bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic alcohol-induced mesenteric lymphatic leakage is associated with local and systemic metabolic dysregulation
Authors: Weaver Kourtney , Simon Liz , Molina Patricia , Souza-Smith Flavia 
Published: May 2023

Introduction: Chronic alcohol administration produces significant metabolic dysfunction as determined in pre-clinical and clinical studies. Our studies using a rodent model of chronic alcohol feeding showed that alcohol induces mesenteric lymphatic leakage and perilymphatic adipose tissue (PLAT) immunometabolic dysregulation. Specifically, chronic alcohol induced localized PLAT inflammation and decreased glucose uptake. Whether chronic alcohol-induced lymphatic leakage is also associated with altered systemic glucose/insulin dynamics remained to be determined. We hypothesized that chronic alcohol feeding impairs the endocrine response to a glucose tolerance test. Methods: Male Fischer 344 rats were randomized to a Lieber-DeCarli liquid diet containing 36% of calories from alcohol or pair-fed an isocaloric diet for 10 weeks. Animals consumed approximately 75 mL of diet per day. Body weights were not significantly different between groups; the average weights were 275.7 grams for control animals and 275.9 grams for alcohol-fed animals. Weights in both groups remained stable for the duration of the study. At 10 weeks, animals were fasted for 16 hours prior to intraperitoneal (IP) injections of 20% glucose solution (2g/kg). Blood samples were collected from the rat tail prior to and at 15-minute intervals following initial glucose injection for 2 hours. Blood glucose was tested at each interval using the AlphaTRAK glucometer. 2-way ANOVA and paired T-test were used to assess significant differences between groups. Results and Conclusion: Prior to IP glucose injection, blood glucose levels averaged 77 mg/dL for control animals and 71.5 mg/dL for alcohol-fed animals. Glucose levels in alcohol-fed animals averaged 38% higher at 15 minutes and 37% higher 30 minutes after IP glucose bolus than that of control animals. Total area under the curve (AUC) calculated from the glucose concentrations measured following IP glucose injection was significantly higher in alcohol-fed animals compared to control animals; average AUC for alcohol-fed animals was 26.8% higher than AUC for control animals. These results suggest that chronic alcohol-induced mesenteric lymphatic leakage and localized PLAT inflammation and altered glucose metabolism are also associated with disturbances in systemic glucose dysregulation. Future studies will examine the potential link between alcohol-induced PLAT immunometabolic dysregulation and alterations in systemic glucose metabolism. Supported by T32 (PM), K01 (FS). 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.
Contribution of local metabolic control to coronary pressure-flow autoregulation
Authors: Warne Cooper , Essajee Salman , Tucker Selina , Figueroa Alberto , Beard Daniel , Dick Gregory , Tune Johnathan 
Published: May 2023

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. This study interrogated the local metabolic hypothesis, which proposes that myocardial oxygen tension, indexed by coronary venous PO2 (CvPO2), determines the degree of coronary pressure-flow autoregulation by increasing the production of vasodilator metabolites as coronary perfusion pressure (CPP) is reduced. We tested this hypothesis by examining the extent to which dobutamine-induced increases in myocardial oxygen consumption (MVO2) under both normoxic and hypoxemic conditions, influences coronary autoregulatory capability. Experiments were performed on open-chest anesthetized swine during 20 mmHg stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg, via servo-controlled roller pump. Measurements were made in 3 conditions: a) normoxia (n = 7); b) normoxia with dobutamine (10 μg/kg/min, iv; n = 7); and c) hypoxemia (PaO2 36-38 mmHg) plus dobutamine (n = 5). Under control-normoxic conditions, CvPO2 decreased from 38 ± 2 to 22 ± 1 mmHg and coronary blood flow fell from 0.93 ± 0.15 to 0.32 ± 0.03 ml/min/g as CPP was reduced from 140 to 40 mmHg. Administration of dobutamine significantly increased heart rate (~60%; P < 0.001), but the combination of hypoxemia plus dobutamine did not further influence heart rate. Further, dobutamine with and without hypoxemia significantly increased MVO2 (P < 0.001); however, CvPO2 was reduced (P < 0.001) only in the presence of hypoxemia. Calculation of closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (value of 1 represents perfect autoregulation) was unaffected by dobutamine alone but tended to increase when dobutamine infusion was combined with reductions in PaO2 ≤ 40 mmHg (P = 0.069). Additional analysis of the autoregulatory slope within this same CPP range revealed no differences between groups. However, there was a significant inverse association between Gc and CvPO2, measured at CPP of 100 mmHg, in the absence and presence of dobutamine-induced increases in MVO2 ± hypoxemic conditions (P < 0.001, r = -0.722). The relationship of coronary resistance (CPP range of 120 to 60 mmHg) relative to respective CvPO2 revealed that decreases in CvPO2 were not associated with changes in coronary resistance until CvPO2 fell below a relative threshold of ~ 25 mmHg (r = 0.88). These findings support the interpretation that the sensitivity of coronary autoregulatory behavior is directly coupled with the activation of local metabolic vasodilator pathways below a critical level of myocardial oxygenation. This work was supported by National Institutes of Health grant R01 HL158723. 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.
Alpha-glucosidase inhibitor mitigates bone loss in type-1 diabetes
Authors: Juin Subir Kumar , Pushpakumar Sathnur , Sen Utpal 
Published: May 2023

Diabetic nephropathy is a hallmark of diabetes mellitus (DM) and is characterized by kidney dysfunction. The kidney plays an important role in bone health by preserving the equilibrium of minerals viz., calcium and phosphate in the blood and 1,25-Dihydoxyvitamin D3 (Calcitriol) production. Previous studies have suggested that renal dysfunction is associated with dysregulated mineral reabsorption due to mineral-hormone imbalance, leading to bone loss and increased fracture risk in DM. Alpha-glucosidase inhibitor (AGI) is known to decelerate carbohydrate catabolism and delay glucose production to improve overall diabetic health. Nimbidiol is an AGI derived from the medicinal plant, Azadirachta indica and is considered a potential anti-diabetic natural compound. The purpose of our present study was to investigate whether AGI mitigates the imbalance of mineral homeostasis and eventual bone loss in type-1 diabetes. Twelve - fourteen weeks old wild-type, C57BL/6J (WT) and type-1 diabetic, C57BL6/‐ Ins2Akita /J (Akita) mice were either treated with saline or AGI (0.40 mg kg-1 d-1) by subcutaneous implantation of micro-osmotic pump for eight weeks. Diabetic Akita mice showed a distinct downregulation of sodium-phosphate co-transporter, Npt2a expression in the renal tubules compared to the WT mice. In addition, Akita mice exhibited a significant increase in alkaline phosphatase activity and decrease in Calcitriol and bone minerals such as calcium and phosphate levels in the blood. The changes were associated with a significant bone loss as evidenced by the increased thinning and porosity of cortical and trabecular bone and reduction of osteoblasts and osteocytes in diabetic femur. AGI treatment mitigated the pathological changes in Akita mice. Taken together, our results suggest that AGI preserves mineral homeostasis and thereby protects from bone loss in type-1 diabetes. DK116591 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.
Endothelial Cell-Selective Adhesion Molecule Enhances Tumor Growth in a HFpEF Mouse Model
Authors: Lang Liwei , Ajith Ashwin , Horuzsko Anatolij , Bagi Zsolt 
Published: May 2023

Accumulating epidemiological evidence shows that the incidence of multiple types of cancer, such as melanoma and GI cancers, is significantly higher in patients with heart failure with preserved ejection fraction (HFpEF). However, the mechanistic relationships between HFpEF and cancer development are poorly understood. Impaired angiogenesis, upregulation of endothelial adhesion molecules and chronic low-grade inflammation are common in HFpEF. Here we examined the role of endothelial cell-selective adhesion molecule (ESAM) in the progression of malignant melanoma in a HFpEF mouse model. Orthotopic melanoma xenografts (B16F10-Luc2) were used and implanted subcutaneously in mice underwent uninephrectomy and aldosterone infusion (UNX-Aldo with 1% high salt drinking water for 4 weeks) and tumor growth was monitored with bioluminescent imaging. We found that ESAM expression and serum levels were elevated in the UNX-Aldo mice, which was accompanied by enhanced melanoma growth and metastasis rate. ESAM promoted tube formation and increased phospho-Akt, phospho-PKCα and phospho-ERK1/2 in cultured endothelial cells. Flow cytometry analysis showed elevated number of tumor-associated neutrophils (CD11b+Ly6G+Ly6C-) and myeloid-derived suppressor cells (MDSCs, CD11b+F4/80-Gr-1+) in the UNX-Aldo mice. UNX-Aldo mice with genetic deletion of ESAM (ESAM KO) showed a reduced tumor growth and reduced number of tumor-associated neutrophils and MDSCs. Collectively, our results indicate that in HFpEF, a proinflammatory ESAM activation may act to promote tumor angiogenesis, neutrophil and MDSCs tumor infiltration, thereby mitigating a proper immune response and facilitate tumor growth. 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.
A circadian oscillator regulates a food anticipatory increase in heart rate and body temperature
Authors: Prabhat Abhilash , Schroder Elizabeth , Stumpf Isabel , Stalcup Rebecca , Seward Tanya , Pendergast Julie , Delisle Brian 
Published: May 2023

Objective: The daily rhythm in heart rate is classically considered to be regulated by the circadian clock in the suprachiasmatic nucleus (SCN). The circadian clock in the SCN entrains to the light-dark cycle. However, some circadian rhythms can be entrained to meal timing independently of the SCN. In this study, we tested the hypothesis that heart rate is entrained by meal timing. Methodology: Wild-type male and female mice were implanted with telemetry devices to continually record HR and CBT in thermoneutral conditions. The mice were initially housed in a 12 h light: 12 h dark cycle (LD) with ad libitum access to food (ALF) for 7 days. Mice were then subjected to light cycle time-restricted feeding (TRF) between hours 2 and 9 (hour 0: lights on; hour 12: lights off) for 5 days, followed by 3 days in constant darkness (DD). The mice were then fed ALF for 3 days in DD to determine if food anticipatory rhythms persisted in constant conditions. Results: During ALF feeding in LD, HR and CBT increased at hours 11-13 and corresponded with the onset of nocturnal activity. In contrast, after 1 day of light cycle TRF, HR increased during the 2 hours prior to mealtime between hours 0-2. The food anticipatory increase in HR persisted during TRF in DD. The food-entrained anticipatory increase in HR and CBT remained phase-locked to prior mealtime when mice were returned to ALF after TRF. In contrast to the food-entrained anticipatory increase in HR and CBT, the circadian rhythms in HR and CBT dissociated and shifted back to the phase seen in ALF in LD. There were no sex differences. Conclusions: These data demonstrate that male and female mice have food-anticipatory increases in HR and CBT. Entrainment of the food anticipatory increase in HR and CBT to meal timing during TRF persisted in the absence of zeitgebers (in constant feeding and lighting conditions). Together these findings suggest that a food-entertainable oscillator regulates food-anticipatory increase HR and CBT rhythms independently of the SCN. Funding sources: The present work is supported by the National Heart Lung and Blood Institute grants R01HL153042 and R01HL141343. 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.
Avian mitochondria respiration is not predicated solely on complex abundance and DNA content
Authors: Yen Con-Ning , Bodmer Jocelyn , Wicks Jordan , Shi Tim , Gerrard David 
Published: May 2023

Skeletal muscle is a collection of heterogenous muscle fiber types differing in their ability to contract and metabolize energy substrates. The relative proportion of each fiber type in muscle drive function, where oxidative muscles are more fatigue resistant and generally have greater amounts of mitochondria than more glycolytic muscles that have less mitochondria because of their reliance on glycolytic reactions for energy production. However, even highly glycolytic muscles, like the breast muscle of chickens have mitochondria. Yet, differences in mitochondrial characteristics across muscle types remain largely unknown.We compared glycolytic and oxidative muscles of two different species in an attempt to understand better the relationship between mitochondrial DNA (mtDNA) and protein abundance, and mitochondria function. Glycolytic muscles longissimus lumborum (LL) and the pectoralis major (PM) and oxidative muscles masseter (MS) and quadriceps femoris (QF) were collected from adult pigs and chickens, respectively. Greater mtDNA abundance (2-ΔΔCT) was noted in oxidative muscles of both species compared to their glycolytic counterparts ( P < 0.01). However, when absolute mtDNA was estimated, porcine MS had more mtDNA than LL ( P < 0.001), whereas both avian muscles were equivalent. Porcine MS muscle had greater succinate dehydrogenase (SDHA, P < 0.05) and citrate synthase (CS, P < 0.001) than LL, while avian QF muscle had greater CS ( P < 0.001) and voltage dependent anion channel (VDAC, P < 0.05) compared to PM muscle. Isolated mitochondria from the MS of pigs had more electron transport chain complex I (CI, P < 0.010) and complex II (CII, P < 0.05) than those isolated from the LL. Avian mitochondria had no differences in either electron transport chain complexes across muscle, but mitochondria from the PM had greater VDAC than those purified from the QF. Oxygen consumption rates (OCR) followed muscle type, where mitochondria from oxidative muscles consumed more oxygen than those of glycolytic muscle when stimulated with ADP ( P < 0.05). These data show that porcine mtDNA abundance, mitochondrial protein abundance, and mitochondrial function is greater in oxidative muscle compared to glycolytic muscle, and that respiration is greater in mitochondria from more oxidative muscle. However, differences in the relative abundance of mtDNA and electron transport chain complexes were not evident in isolated mitochondria from the chicken, yet respired differently nonetheless suggesting mtDNA and protein may not be directly correlated to the overall function of mitochondria. 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.
A humanized protease-activated receptor-2 mouse as a model for allergic asthma
Authors: Gillman Samuel , Schiff Hillary , Pederson Wil , Sandoval Estevan , Rivera Benjamin , Dussor Gregory , Price Theodore , Vagner Josef , Defea Kathryn , Boitano Scott 
Published: May 2023

Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) inflammation, and mucus overproduction, and has differential presentation in males and females. There exists strong demand to improve upon current asthma treatments by targeting upstream signaling pathways, including the G-protein coupled receptor protease-activated receptor-2 (PAR2). We have recently shown effectiveness of full (C391) and ß-arrestin biased (C781) PAR2 antagonism in limiting allergen-induced asthma indicators in mouse models (C57Bl/6 and Balb/C). To better test PAR2 antagonists as asthma drugs, we have developed a transgenic mouse model that expresses human PAR2 without mouse PAR2 expression in a C57Bl/6 background (htgPAR2). The htgPAR2 mice have heightened responses to asthma allergens [house dust mite (HDM) or Alternaria alternata] following acute exposure. Limited sex differences were observed in the HDM challenge model. However, when challenged with A. alternata there was significantly higher AHR in the male mice and significantly higher inflammatory and mucus responses in the female mice. The full and ß-arrestin biased PAR2 antagonists also displayed differential effects with C781 providing broader control of allergen-induced indicators (AHR, inflammation and mucus overproduction). We conclude that the htgPAR2 mouse model is a promising tool for preclinical in vivo screening of potential asthma treatments targeting PAR2. Grants from the National Institute of Health (NS098826, AI140257, HL16024, HL152942) 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.
Seasonal changes in the metabolomic profile of white adipose tissue in hibernating thirteen-lined ground squirrels
Authors: Heinis Frazer , Alvarez Sophie , Rugira Kevin , McMurchie Ashley , Schuster Olivia , Andrews Matthew 
Published: May 2023

Hypothesis: Hibernator white adipose tissue will exhibit season-dependent remodeling of metabolic pathways. Methods: Thirteen-lined ground squirrels were captured near Lincoln, Nebraska, and housed in University of Nebraska-Lincoln veterinary facilities. Seasonal adjustments in environmental chamber lighting and air temperature were used to induce hibernation, and tissues were taken at different timepoints throughout the seasonal activity-torpor cycle. Polar compounds were extracted from white adipose tissue (N=47 across five groups) and analyzed by hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) in both positive and negative ion modes. Spectra were aligned, and peaks detected and identified using MS2 libraries search (mzCloud, MoNA, in-house) with Compound Discoverer (Thermo). Normalized and QC corrected feature intensities were processed using MetaboAnalyst 5.0 for statistical analysis and pathway enrichment. Results: We identified 185 compounds and 85 compounds from positive and negative HILIC-MS, respectively, including 15 compounds identified in both ion modes. Unsupervised clustering using principal component analysis revealed discrete clusters representing the different seasonal timepoints throughout hibernation. One-way analysis of variance and feature intensity heatmaps revealed metabolites that varied in abundance between active and torpid timepoints. Pathway analysis compared against the KEGG database demonstrated enrichment of amino acid metabolism and aminoacyl-tRNA biosynthesis pathways among our identified compounds. Carnitine derivatives and ketones were among molecules found to be elevated during torpor-associated timepoints relative to the active state. Summary and Conclusion: We report here the polar metabolomic profile of ground squirrel white adipose tissue at different points throughout the seasonal hibernation cycle. We identified 255 compounds and showed seasonal differences in white adipose metabolites indicating a shift of hibernator metabolism associated with torpor. Our findings indicate it is possible that white adipose directly produces ketones, rather than solely relying on hepatic ketogenesis. As our results represent steady-state measurements of metabolite abundance, further work is currently underway to identify whether hibernator adipose tissue can directly synthesize these compounds and contribute to the elevated plasma ketone concentrations during torpor observed in previous work. Funding: University of Nebraska 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.
Chronic RAS Inhibition Prevents Aberrant Irritant-evoked Pulmonary-Cardiac Reflexes in the Spontaneously Hypertensive (SH) Rat
Authors: Hooper Justin , Taylor-Clark Thomas 
Published: May 2023

Cardiopulmonary reflexes evoked by activation of airway vagal afferent nerves via irritant/pollution inhalation are remodeled from bradycardia in normal subjects to tachycardia and ventricular arrhythmia in patients with pre-existing cardiovascular disease (CVD). We have shown similar remodeling in the spontaneously hypertensive (SH) rat: selective activation of airway vagal afferent nerves via inhalation of the transient receptor potential ankyrin 1 (TRPA1)-specific agonist allyl isothiocyanate (AITC) evoked parasympathetic-mediated reflex bradycardia in normotensive wistar-kyoto rats but evoked sympathetically-mediated tachycardia and premature ventricular contractions (PVCs) in spontaneously hypertensive (SH) rats. Hypertension in the SH rat develops with age (~7 weeks) and this is accompanied by autonomic dysfunction.The renin-angiotensin system (RAS) is closely linked with blood pressure (BP), cardiac remodeling and autonomic dysfunction, with the main effector being angiotensin II (Ang II), produced downstream of angiotensin converting enzyme (ACE). Acute treatment with ACE inhibitors or antagonists of Ang II-sensitive receptor AT1R causes temporary BP normalization in SH rats. Chronic treatment with ACE inhibitors or AT1R inhibitors prevents the development of hypertension, baroreceptor dysfunction and cardiac remodeling in SH rats. Previously, we have shown that acute normalization of BP with the ACE inhibitor captopril had no effect on the AITC-evoked pulmonary-cardiac reflexes in the SH rat. Here, we investigated the impact of chronic ACE inhibitor treatment (captopril, 20mg/kg/ ad libitum) or chronic AT1R treatment (losartan, (15mg/kg/ ad libitum) from 6-15 weeks of age in SH rats on AITC-evoked pulmonary-cardiac reflexes. Both chronic captopril and losartan normalized BP and prevented AITC-evoked tachy-arrhythmia (% of tachycardic beats and PVCs) in SH rats at 15 weeks of age. As such, following antiRAS treatment, AITC only evoked reflex bradycardia in SH rats (similar to our previous studies of normotensive rats). These findings suggest that the remodeling of the irritant-evoked pulmonary-cardiac reflexes can be prevented by targeting the renin-angiotensin system. Reducing tachyarrhythmia evoked by the inhalation of irritants/pollution in susceptible individuals may reduce the risk of CVD exacerbations associated with air pollution. 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.