer survivors. Therefore, the objective of the THRIVE clinical trial is to determine the effects of resistance exercise training on modulating skeletal muscle bioenergetics in BCS. Hypothesis: We hypothesized that 12 weeks of resistance exercise would improve skeletal muscle bioenergetics, strength and body composition in BCS. Methodology: Preliminary analysis was performed on BCS (n=10; 45.7 ± 11.5 yr) who had completed chemotherapy within the previous 6 months and were recruited to complete 12 weeks of progressive, home-based resistance exercise program (3 supervised training bouts per week). Baseline and 12 weeks strength was assessed with isometric dynamometry and 1 rep max (RM) testing, body composition was measured with DEXA, and physical function was assessed with a 6 minute walk test. Changes in muscle bioenergetics, specifically changes in resting phosphorus metabolites, were assessed using 31-phosphorus magnetic resonance spectroscopy. In the original study design, participants were randomized to either receive creatinine supplement + exercise (n=5) or exercise alone (n=5); however, there were no significant differences between the interventions on the primary outcomes reported here, so the intervention groups were collapsed. Data: Handgrip strength, 1 RM chest press, 1 RM bicep curl, 1 RM leg press and 1 RM leg extension significantly increased (p<0.05) following 12 weeks of training in breast cancer survivors. Twelve weeks of resistance exercise training also significantly increased skeletal muscle phosphodiester (PDE) content and tended to increase total phosphocreatine and gammaATP. There were no significant changes in isometric knee strength, fat mass, lean mass, 6 minute walk testing distance or skeletal muscle inorganic phosphorous. Summary: This preliminary analysis indicates changes in strength and skeletal muscle bioenergetics occur in BCS following a 12-week home-based resistance exercise intervention. Further research is needed to validate these results. The ThriveWell Foundation, NIH (P30 CA054174 and P30 AG044271). 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.
Exploring the Role of Visceral Fat as a Negative Regulator of Vascular Function In Obesity
Authors: Alradi Malak 
Published: May 2024

Background and Objective. Obesity promotes endothelial dysfunction, a major contributor to the development of cardiovascular disease. Work from our lab and others previously showed robust impairment of arteries embedded within visceral adipose tissue as compared to those within subcutaneous adipose tissue. Here, our research is focused on obesity-induced changes in adipose tissue gene expression, and how it may negatively or positively impact the functioning of the vascular system within the tissue. Method. Visceral adipose tissue and subcutaneous adipose tissue were extracted from lean and diet-induced obese mice after 12-14 months on respective diets (normal chow and high fat, Western diet, respectively). RNA-seq was conducted to analyze the gene expression profiles, followed by quantitative polymerase chain reaction (qPCR) to validate specific gene expression changes. Finally, Western blots were performed to evaluate if changes were occurring at the protein level. Result. We identified obesity-induced changes in over two hundred eighty genes in visceral adipose tissue and more than two hundred twenty genes in subcutaneous adipose tissue when compared to visceral and subcutaneous adipose tissue from lean mice through RNA-seq analysis. We further identified genes that are over-expressed in subcutaneous adipose tissue but not in visceral adipose tissue, and vice versa, in response to diet-induced obesity. Changes in select genes were confirmed by polymerase chain reaction as well as Western blot. Discussion and Conclusions. These data may lead to important insights into the role of the identified adipose genes as they relate to the impact on arterial function. Future directions will involve approaches that delve deeper into the molecular and physiological understanding of the roles of specific adipose genes in influencing both adipose and endothelial function of the embedded arteries. We aim to ultimately determine if identified genes upregulated only in subcutaneous adipose tissue with obesity serve to spare the embedded vasculature from endothelial dysfunction and whether overexpressing such genes can restore visceral adipose artery endothelial function in obesity. This study was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under award number 2P20GM113125 (Ibra Fancher). 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 pilot study of a novel brain penetrant Mn(III) porphyrin-based SOD mimic on middle cerebral artery occlusion in mice
Authors: Uchikawa Hiroki , Margaryan Tigran , Tovmasyan Artak , Wendt Trevor , Gonzales Rayna , Hashimoto Tomoki 
Published: May 2024

Introduction: Oxidative stress exacerbates acute ischemic stroke (AIS). Manganese Porphyrin (MnP)-based superoxide dismutase (SOD) mimics have shown therapeutic benefits for AIS. However, earlier MnP versions faced limited blood-brain barrier (BBB) penetration and hypotension. A novel SOD mimic MnP-05 is designed to overcome the limitations of previous generation structural analogs. Our study aimed to assess whether MnP-05 improves transient middle cerebral artery occlusion (tMCAO) outcomes in mice. Methods: Male and female C57BL/6J mice aged 12-14 weeks were used and data collection was aggregated. Initially, a safety study was conducted using uninjured mice to establish safe dosage levels independent of hypotension. Subsequently, pharmacokinetic (PK) analysis assessed BBB penetration of MnP-05. Finally, effcacy studies of MnP-05 were assessed following a 60-minute tMCAO. Intravenous administration of 1 mg/kg of MnP-05 occurred 10 minutes after recanalization, followed by intraperitoneal implantation of an osmotic pump delivering 5 mg/kg/day of MnP-05 for 72 hours after tMCAO. The concentration of MnP-05 was evaluated in ischemic core and contralateral normal brain by LC-MS/MS. The neurological symptoms were assessed by Garcia score and neurological deficit score (NDS) and compared at 72 hours between the control and MnP-05 groups in the effcacy study. Results: The safety study revealed that doses of 10mg/kg or less were considered safe, not causing hypotension (Fig.1). In the PK study, MnP-05 demonstrated preferential distribution to ischemic lesions compared to contralateral side (p = 0.03, Fig.2). In the effcacy study, MnP-05 group demonstrated improved neurological symptoms at 72 hours in Garcia score (p = 0.02), NDS (p = 0.006), and probability of survival (p = 0.03)(Fig.3). Conclusions: We established the safety dose of MnP-05 in tMCAO mice. It penetrates in ischemic lesions through BBB. Our findings suggest that MnP-05 is a promising therapeutic agent for AIS. None. 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.
Chronic e-cigarette use in young adults is associated with reduced cardiopulmonary function at rest and during exercise
Authors: Williams Thomas , Brotto Andrew , D'Souza Andrew , Leung Janice , Stickland Michael 
Published: May 2024

E-cigarette aerosols produce contaminant particles that have the potential to impair cardiopulmonary function. However, the current understanding of the impact of e-cigarette use on cardiopulmonary function remains inconclusive. Exercise represents a stress on the cardiopulmonary system and may help identify cardiopulmonary dysfunction in chronic e-cigarette users. Consequently, the purpose of this study was to investigate if e-cigarette users exhibit cardiopulmonary abnormalities under physiological stress of exercise. To further investigate pulmonary vascular responses, the secondary purpose of the study was to examine how diffusing capacity (DLCO), pulmonary capillary blood volume (VC), and membrane diffusing capacity (DM) respond to positional changes, as the transition from the upright to supine position should increase DLCO, VC, and DM, secondarily to increased perfusion pressure. We hypothesized that e-cigarette users would exhibit impaired cardiopulmonary function during exercise and reduced pulmonary vascular responsiveness to postural changes. Six chronic e-cigarette (e-cig) users (age: 24±5yrs, 5±2 years of e-cigarette use) with <5 pack years of traditional cigarette smoking history and six non-smoking controls who were age-, height-, and sex-matched completed two experimental trials. Day 1: Pulmonary function test and cardiopulmonary exercise test. Day 2: multiple fraction of inspired oxygen DLCO technique to quantify DLCO, VC, and DM at rest in the upright and supine positions. Resting pulmonary function was not significantly different between groups. The change in DLCO from upright to supine was significantly lower in e-cig users compared to controls (Control: 7.61±2.32 ml/min/mmHg vs. E-cig: 3.17±2.09 ml/min/mmHg; p=0.01), due to a smaller change in VC ( p=0.03), which suggests reduced pulmonary vascular distention in e-cig users. V̇O2peak was significantly lower in e-cig users compared to controls (Control: 4.4±1.2 L/min vs. E-cig: 2.6 ±0.7 L/min; p=0.01). E-cig users exhibited significantly elevated V̇E/ V̇CO2nadir ( p=0.02) indicating worse ventilatory effciency, and greater dyspnea relative to power output ( p=0.02) compared to controls. Preliminary findings suggest that e-cigarette use is associated with normal resting lung function but reduced pulmonary vascular distensibility. Further, e-cigarette users demonstrate ventilatory ineffciency and greater exertional dyspnea along with exercise intolerance. Canadian Institutes of Health 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.
CD4+ T Cell Effector Status Is Dependent on Aryl Hydrocarbon Receptor Activation during High Salt Diet
Authors: Molina Patrick , Edell Claudia , Dunaway Luke , Kellum Cailin , Colson Jackson , De Miguel Carmen , Rhoads Megan 
Published: May 2024

Recent studies suggest that patients with hypertension and individuals that consume a HSD are depleted of numerous tryptophan-derived indoles and other AHR-binding metabolites that are key in intestinal CD4+ T cell homeostasis. Thus, the inappropriate immunologic response by CD4+ T cells, and their role in hypertension, may be due in part to loss of AHR activation. Therefore, we hypothesized that AHR activation contributes to maintaining effector T cell status in salt-sensitive mice. To examine the influence of a representative homeostatic or proinflammatory environment and the subsequent response to salt, we cultured naïve CD4+ T cells under homeostatic cytokine or pathogenic cytokine conditions and exposed the cultures to increased NaCl conditions with or without the AHR-activating metabolite, FICZ (6-Formylindolo(3,2-b)-carbazole). TH17 cells cultured under homeostatic high salt conditions were depressed with a concomitant increase in response to FICZ. In contrast, TH17 cells cultured under pathogenic high salt conditions had augmented IL-17A-expressing cells without a response to AHR activation. These data suggest that excess salt is disrupting the ability to induce IL-17A and increasing AHR activity overcomes this disruption to promote IL-17A, without expansion of the pathogenic TH17 pool, and this observation was specific to non-pathogenic microenvironments (homeostatic TH17: media: 11±0.6%, +NaCl: 4.9±0.3%*, +NaCl/FICZ: 9.9±0.8%, of CD4; pathogenic TH17: media: 1.0±0.2%, +NaCl: 2.2±0.2%*, +NaCl/FICZ: 2.2±0.2%*, *vs respective media, n=8/group). Given these data, we then fed salt-sensitive mice (nitric oxide synthase inhibition) a HSD or a HSD supplemented with the AHR agonist indole-3-carbinol (I3C) and examined Peyer’s patches, a lymphoid tissue in close proximity to intestinal lumen contents enriched with salt and the I3C-metabolites and noted expansion of non-pathogenic TH17 cells. In conclusion, increasing AHR ligand availability through supplementing I3C may provide a gut-centric experimental approach in targeting experimental salt-sensitivity as it relates to immunologic disturbances. F31HL151264. 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.
ProBDNF-p75NTR signaling in sterile inflammation
Authors: Aby Katherine , Antony Ryan , Li Yifan 
Published: May 2024

Trauma, injury, and surgical procedures cause tissue damage, sterile inflammatory responses, and significant immune system stress leading to immune dysregulation and increased susceptibility to secondary infections. The spleen is a reservoir of myeloid immune cells that are involved in inflammation following various tissue injuries. One potential signaling pathway that may be involved in this process is proBDNF-p75NTR signaling in myeloid cells. Brain derived neurotrophic factor (BDNF) is a previously reported myokine, however there is little known about its role in skeletal muscle injury. We recently found that p75NTR, the receptor for proBDNF, was significantly upregulated (p=0.004) in myeloid cells isolated from the spleen of animals with hindlimb IR injury compared to sham controls, potentially in a sexually dimorphic manner. Our previous studies have shown that proBDNF, the precursor protein to BDNF, is the predominant form of BDNF expressed in skeletal muscle tissue and is significantly upregulated following tourniquet induced hind limb IR injury in mice (p=0.013). We hypothesize that proBDNF released from injured skeletal muscle could act through p75NTR in myeloid cells to regulate inflammatory responses following IR injury. The hind limb IR injury was induced using a tourniquet model in which an orthodontic rubber band placed on the hind limb at the level of the hip and left in place for 1.5 hours followed by tourniquet removal and reperfusion. A series of in vitro experiments were conducted on myeloid cells isolated from the spleen of sham mice, or mice with skeletal muscle IR injury. As a model of secondary infection, myeloid cells were stimulated with lipopolysaccharide (LPS) and cytokine release into culture media was measured using ELISA assays. We found that in myeloid cells isolated from IR injured animals, LPS stimulated cytokine release was increased. Further, treating isolated myeloid cells from IR injured animals with recombinant cleavage resistant proBDNF increased cytokine release compared to controls. To confirm that p75NTR on myeloid cells was at least partially responsible for the induction of cytokine expression following LPS or proBDNF stimulation, myeloid cells were treated with LM11A-31, a modulator of p75NTR in combination with LPS or proBDNF. Treatment with C31 (100ng) blunted cytokine release following LPS and proBDNF stimulation. These results suggest that the p75NTR pathway is involved in the innate immune function of splenic myeloid cells in injury induced inflammation and therefore is potentially a novel therapeutic target. This work was funded by NIH grant R01HL147105, NIH Training Grant T32-GM136503, and NIH F31 Fellowship F31HL167480. 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 Contribution of Na+ or Cl− to Central NaCl−induced Cardiovascular Responses in Rodents
Authors: B. Ferreira Caroline , D. Stocker Sean 
Published: May 2024

A high salt diet elevates plasma and cerebrospinal fluid NaCl concentrations in salt-sensitive hypertensive humans and animals. Acute or chronic intracerebroventricular (ICV) infusion of hypertonic NaCl elevates sympathetic nerve activity and blood pressure. However, it is unclear which ion, Na+ or Cl−, contributes to this response. The purpose of the present study was to investigate the extent to which acute increases in cerebrospinal fluid Na+ and Cl− increase ABP and HR in rodents. Male Sprague Dawley rats (n=6; body weight: 270-350 g) were anesthetized with isoflurane (2-3% in 100% O2) and instrumented with a lateral ventricle cannula for ICV infusions. Additionally, arterial and venous catheters were implanted to record BP and administer drugs, respectively. At least 4 days after recovery, ABP and HR were measured in response to ICV infusion (10uL over 10 min) of the following solutions: artificial cerebrospinal fluid (aCSF); 0.3 M and 0.6 M NaCl; 0.15 M and 0.3 M Na2SO4, and 0.3 M and 0.6 M NH4Cl. Each animal received one ICV infusion of each solution every other day. Data are presented as mean ± SE. Baseline ABP and HR did not differ across each ICV infusion (ABP: from 98 ± 6 mmHg to 106 ± 6 mmHg; and HR: from 337 ± 17 bpm to 363 ± 12 bpm). As expected, ICV infusion of 0.3 M and 0.6 M NaCl produced concentration-dependent increases in ABP (Δpeak ABP 0.3 M NaCl: 17 ± 2 mmHg; 0.6 M NaCl: 26 ± 3 mmHg). While ICV infusions of Na2SO4 at both concentrations also increased ABP, the magnitudes were reduced compared to NaCl (Δpeak ABP 0.15 M Na2SO4: 11 ± 2 mmHg; 0.3 M Na2SO4: 17 ± 3 mmHg). On the other hand, infusion of NH4Cl produced a modest increase in ABP (Δpeak ABP 0.3 M NH4Cl: 8 ± 2 mmHg and 0.6 M NH4Cl: 9 ± 3 mmHg). However, it did not differ from aCSF (Δpeak ABP aCSF: 6 ± 2 mmHg). HR responses induced by NaCl varied greatly (Δpeak HR 0.3 M NaCl: 15 ± 22 bpm; 0.6 M NaCl: 19 ± 17 bpm). In contrast, both concentrations of Na2SO4 consistently increased HR (Δpeak HR 0.15 M Na2SO4: 64±10 bpm; 0.3 M Na2SO4: 60±10 bpm). Additionally, ICV infusions of NH4Cl also tended to enhance HR (Δpeak HR 0.3 M NH4Cl: 38 ± 13 bpm and 0.6 M NH4Cl: 41 ± 23 bpm). To end, ICV infusion of aCSF increased HR by 18 ± 3 bpm. These results suggest that the NaCl−induced pressor response is largely attributed to Na+. However, Na+ alone cannot fully account for the NaCl−induced pressor response. NIH R01 HL163906, HL152680, HL145875. 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.
Effects of nanoparticles on sensitivity to injury and role of autophagy in alveolar epithelial cells
Authors: Sipos Arnold , Kim Kwang-Jin , Alvarez Juan R. , Crandall Edward D. 
Published: May 2024

Autophagy, a housekeeping mechanism, is crucial in the maintenance of normal cellular function. Although the involvement of autophagic processes is recognized in numerous diseases, it is unknown how cellular homeostasis might be affected by alterations in available autophagic activity and/or autophagic capacity. In this study, we measured autophagic flux and cellular damage in primary cultured monolayers of rat alveolar epithelial cells (AEC) exposed separately and sequentially to two different autophagy inducers. Rat AEC monolayers were exposed apically for 24 hrs to (1) polystyrene nanoparticles (PNP, 20 nm, carboxylated, near-infrared dye-labeled), (2) tunicamycin (TN, a disruptor of protein synthesis and inducer of the unfolded protein response, at 1-15 μg/mL), or (3) TN (1-15 μg/mL) after 12 hrs of PNP pre-incubation. Release of the cytoplasmic enzyme lactate dehydrogenase (LDH) was used as an indicator of cellular damage and quantified by an LDH assay from Dojindo (Rockville, MD). Autophagic flux was assessed by live cell imaging using confocal microscopy and 0.1 μM DAPRed (Dojindo; Rockville, MD) in the presence (for 1 hr) and absence of 40 μM chloroquine. Serial z sections were collected over the entire cell volume of live single cells to detect DAPRed (autophagosome) fluorescence. PNP were taken up into AEC, where their cytosolic presence induced a gradually increased autophagic flux, reaching a steady state at ~10-24 hrs. When AEC were exposed to TN alone for 24 hrs, autophagy was also activated. Cellular damage in the presence of TN, determined by increased LDH release, revealed dose-dependent injury with LD50 of 8.12 μg/mL over 24 hr TN exposure. When AEC were pre-exposed to PNP for 12 hrs and subsequently exposed to TN, increased LDH release was seen with LD50 of 3.95 μg/mL. In summary, the intracellular presence of PNP taken up from apical fluid of rat AEC monolayers activated autophagy. When cellular protein synthesis was disrupted with TN alone, autophagy was also activated. Furthermore, TN induced dose-dependent cellular damage in AEC. However, after pre-exposure to PNP, TN induced greater cellular damage observed as increased LDH release. These results suggest that autophagic capacity is limited and that pre-induction of autophagy by inhaled PNP makes AEC more susceptible to secondary injury by TN. These findings are consistent with the hypothesis that environmental stressors (e.g., ambient air nanoparticles) exert their harmful effects, at least in part, by reducing available autophagic activity/capacity, thereby causing nanoparticle-exposed AEC to be more susceptible to secondary injury. Funding: NIH; WRMPPF. 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.