bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Neonatal Curcumin Intake on Key Molecular Markers in Lipid and Glucose Metabolism
Authors: Matumba Mashudu , Mukwevho Emmanuel 
Published: May 2024

The high prevalence of obesity, resulting from the increased consumption of a fructose-rich diet, poses a serious global threat to children's public health. Obesity is linked to several metabolic disorders, including insulin resistance and type-2 diabetes. Furthermore, type-2 diabetes is characterized by impaired lipid and glucose metabolism. This study investigated the impact of neonatal curcumin intake on the expression of key molecular markers related to liver lipid metabolism [Liver kinase B-1 (LKB-1), AMP-activated protein kinase (AMPK), Carnitine palmitoyltransferase-1 (CPT-1), and Acetyl-coenzyme A carboxylase-1 (ACC-1)] and glucose metabolism [serine/threonine-protein kinase (AKT-1), Glucose transporter-2 (GLUT-2), glycogen phosphorylase (GP), and Phosphoglucomutase (PGM)]. Curcumin, a polyphenolic compound derived from turmeric, is currently under extensive research for its potential therapeutic applications in various diseases. In this study, a metabolic syndrome model was induced in Sprague Dawley rats by feeding them a high fructose diet, with curcumin administered as the treatment. Gene expression was assessed through Real-Time quantitative PCR, and protein expression was analyzed using the western blot technique. The study observed that a high fructose diet led to the upregulation of genes and proteins associated with lipid metabolism, such as AMPK, LKB-1, ACC-1, and CPT-1 in liver tissues. Curcumin treatment reversed these effects, restoring normal lipid metabolism. Additionally, the high fructose diet downregulated the expression of AKT-1 in hepatic insulin signaling, which was counteracted by curcumin. Moreover, the high fructose diet increased hepatic glucose production, as indicated by the upregulation of GP and PGM gene and protein expression, while curcumin treatment suppressed hepatic glucose production by downregulating GP and PGM expression. The findings improve our understanding of curcumin's molecular mechanisms, which are not yet fully understood. They offer further evidence of curcumin's positive effects. Thus, early neonatal consumption of curcumin could be a potential strategy to prevent high fructose diet-induced obesity and related metabolic disorders, including insulin resistance and type-2 diabetes. Lipid and Glucose Metabolism. This project was funded by the North-West University. 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.
Effect of Inactivation of Prefrontal Cortex on Sleep-Wake States in Rat
Authors: Ponnaluri Sumegha , Groenhout Trent , Sharba Lana , Liu Tiecheng , Mashour George A. , Pal Dinesh 
Published: May 2024

There is a large body of literature to support subcortical regulation of sleep-wake states, but there have been limited studies to investigate the role of cortex in sleep-wake regulation. Previously, we have demonstrated that cholinergic stimulation of prefrontal cortex can reverse general anesthesia and promote wakefulness in unanesthetized rats, and there is emerging evidence to suggest that the prefrontal cortex might be a critical node in arousal state control. To better understand the direct role of prefrontal cortex in the regulation of sleep-wake states, we quantified the effect of prefrontal cortex inactivation, via local tetrodotoxin (156 μM) infusion, on sleep architecture. Under surgical isoflurane anesthesia, adult Sprague Dawley rats (n=7 male) were instrumented with electrodes to record electroencephalogram (EEG) from frontal and parietal cortices, and electromyogram (EMG) from dorsal nuchal muscles. In addition, a bilateral guide cannula was implanted aimed at the medial prefrontal cortex for tetrodotoxin infusion. After at least a week of post-surgical recovery and conditioning to the recording chambers, rats received bilateral microinjection (500 nL) of either 156 μM tetrodotoxin or 0.9% saline (vehicle control). The tetrodotoxin and 0.9% saline infusions were performed 30-minutes before the start of lights-OFF period (8:00 pm) after which EEG and EMG data were recorded for 24h across dark and light cycles. The EEG and EMG data were manually scored (SleepSign, Kissei Comtec Inc.) in 4-second intervals into wakefulness, slow-wave sleep, and rapid eye movement sleep, and then averaged in 3h bins across 24h recording period. A linear mixed model was used to compare the changes in percent time spent in each state, mean duration per episode for each state, and mean number of episodes for each state, between the vehicle control and tetrodotoxin-infusion sessions. Inactivation of prefrontal cortex via tetrodotoxin infusion produced long-lasting statistically significant increase in slow-wave sleep (p<0.05 for 0-3h, 4-6h, 7-9h, 10-12h, 13-15, 16-18, 22-24) and decrease in wakefulness (p<0.05 for 0-3h, 4-6h, 10-12h) and rapid eye movement sleep (p<0.05 for 7-9h, 10-12h, 13-15h). These data further support a causal contribution of prefrontal cortex in regulating arousal states. This work was supported by the National Institutes of Health (Bethesda, MD, USA) grant (R01 GM111293) to GAM and DP, and funding from the Department of Anesthesiology, University of Michigan Medical School, Ann Arbor. 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.
Habitual Sleep and Muscle Sympathetic Nerve Activity in Humans
Authors: Bigalke Jeremy A. , Greenlund Ian M. , Tyra Alexandra T. , Bigalke Jennifer R. , Carter Jason R. 
Published: May 2024

Short habitual sleep duration and inadequate sleep effciency are associated with poor cardiovascular health. Although a potential mediator of this relationship is augmented sympathetic activity, only one study to date has assessed the relationship between objectively measured habitual sleep duration and direct muscle sympathetic nerve activity (MSNA) in humans. Moreover, the proportion of resting MSNA that can be independently explained by habitual sleep while controlling for other key variables remains unknown. The purpose of the present study was to assess the independent relationship between total sleep time (TST), sleep effciency (SE), and MSNA in a large population of young males and females. We hypothesized that short TST and low SE would be associated with elevated MSNA and blood pressure. A minimum 7 days of at-home, objective actigraphy sleep monitoring was collected in 66 healthy young adults (35 males, 31 females; 24±1 years; 26±1 kg/m2). In each participant, the average of three seated brachial blood pressures was recorded and used to determine resting mean arterial blood pressure (MAP). All participants underwent an autonomic function test that simultaneously assessed heart rate (HR, electrocardiogram), beat-to-beat blood pressure (finger plethysmography) and MSNA (microneurography) during 10 minutes of quiet rest. Resting MAP (83±1 mmHg), HR (64±1 beats/min) and MSNA (19±1 bursts/min) were normally distributed. Habitual TST was significantly correlated with MSNA (r=-0.265, p=0.032), but was not associated with resting MAP (r=-0.153, p=0.219) or HR (r=-0.205, p=0.098). SE was not associated with any of the outcome variables (all p>0.25). Multiple regression was used to test the independent relationship between TST, MAP, HR, and MSNA while accounting for effects of age, sex, and body mass index (BMI). The regression model significantly predicted MAP (R2=0.253, p=0.001) and MSNA (R2=.211, p=0.005), but not HR (R2=.047, p=0.560). TST did not independently explain any additional variance in MAP (ΔR2=0.004, p=0.562) beyond that ascribed to the effects of age, sex, and BMI. In contrast, TST independently explained an additional 5% of the variance in MSNA (ΔR2=0.053, p=0.048). In a large sample of healthy young males and females, our results indicate that habitual TST explains only a minor proportion of the observed variance in resting MSNA between participants. NIH (AA-024892). 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.
Does Uromodulin Play a Role in Tacrolimus-Mediated Upregulation of the Sodium Chloride Cotransporter?
Authors: Nshuti Adeline , Ume Adaku , Wenegieme Tara-Yesomi , Kamau John , Paul-Onyia Chiagozie , Williams Clintoria 
Published: May 2024

Background: Tacrolimus, a calcineurin inhibitor (CNI), is a medication commonly prescribed to prevent organ transplant rejection. However, chronic CNI use has several adverse effects, including hypertension. Recent studies have revealed that the renal sodium chloride cotransporter (NCC) mediates tacrolimus-induced hypertension. However, the mechanisms underlying NCC upregulation are not fully understood. Previous studies indicate that uromodulin plays a key role in renal ion channel regulation. As such, we hypothesize that uromodulin mediates tacrolimus induced NCC upregulation. Experimental Design: To test this hypothesis, male C57BL/6 mice received tacrolimus (10 mg/kg/day) or vehicle (ethanol/DMSO/saline) for 21 consecutive days via intraperitoneal injection. The impact of tacrolimus on systolic blood pressure (BP) was monitored by tail-cuff plethysmography. To examine uromodulin and NCC expression, kidneys were harvested and processed for immunohistochemistry. Results: Compared to the BP of vehicle-treated mice (120 mm Hg ± 4.252), mice administered tacrolimus had significant increases in BP (170 mm Hg ± 3.528). Furthermore, tacrolimus treatment increased phosphorylated NCC (pNCC) and uromodulin expression. Conclusions: These results indicate that tacrolimus-induced hypertension is accompanied by pNCC and uromodulin upregulation in distal convoluted tubules. Significance: Overall, these findings highlight uromodulin as a possible regulator of NCC. Funding: R21 DK119879, R01 DK-133698, R25DK07838. 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.
Cerebral autoregulation metrics correlate with some major morbidity and mortality outcomes after cardiac surgery
Authors: Melvin Ryan , Godwin Ryan , Benz David , Berkowitz Dan , Mladinov Domagoj 
Published: May 2024

Background: Personalized arterial blood pressure management based on cerebral autoregulation has shown clinical relevance in cardiac surgery. Here we explore the associations between lower limit of cerebral autoregulation (LLA) metrics and postoperative outcomes in a heterogenous and high-acuity population of patients undergoing high-risk cardiovascular surgery. Methods: Autoregulation parameters were determined retrospectively in 686 patients undergoing cardiac surgery at UAB Hospital. Cerebral oximetry index (COx) and hemoglobin volume reactivity index (HVx) determine a patient’s unique LLA by examining the correlation between mean arterial pressure (MAP) and near-infrared spectroscopy signals. Logistic regression analyses explored associations of area under the time-pressure curve and duration below LLA with stroke, acute kidney injury, operative mortality, low cardiac output syndrome, and mechanical ventilation lasting more than 48 hours. Any incidence of these outcomes was considered as the primary outcome of interest: major morbidity or operative mortality (MMOM). Results: We explored the association of Area under the time-pressure curve for pressures less than patient-specific Lower Limits of Autoregulation (AUCABP<LLA: and MMOM. Results are reported with odds ratio (OR) and 95% confidence intervals (CI). AUCABP<LLA was not significantly associated with MMOM incidence (HVx: Odds Ratio 1.000, 95% CI 0.970-1.030, p=0.979; COx: OR 1.006, 95% CI 0.990-1.023, p=0.456). However, for components of MMOM, specifically operative mortality (HVx: OR 1.063, 95% CI 1.013-1.115, p=0.013; COx: OR 1.027, 95% CI 1.001-1.052, p=0.038) and low cardiac output syndrome (HVx: OR 1.036, 95% CI 1.004-1.068, p=0.025), there were statistically significant relationships with AUCABP<LLA when controlling for logistic Euroscore and preoperative hemoglobin levels. Conclusions: Area under the time-pressure curve for pressures less than patient-specific LLA was not significantly associated with MMOM incidence. However, we found significant associations between components of MMOM, specifically operative mortality and low cardiac output syndrome, with an AUCABP<LLA and time under LLA. These results suggest that LLA metrics might have utility in predicting specific postoperative outcomes, but their role in predicting overall MMOM may be limited in heterogenous and high-acuity patient populations. 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.
Increases in Central Arterial Stiffness and Reductions in Diastolic Velocity in the Large Cerebral Arteries are Associated with Age-Related Decline in Cerebral Blood Flow
Authors: Ashley John , Won Junyeon , Cardim Danilo , Tomoto Tsubasa , Zhang Rong 
Published: May 2024

Background: Advanced aging is characterized by a reduction in cerebral blood flow (CBF) and an increase in central arterial stiffness. Increased central arterial stiffness results in reduced Windkessel effects and augmented pulsatile arterial blood pressure and CBF. These changes are detrimental to small cerebral blood vessels because of increases in biomechanical stresses associated with the augmented pulsatile arterial blood pressure and CBF. Purpose: To examine the associations of central arterial stiffness with cerebral hemodynamics and age-related reductions in CBF. Methods: 171 healthy subjects (20-81 yrs, 63% F) underwent color-coded duplex ultrasonography of the left and right internal carotid (ICA) and vertebral artery (VA) to characterize individual artery blood flow (BF), velocity, pulsatility, and CBF. Structural Magnetic Resonance Imaging (MRI) was used to measure total brain tissue volume (TBV). Carotid β-stiffness and carotid-femoral pulse wave velocity (cfPWV) were measured via applanation tonometry to assess central artery stiffness. Data: Age was negatively associated with global CBF (r = -0.425, p < 0.001), and positively with cfPWV (r = 0.701, p < 0.001), and carotid β-stiffness (r = 0.660, p < 0.001). Arterial stiffness was negative associated with ICA diastolic velocity (r = -0.280, p < 0.001; r = -0.259, p < 0.001) and VA diastolic velocity (r = -0.280, p < 0.001; r = -0.248, p = 0.001) controlling for sex, body mass index (BMI), education, and TBV. Carotid β-stiffness moderated indirect effect between age and CBF through ICA diastolic velocity (index of moderated-mediation -0.47 ± 0.13, [-0.74,-0.23]. cfPWV did not moderate the indirect effect between age and CBF through ICA diastolic velocity (index of moderated-mediation -0.36 ± 0.18, [-0.69, 0.03]. The indirect effect of age on CBF through VA diastolic velocity was not moderated by cfPWV (0.03 ± 0.09, [-0.13, 0.23]) or carotid β-stiffness (-0.17 ± 0.09, [-0.33, 0.01]). Conclusions: Age-related decline in CBF is mediated by the decreases in ICA blood flow diastolic velocity, and this relationship was moderated by carotid β-stiffness. This data suggests that increases in central arterial stiffness and reductions in CBF diastolic velocity in the large cerebral arteries likely plays an important role in age-related decline in CBF. This study was supported by NIH R01HL102457-01 and NIH R01AG033106-01. 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.
Heme Scavenging by Hemopexin Attenuates Sepsis-Induced Proinflammatory Cytokines and Kidney Insuffciency in a Humanized Mouse Model of Sickle Cell Disease
Authors: Falayi Olufunke , Williams Jada , Kumar Ravi , Afolabi Jeremiah , Adebiyi Adebowale 
Published: May 2024

Sickle cell disease (SCD) is a genetic blood disorder characterized by abnormal hemoglobin production, leading to sickle-shaped red blood cells (RBC). Alteration in RBC shape results in vasoocclusion, chronic hemolysis, and multiple organ damage. One of the severe complications of SCD is an increased susceptibility to infections, including sepsis, which can be life-threatening. Kidney injury, a common and severe complication of sepsis, contributes to the complexity and poor outcomes associated with morbidity and mortality in SCD. However, the mechanisms that underlie septic acute kidney injury (AKI) in SCD are poorly understood. Here, we examined the effects of sepsis in transgenic homozygous SCD (SS; Townes model) mice and their non-sickling (AA) counterparts. We tested the hypothesis that aggravation of inflammation and oxidative stress by free heme released during hemolysis contribute to sepsis-induced kidney insuffciency in SCD. AA and SS mice were subjected to 18 h of sham operation and cecal ligation and puncture (CLP), a pre-clinical model of polymicrobial sepsis, after which kidney function was evaluated by transdermal measurement of glomerular filtration rate (GFR). AKI biomarkers, renal oxidative stress, and cytokines levels were also investigated. We demonstrate that mid- to high-grade CLP (ligation of 60-75% of the cecum and multiple punctures with 21-gauge needles) caused 100% mortality in SS mice. Unlike AA mice (100% survival), SS mice subjected to low-grade CLP (LgCLP; ligation of <45% of the cecum and a single puncture with 21-gauge needles) exhibited 40% survival. LgCLP reduced body weight but did not exacerbate splenomegaly in SS mice. Basal plasma bilirubin, heme, and ferritin were significantly higher in SS than in AA mice. In contrast to AA, LgCLP amplified the increase in plasma bilirubin, heme, and ferritin in SS mice. LgCLP also decreased GFR and increased renal oxidative stress, AKI biomarkers, and kidney-to-body weight ratio in SS mice. Luminex multiplex cytokine analysis indicated that the plasma levels of multiple pro-inflammatory cytokines were elevated in septic SS mice. Heme scavenger hemopexin (HX) diminished LgCLP-induced plasma heme increase. HX also mitigated kidney insuffciency, inflammation, and mortality in the septic SS mice. Our findings suggest that free heme contributes to septic AKI in SCD mice and that HX therapy may attenuate the harmful effect of heme in SCD during sepsis. NHLBI: R01 HL151735. 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.
Mechanisms of PAK1-Induced Skeletal Muscle Myokines in Improving Islet β-Cell Function
Authors: Balakrishnan Rekha , Kebrom Leah , Veluthakal Rajakrishnan , Thurmond Debbie 
Published: May 2024

The critical role of skeletal muscle in regulating metabolic homeostasis is well-acknowledged. The p21-activated kinase (PAK1), a prominent signaling molecule in skeletal muscle, has garnered attention for its potential modulatory role in glucose and mitochondrial metabolism. By applying conditioned media derived from PAK1-enriched L6 Glut4 myc myotubes or myoblasts to INS-1 832/13 clonal β-cells, we confirmed that a muscle-derived circulating factor(s) could enhance β-cell function. Furthermore, our mass spectrometry analysis in the conditioned media (CM) collected from PAK1 enriched L6.GLUT4myc myotubes revealed elevated levels of one protein in particular, hepatocyte growth factor activator (HGFAC), which is categorized as a secreted myokine. HGFAC is secreted into the circulation, where, upon activation, it can act in a paracrine or endocrine fashion to proteolytically cleave and activate HGF. It has been reported that HGF has a vital role in islet β-cell mass and function and HNFα, a transcription factor that is expressed in pancreatic β-cells regulates β-cell mass or function by modulating HGFAC expression. Thus, we hypothesize that PAK1-enriched skeletal muscle releases HGFAC into the serum-free conditioned medium and the medium carrying HGFAC when applied to islet β-cells enhances insulin secretion. Elevated levels of HGFAC protein were detected in the cells and their associated CM from PAK1-enriched skeletal myotubes, as compared with that of GFP-transduced control myotubes, using sandwich ELISA to quantify HGFAC. Notably, these cells were incubated in a serum-free medium, a means to eliminate serum factors that might impact HGFAC levels or detection capacity. Given this, we tested the effect of this serum-free CM collected from PAK1-enriched L6.GLUT4myc myotubes application to species-matched (rat) clonal β-cells functional capacity. Indeed, CM from PAK1-enriched myotubes significantly enhanced glucose-stimulated insulin secretion (GSIS), as compared that of the control CM. The presence of elevated HGFAC levels in PAK1-enriched cells, and the beneficial impact of this HGFAC-enriched CM upon beta cell function, reveals a new mechanism by which PAK1-enrichment in skeletal muscle imparts improved overall whole-body glucose homeostasis. further hints at a possible intricate relationship between muscle-pancreas crosstalk in the regulation of islet β-cell insulin secretion. Future investigations into possible autocrine functions of PAK1-enriched skeletal muscle are underway. This research was funded by the National Institutes of Health to D.C.T. (DK067912, DK112917, and DK102233), and an American Heart Association Postdoctoral fellowship to R.B. (#905770). 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.