bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventing kidney failure in hemolytic anemias with a novel heme and hemoglobin scavenger
Authors: Lucas Daniela , Munoz Carlos , Rodrigues Muller Cynthia , Palmer Andre F. , Cabrales Pedro 
Published: May 2024

Chronic hemolytic conditions, seen in genetic and acquired hemolytic diseases, result in increased levels of circulatory hemoglobin (Hb) released from erythrocytes, free heme, and iron. Cell-free Hb's toxicity arises from the Hb dissociation into dimers that can traverse tissue barriers, impacting crucial compartments like arterial smooth muscle cells and renal glomeruli. Chronic hemolysis leads to vasoconstriction, renal injury, and activates pathways via Hb oxidation and heme-ligation of TLR4 on endothelial cells, as well as leukocytes, affecting adhesion pathways. Hb and heme exposure to the immune system causes phagocyte dysfunction, inflammation suppression, and impaired antigen presentation. Kidneys are particularly susceptible to Hb toxicity due to Hb and dimer penetration into glomeruli and tubules, disrupting filtration forces, elevating the glomerular filtration rate (GFR), and causing acute kidney injury (AKI). To combat this issue, our group developed a novel Hb and heme scavenger based on apohemoglobin-haptoglobin (apoHb-Hp), functioning as both a hemopexin (Hpx) and Hp mimetic to scavenge cell-free Hb and heme during hemolytic states. Our study utilized the dorsal window chamber model in Golden Syrian hamsters, employing FITC-Sinistrin for non-invasive GFR measurement, avoiding the need for blood and urine sampling throughout time to estimate GFR. Two experiments were conducted, volumetric exchange groups with 20% of the animal’s blood volume either with Hb at different concentrations or a combination ApoHb-Hp and Hb. Results showed a significant acute decrease of 35% in half-life of the Hb group at 1.2g/dL and 5g/dL after two hours, and further decrease is seen of 45% at 24hrs. In contrast, the ApoHb-Hp group experienced a 30% decrease at 2hrs but reverted back to baseline at 24hrs, signifying Hb's predominant effect on the acute decrease rather than the volume change. Furthermore, the ApoHb-Hp group demonstrated a quicker return to baseline compared to the Hb group after the 24-hour mark, suggesting prolonged Hb exposure's lasting impact on kidney filtration rate, potentially leading to irreversible damage. Further research is required to comprehend these findings fully and explore ApoHb-Hp's protective role in mitigating Hb-induced kidney damage. Title of the project: Bioengineering a Dual Function Protein Construct to Detoxify Heme and HemoglobinProject number: R01HL159862Title of the project: Bioengineering a novel therapeutic protein complex to minimize the effects of medical device induced hemolysis.Project number: R01HL162120. 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.
Female Sex Protects Cerebral Arteries from Mitochondrial Membrane Potential Depolarization and Cell Death Induced by Reactive Oxygen Species
Authors: Safa  , Norton Charles E. 
Published: May 2024

Stroke and traumatic brain injury augment the production of reactive oxygen species (ROS) leading to apoptosis in cerebral arteries, and females are more resilient to vascular damage than males. Depolarization of mitochondrial membrane potential (ΔΨm) is a key event in apoptosis, however, when ΔΨm is suffciently depolarized, ATP synthase can reverse directions and act as a proton pump to limit ΔΨm depolarization. We hypothesized that ATP synthase attenuates depolarization of ΔΨm in cerebral arteries during acute oxidative stress thus limiting cell death. Posterior cerebral arteries (PCA; ~80 μm diameter) from male and female mice (age, 4-6 mo) were isolated, cannulated, and pressurized to 90 cm H2O at 36°C. Cell death was quantified with Hoechst 33342 (1 μM, labels all nuclei) and propidium iodide (2 μM, labels dead nuclei), and ΔΨm was evaluated with tetramethylrhodamine methyl ester (TMRM, 10 nM). Vessels were exposed to H2O2 (200 μM) in the presence/absence of ATP synthase inhibitor oligomycin (2 μM). H2O2 exposure (50 min) led to significantly (p<0.05) greater smooth muscle cell death in males compared to females (30±7.4% vs. 7±3%; n=8); there was a similar trend for endothelial cell death. Oligomycin greatly augmented apoptosis in PCAs from both males and females to ~80% and eliminated differences between sexes. Consistently, H2O2 evoked a more robust depolarization of ΔΨm in males vs. females and oligomycin enhanced ΔΨm depolarization to H2O2 leading to a similar response in both sexes. To directly depolarize ΔΨm, PCAs were treated with the protonophore FCCP (10 μM). Surprisingly, depolarization of ΔΨm to FCCP was greater in males vs. females, and oligomycin augmented depolarization and eliminated differences between sexes. FCCP initiated minimal (<5%) cell death at 50-min or 3-h exposure; oligomycin did not alter cell death to FCCP. We conclude that: 1) cerebral vessels from female mice possess greater resilience to H2O2 -induced apoptosis than males by limiting depolarization of ΔΨm; and 2) oxidative stress triggers cell death through pathways in addition to ΔΨm depolarization. Support: NIH R01NS134690. 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.
AgRP Neurons Encode Circadian Feeding Time
Authors: Sayar Nilufer , Aklan Iltan , Yavuz Yavuz , Laule Connor , kim Hyojin , rysted Jacob , Alp Muhammed Ikbal 
Published: May 2024

Food intake follows a predictable daily pattern and synchronizes metabolic rhythms. Neurons expressing Agouti-related protein (AgRP) read out physiological energetic state and elicit feeding, but the regulation of these neurons across daily timescales is poorly understood. Using a combination of neuron-dynamics measurements and timed optogenetic activation in mice, we show that daily AgRP-neuron activity was not fully consistent with existing models of homeostatic regulation. Instead of operating as deprivation counter, AgRP-neuron activity primarily followed the circadian rest-activity cycle through a process that required an intact suprachiasmatic nucleus (SCN) and synchronization by light. Imposing novel feeding patterns through time-restricted food access or periodic AgRP-neuron stimulation was suffcient to resynchronize the daily AgRP-neuron activity rhythm and drive anticipatory-like behavior through a process that required DMHPDYN neurons. These results indicate that AgRP-neurons integrate time-of-day information of past feeding experience with current metabolic needs to predict circadian feeding time. This work is supported by NIH to D.A. R01DK126740. 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.
SLAB51 Probiotic Improves Oxygen Saturation and Acute Mountain Sickness Score at High Altitude
Authors: Kaya Kiana , Yu James , Moya Esteban , Cheng Hunter , Ochoa Tim , Simonson Tatum 
Published: May 2024

Hypobaric hypoxia imposes various challenges at high altitude that initiate differentphysiological responses as part of the acclimatization process. Current interventions foraccelerating and/or improving acclimatization to high altitude are limited. Preliminarystudies of the multi-strain probiotic SLAB51 (O2booster; Hecto, Seoul, South Korea)have shown its potential to improve oxygenation, a crucial component ofacclimatization, in clinical conditions of hypoxemia. We hypothesized that treatment withSLAB51 at high altitude will lead to improved acclimatization as measured by oxygensaturation (SpO2) and scores from the Acute Mountain Sickness (AMS) survey (2018Lake Louise Questionnaire). A group of 17 (9 males, 8 females) healthy Latino/a adultsfrom the San Diego area, ranging from ages 19-63, were taken from sea-level to WhiteMountain Barcroft Station (3800 m) for up to four days. Participants underwent adouble-blind, placebo-controlled study where nine participants consumed the SLAB51probiotic and eight consumed a placebo up to three times a day. SpO2 was measuredusing a forehead pulse oximeter, and an AMS survey score was attained daily. Ouranalyses revealed that SpO2 was significantly higher in participants who received theSLAB51 probiotic at high altitude versus those who received the placebo (Two-wayANOVA, p-value < 1.12e-05). Furthermore, AMS scores were significantly lower inparticipants treated with SLAB51 than those who received the placebo (Two-wayANOVA, p-value < 0.007). Our results indicate that SLAB51 ingestion at high altitudeimproved SpO2 compared to a placebo and may improve acclimatization to high altitude. Funding: LEA Altitude Performance Fund. 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.
Carotid body-mediated peripheral chemoreflex drive sets exercise tolerance in adult mice
Authors: Vicencio Sinay , Del Rio Rodrigo 
Published: May 2024

Exercise tolerance (EXT) has been primarily explained by individual body/physical features, partly neglecting the complex cardiorespiratory response needed to cope with exercise. While in healthy conditions most people display good EXT, the presence of exercise intolerance (EXINT) has also been documented. More importantly, EXINT increases in several pathological conditions. Despite the precise mechanism underpinning EXINT is not fully understood. It is well known that exaggerated sympathetic outflow to skeletal muscle impairs proper muscle function and that activation of the carotid body (CB) chemoreceptors elicits a robust increase in sympathetic activity. Therefore, it is plausible to hypothesize that an exaggerated CB-chemoreflex drive may impair EXT. Accordingly, we aimed to determine: i) differences in CB-chemoreflex drive between EXT and EXINT mice, and ii) the role played by the CB-chemoreflex on setting EXINT. Male C57/BL6 mice (n=24) were used to study chemoreflex function using whole-body plethysmography. Exercise tolerance/intolerance was determined by a three-day maximal performance exercise test. CB-chemoreflex drive was assessed by allowing the mice to breathe hypoxic gas (FiO2~5%). We found that the incidence of EXINT among healthy mice was ~30%. Notably, compared to EXT mice, animals with EXINT exhibited a heightened CB-mediated chemoreflex drive as evidenced by larger increases in the hypoxic ventilatory responses (HVR). Indeed, HVR was ~1.4-fold larger in EXINT compared to the values obtained in EXT mice (VE: 17 ± 1.6 vs. 12 ± 3.2, mL/min, EXINT vs. EXT, respectively). Then, we tested whether high chemoreflex drive was associated with EXINT. For this, we reduced the chemosensory drive by using the Dejour´s maneuver (FiO2~35%) while EXINT mice continues to exercise. We found that chemoreflex unloading in EXINT markedly improves exercise tolerance. Indeed, exercise tolerance was almost fully restored by reducing chemoreflex drive in EXINT. Our findings underscore the potential role of heightened CB-chemoreflex on setting exercise tolerance. Supported by Fondecyt 1220950. 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.
Genotypic Variations in Exercise-Induced Hemoglobin Oxygen Desaturation in Sickle Cell Disease: The Role of Hemoglobin Levels
Authors: Antwi-Boasiako Charles , Asare Chamila , Hayfron-Benjamin Charles , Aryee Robert , Boatemaa Gifty , Asare Michael , Afriyie-Mensah Jane 
Published: May 2024

Background: Sickle cell disease (SCD) presents abnormal hemoglobin S (HbS) and frequent vaso-occlusive crises. Previous studies reveal exercise intolerance in SCD patients. However, the role of exercise-induced hemoglobin oxygen desaturation (EIHOD) and its predictors remains unclear. This study investigates EIHOD in adult SCD patients, focusing on potential predictors, aligning with the hypothesis that EIHOD is prevalent and varies across genotypes, with hemoglobin as a predictor. Methods: A cross-sectional study was conducted on adult patients with HbSS and HbSC genotypes in a steady state at the Korle-Bu Teaching Hospital, Ghana. Clinical, hematological, and haemolytic markers were assessed. Lung function was evaluated through spirometry, and a six-minute walk test (6MWT) was performed to assess EIHOD. Logistic regression was used to identify predictors of EIHOD. We hypothesis that, EIHOD is common in SCD, varying across genotypes, with hemoglobin predicting its occurrence. Results: The prevalence of EIHOD was 41% in HbSS patients and 36.1% in HbSC patients. No significant differences were observed in age, white blood cell count, platelet count, hemolytic markers, hemoglobin levels, or lung function parameters between SCD patients with and without EIHOD. In the logistic regression model, none of the variables predicted EIHOD in HbSS patients. In HbSC patients, reduced hemoglobin was the only predictor of EIHOD (OR=0.551; 95% CI=0.315-0.964; p-value= 0.037). Discussion: The study highlights a high prevalence of EIHOD within the HbSS genotype, emphasizing the importance of hemoglobin levels as a predictor of EIHOD in SCD. Contrarily, hemolytic markers and lung function were not predictors of EIHOD across either genotype. These results suggest the potentially heightened significance of EIHOD-related complications in patients with the HbSS genotype. Conclusion: EIHOD is common in SCD, more so in HbSS. Reduced hemoglobin predicts EIHOD in HbSC. Lung function and hemolytic markers don't. Understanding the impact of EIHOD in SCD may guide interventions to improve exercise tolerance and reduce complications in this population. No Funding. 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.
Deletion of irisin exacerbate cardiac dysfunction and increase inflammatory response in hemorrhage
Authors: Kulthinee Supaporn , Wang Lijiang , zhang Ling , zhao Thomas , Slate-Romano John , Zhao Ting 
Published: May 2024

Introduction: Irisin plays an important role in regulating tissue stress, cardiac function, and inflammation. The objective of this study is to investigate whether deletion of irisin would exacerbate hemorrhage induced cardiac depression and inflammatory response. Method: Irisin knockout mice was generated by using the CRISPR/Cas-9 genome-editing system. Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Experimental groups were divided as followings: I) WT+Hemorrhage (control, n=6): WT mice were subjected to hemorrhage for 60 minutes followed by resuscitation; II) Irisin −/− +Hemorrhage (n=6): Irisin −/− mice underwent hemorrhage and resuscitation; III) WT +Hemorrhage+Irisin (n=8): The same as the group I except that irisin (50ng/kg) was infused during resuscitation; IV) Irisin −/− +Hemorrhage+ Irisin (n=7): The same as the groups III except that Irisin −/− was used. Cardiac function and hemodynamics were measured using echocardiography and femoral artery catheterization. Systemic cytokine releases were measured using Enzyme-linked immunosorbent assay (ELISA). Histological analyses were used to determine tissue damage in myocardium and skeletal muscles. TUNEL was carried out to assess apoptosis in tissues. Results: As compared to wild type mice, irisin knockout mice attenuated the cardiac function and recovery of hemodynamics, which was associated with the increased release of IL6 and TNF-α in hemorrhage. The infiltration of inflammatory cells and TUNEL positive apoptosis in muscles were increased by deletion of irisin. Irisin treatment demonstrated the profound protection against hemorrhage-induced detrimental effect as compared to control. Furthermore, re-infusion of irisin into irisin-knockout mice rescued mitigated the detrimental effect in hemorrhage by deletion of irisin. Conclusion. Deletion of irisin exacerbate hemorrhage induced cardiac depression and inflammatory response, suggesting critical protection of irisin in modulating hemorrhage. National Institute of General MedicalSciences (R01GM 141339); National Heart, Lung, andBlood Institute Grants (R01 HL089405). 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.
Multi-Functional Role of RECK in Metabolic Dysfunction-Associated Steatotic Liver Disease Development: A Mass Spectrometry-Proteomic Approach
Authors: Dashek Ryan , Kelty Taylor , Krause Alexa , Taylor Chris , Meers Grace , Chandrasekar Bysani , Rector R. Scott 
Published: May 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD, previously referred to as nonalcoholic fatty liver disease) is characterized by increased fat deposition and inflammation in the liver as well as dysregulation of cellular processes that affect the extracellular matrix (ECM). We previously observed that the expression of Reversion Inducing Cysteine Rich Protein with Kazal motifs (RECK), a key ECM regulatory protein, negatively correlates with MASLD-associated fibrosis and inflammation (metabolic dysfunction-associated steatohepatitis, MASH). However, mechanisms governing this relationship remain unclear. Therefore, we hypothesized that overexpression of RECK is hepatoprotective in the setting of MASH by altering several ECM-linked pathways, as analyzed by proteomics. Accordingly, we generated hepatocyte-specific Reck-overexpressing transgenic mice. Male hepatocyte-specific Reck-overexpressing transgenic mice and littermate controls were fed a Western diet high in fat, carbohydrate, and cholesterol for 24 weeks (n=6/group). Whole liver tissue was submitted for mass spectrometry-proteomic analysis. We identified 370 differentially expressed proteins out of a total of 4693 proteins using a q-value cutoff of ≤0.10; of which 90 proteins were significantly upregulated while 280 significantly downregulated. This included an upregulation of Cyp2b (adjusted p≤0.01) and downregulation of Taok1, C/EBPβ, and Vitronectin (all adjusted p≤0.01), all of which have been shown to be important in liver health and metabolism in the context of MASH. Predictive pathway analysis using Ingenuity Pathway Analysis software (Qiagen) identified several significantly altered pathways, including those involved in ECM regulator pathways (integrin signaling, z-score=6.0; mTOR signaling, z-score=5.3; leukocyte extravasation signaling, z-score=5.1), cell-signaling (chemokine signaling, z-score=5.4; CXCR4 signaling chemokine signaling, z-score=5.0), and inflammatory responses (leukocyte extravasation signaling, z-score=5.1; CXCR4 signaling, z-score=5.0). Interestingly, pathway analysis based on significantly altered proteins predicted the downregulation of critical components of hepatic inflammation and fibrosis, including TGF-β, IL-1β, and TNFα. These novel results reveal the regulatory role of RECK in MASH progression, specifically governing the components of ECM remodeling and inflammation. Our goal is to develop RECK inducers and identify additional therapeutic targets in MASH development and progression. This work was funded by the NIH award R01DK130243. 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.
Feasibility of remotely supervised home-based high intensity interval training and effects on aerobic fitness and body composition in healthy older adults
Authors: Casella Cameron , Lapierre-Nguyen Stephanie , Kim Jin-Su , Soonhuae Chatchamarn , Sakarya Yasemin , Riesco Eléonor , Robinson Katherine 
Published: May 2024

Aging is associated with declines in aerobic fitness and increases in adiposity, both of which increase the risk of cardiovascular disease in older adults. High intensity interval training is an effective strategy for cardiovascular disease risk reduction; however, this promising exercise regimen may be inaccessible to older adults due to weight-bearing limitations or inability to travel to a fitness center. To address these barriers, we have developed a remotely supervised, home-based exercise intervention using high intensity interval training on an all-extremity non-weight-bearing ergometer (HIIT-ANE). The purpose of this study was to investigate the hypotheses that remotely supervised home-based HIIT-ANE would be feasible and lead to improvements in aerobic fitness and body composition in healthy older adults. Twenty sedentary older adults free of major clinical disease (66±1 yrs, mean ± SE) participated in this study. HIIT-ANE was remotely delivered at home under supervision via video conferencing (Zoom) and live heart rate monitoring (Zephyr OmniSense, Medtronic). HIIT-ANE consisted of a 10-min warm-up, 4 × 4-min intervals at 90% HRmax interspersed by 3 × 3-min bouts of active recovery at 70% HRmax, and a 5-min cool down and was performed on 4 days/week. Feasibility was assessed throughout the 8 weeks of HIIT-ANE. Aerobic fitness (maximal oxygen consumption) and body composition (dual-energy x-ray absorptiometry) were assessed at baseline and following an 8-week control period of normal lifestyle and an 8-week HIIT-ANE period. We found that exercise compliance to HIIT-ANE — the number of completed sessions relative to the number of scheduled sessions — was 96±1% and there were no adverse events related to the exercise intervention. Aerobic fitness increased in response to HIIT-ANE (baseline vs. post-HIIT-ANE: 23.7±1.2 vs. 27.0±1.1 ml/kg/min, P=0.001; pre- and post-HIIT-ANE: 22.5±1.2 vs. 27.0±1.1 ml/kg/min, P<0.001), but decreased following the control period (23.7±1.2 vs. 22.5±1.2 ml/kg/min, P=0.04). Body fat % (36±2 vs. 35±2%, P=0.001) and fat mass (28.4±2.0 vs. 27.0±2.0 kg, P=0.003) decreased following HIIT-ANE, but fat free mass did not significantly change ( P=0.05 for time effect; 48.5±1.7 vs. 49.3±1.7 kg). Body weight and body mass index did not change throughout the study duration ( P≥0.8 for time effect). In conclusion, remotely supervised home-based HIIT-ANE was feasible and safe and was associated with improved aerobic fitness and body composition in healthy older adults. This work was supported by the National Institute of Aging grant AG063143. 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.