American journal of physiology. Regulatory, integrative and comparative physiology最新文献

Preeclampsia, new-onset hypertension with proteinuria or end-organ dysfunction after 20 wk gestation, is associated with placental ischemia, maternal endothelial dysfunction, and chronic inflammation. Preeclamptic women and the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia have higher placental expression and activation of NLRP3 inflammasome and its associated cytokine, interleukin 1β (IL-1β). We hypothesized that higher IL-1β signaling through the IL-1 receptor type 1 (IL-1R1), contributes to maternal hypertension, fetal growth restriction (FGR), and endothelial dysfunction in response to placental ischemia. GD14 timed-pregnant Sprague-Dawley rats underwent RUPP or sham surgery with implantation of minipumps infusing IgG or IL-1R1 neutralizing antibody (αIL-1R1; 2 μg/kg/day). On GD19, mean arterial pressure (MAP), fetal and placental weights, blood, and tissues were collected. Plasma IL-1β was higher in RUPP vs. Sham IgG controls (8.79 ± 2.01 vs. 3.24 ± 1.05 pg/mL; P < 0.01) and normalized in RUPP + αIL-1R1 (1.23 ± 0.51 pg/mL; P < 0.01 vs. RUPP + IgG). MAP was higher at 120 ± 4 mmHg in RUPP + IgG from 100 ± 3 mmHg in Sham + IgG (P < 0.01). αIL-R1 treatment reduced MAP to 106 ± 12 mmHg in RUPP (P < 0.01 vs. RUPP + IgG). RUPP + IgG placenta weight (0.46 ± 0.1 g) was lower than Sham + IgG (0.54 ± 0.1 g; P < 0.01) and significantly higher in RUPP + αIL-R1 (0.52 ± 0.02 g; P < 0.05 vs. RUPP + IgG). Fetal weight was higher in RUPP + αIL-1R1 (2.77 ± 0.22 g) vs. control RUPP (1.97 ± 0.11 g; P < 0.01). Placental cNK, T_H17s, and macrophages were higher, and T_Regs were lower in RUPP + IgG vs. Sham, and were normalized in RUPP + αIL-1R1 (P < 0.05). IL-1R1 inhibition decreased IL-1R1 expression but did not reverse RUPP-induced changes in NFκB, preproendothelin, or endothelial nitric oxide synthase expression. IL-R1 activation contributes to maternal hypertension and FGR via mediating immune populations during ischemia.NEW & NOTEWORTHY IL-1R1 inhibition in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia lowered maternal blood pressure, reduced fetal reabsorptions, and improved fetal and placental growth. These effects were accompanied by restored systemic and placental immune balance but no improvement in vascular markers such as VEGF or preproendothelin. Thus, IL-1R1 blockade, including the clinical agent anakinra, is a promising therapeutic avenue that may require combination strategies for optimal benefit.

Exercise during heat exposure induces skin microvascular and systemic cardiovascular changes. When standardized exercise tasks are completed, such as during military training or in workplace settings, sex differences in responses may be apparent. Nineteen males and 19 females participated in a set-pace laboratory walking test (treadmill walking 5 km/h; 2% incline) in a climate chamber (40°C; 50% RH) for 90 min. Body composition (DXA) and aerobic capacity (V̇o_2max) were measured in a preliminary session. Metabolic heat production, skin blood flow (SkBF; laser Doppler flowmetry), limb blood flow (Doppler ultrasound), stroke volume, cardiac output (CO), heart rate (HR), oxygen consumption (V̇o₂), and core temperature (Tc) were measured at baseline, 30, 60, and 90 min. No sex difference in Tc at 90 min was evident (male 38.3 ± 0.5°C vs. female 38.5 ± 0.4°C; P = 0.403) and a similar change from baseline to 90 min (Δ 1.40 vs. 1.28°C; P = 0.447) occurred, despite males producing more heat (3.4 ± 1.0 vs. 2.1 ± 0.7 W/kg; P = 0.001), exhibiting higher SkBF (192 ± 50 vs. 160 ± 21 PU; P = 0.026), and higher sweat production rate (16.5 ± 5.1 vs. 12.3 ± 3.3 mL/min; P = 0.009). Males also had higher CO (7.25 ± 1.38 vs. 6.11 ± 1.72 L/min; group P = 0.026) and femoral blood flow (1.00 ± 0.23 vs. 8.22 ± 0.19 L/min; P = 0.026) responses than females. Males compensated for more lean mass and higher metabolic heat production via a larger increase in cardiac output, with more blood flow distributed to active muscle and, as heat and exercise exposure continued, to the skin. Tc in females did not rise more than in males, possibly due to body size and/or anthropometric factors.NEW & NOTEWORTHY In military, workplace, and sporting settings, challenging environmental conditions while performing external workloads are not always avoidable. We assessed sex differences during a 90-min treadmill walk (40°C). Males produced more metabolic heat, had higher skin blood flow, sweat rate, and cardiac output than females. Change in core temperature remained similar between sexes, challenging the proposition that women are more heat-intolerant than men. Our findings underscore the need for tailored heat tolerance strategies for both sexes.

Findings of falling urine pH with age among stone formers have not been explained by changes in renal function or renal ammonia production with age. We collected and analyzed 245 urine samples from 190 stone-forming subjects (95 male) and 55 normal subjects (18 male) to expand on our previous study using urine titration to explore whether urine organic anion (Uoa) contributes to acid load and rises with age. We stratified our previous titration protocol to include three pKa subranges, 2.70-3.60, 3.61-4.30, and 4.31-7.40, to measure effects of Uoa of differing pKa values on renal acid excretion. We found that Uoa behaves as a metabolic acid, and associates independently and positively with ammonia (P < 0.001). Uoa in pKa range 2.70-3.60 is the principal acid component and rises with age (P < 0.001), whereas Uoa in pKa range 4.31-7.40 seems to reflect net alkali excretion when studied in a regression model with the kidney as a reporter organ. When factored per urine creatinine, we found significant age and sex effects of nearly all components of renal acid-base balance. Effects from subject type (stone former vs. normal) were minimal, though we are limited by the oldest tertile having few normals. As acid anions with pKa within 2.70-3.60 are used in the tricarboxylic acid cycle, markers of acid excretion may reflect mitochondrial abnormalities associated with aging.NEW & NOTEWORTHY When assessed using the kidney as a reporter organ, titrated urine anions behave overall as an acid load. However, those in the pKa range of 2.70-3.60 account for much of that behavior, whereas anions in the pKa ranges above 3.60 variably behave as alkali or acid, indicating that the urinary anions are heterogeneous. Despite their differences in function, they all rise with age. This may explain acid stress reported as part of the aging phenotype.

The goal of this study was to determine which phase of swallowing causes deglutitive inhibition (DI). DI is inhibition of ongoing peristalsis by a new swallow. Pharynx and esophagus of decerebrate cats (n = 25) were instrumented to record esophageal peristalsis. Injecting saline into pharynx or esophagus activated primary (pharyngeal and esophageal phases) peristalsis repeatedly and randomly, or secondary (esophageal phase) peristalsis once, respectively. When a new primary peristalsis occurred during ongoing primary peristalsis, the occurrence of ongoing esophageal peristalsis was blocked when it was 1-10 cm from upper esophageal sphincter, then secondary peristalsis occurred 1.3 ± 0.1 s (n = 22) later at same location. This esophageal blockade occurred almost simultaneously [0.15 ± 0.01 s (n = 17) before] with activation of thyropharyngeus activation during the new pharyngeal phase. When ongoing primary peristalsis was at or below 13 cm from upper esophageal sphincter, the magnitude of primary esophageal peristalsis significantly decreased (102 ± 14 vs. 49 ± 8 mm Hg, n = 8, P < 0.01) during the new pharyngeal phase, but peristaltic progression was not altered. DI had same effects on secondary peristalsis. DI of ongoing peristalsis in distal esophagus occurred before or without new esophageal phase in every case (21 cases, n = 9), except one. DI is central inhibition of ongoing esophageal phase of swallowing by the new pharyngeal phase as short-term cessation of striated muscle peristalsis and longer-term reduction in smooth muscle peristaltic magnitude. Esophageal or oral phase of swallowing does not cause DI.NEW & NOTEWORTHY Deglutitive inhibition is caused by central inhibition of ongoing esophageal phase of swallowing during the new pharyngeal phase by short-term cessation of striated muscle peristalsis and longer-term reduction in smooth muscle peristaltic magnitude. The esophageal or oral phase of swallowing does not cause deglutitive inhibition. Deglutitive inhibition is pharyngeal phase central inhibition of the esophageal phase of swallowing.

Accurate and reproducible tools to evaluate skeletal muscle contractility help to advance the field of physiology by defining skeletal muscle function in the context of skeletal muscle development, disease, aging, and injury recovery. The biomechanical assessment of muscle strength can be accomplished by measuring in vivo muscle torque, specifically, the muscle force generated at a moment arm around a joint. This approach to assess skeletal muscle contractility in preclinical animal studies primarily measures muscle torque in anesthetized animals using noninvasive electrophysiological stimulation. This method is advantageous because skeletal muscle contractions are evoked in a controlled, quantifiable manner that is independent of subject motivation, allowing for maximal functional data and reproducible research outcomes. The purpose of this Cores of Reproducibility in Physiology (CORP) review is to discuss the underlying physiology of the in vivo method, to highlight common outcomes and their physiological importance, and to provide considerations for technical reproducibility and data interpretation. The hope is this CORP will provide skeletal muscle researchers with the foundational and practical knowledge to better incorporate the in vivo technique in their future studies.

Dynamic cerebral autoregulation (dCA) demonstrates directional sensitivity (DS_CA), depending on increases or reductions in mean arterial blood pressure (MAP). DS_CA dependence on the efficiency of dCA has not been reported. A retrospective study of 172 healthy subjects (88 female, age 19-82 yr), with 5-min recordings of MAP, cerebral blood velocity (middle cerebral artery, MCAv), end-tidal CO₂, and electrocardiogram, led to estimates of the MCAv step response to changes in MAP. The strength of DS_CA was expressed by the difference between the MCAv step responses for the positive derivative component of MAP and the corresponding negative derivative component. The efficiency of dCA was expressed by the original autoregulation index (ARI_orig), ranging from 0 to 9, calculated from the original MAP. For the entire population, DS_CA strength was not associated with ARI_orig or any other parameters. However, when taking biological sex and age into account, markers of DS_CA strength showed significant linear regressions with ARI_orig, with negative slopes for younger females (P = 0.0037-0.011, late phase of the step responses), no influence in older females (P > 0.69), and positive slopes for both younger and older males (early phase of the step responses, P = 0.003-0.041). This contrasting pattern of the influences of sex and age is in agreement with the known effects of gonadal hormones on the myogenic response and endothelial function of the cerebral circulation. Clinical studies of the diagnostic and/or prognostic value of DS_CA parameters need to take into account the influences of sex, age, and the ARI_orig.NEW & NOTEWORTHY Dynamic cerebral autoregulation (dCA) is more efficient for increases in mean arterial blood pressure (MAP) compared with reductions in MAP. We found that directional sensitivity of dCA is dependent on its efficiency, with differences depending on sex and age. In older women, strength of directional sensitivity (DS_CA) is not affected by dCA efficiency, but in younger women, DS_CA decreases with dCA efficiency, whereas in both younger and older men, DS_CA strength increases with dCA efficiency.

The differential diagnosis within polyuria-polydipsia syndrome, especially in the pediatric population, remains challenging. Despite its limited accuracy, the water deprivation test (WDT) is the reference test in pediatrics. We retrospectively analyzed WDT performed in 65 pediatric patients (mean age 8.2 yr; 0-17.9). We evaluated the accuracy and safety of the WDT, investigated possible baseline variables that could predict outcomes, and reevaluated interruption and interpretation criteria. Among the 83 WTDs performed, 47 (56.6%) were conclusive (accuracy = 53%). The simplified 2-h WDT was inconclusive in 47.6% of the sample. A baseline urinary osmolality (uOsm) greater than 279 mosmol/kgH₂O excluded arginine vasopressin deficiency (AVP-D) and/or AVP resistance (AVP-R) in all patients (sensitivity = 100%; specificity = 74%; P < 0.01). A uOsm greater than 533 mOsm/kgH₂O at the time of WTD discontinuation also excluded the diagnosis of AVP disorders in all subjects (sensitivity = 100%; specificity = 100%; P < 0.01). Therefore, a baseline uOsm > 279 mOsm/kgH₂O and a peak uOsm > 533 mOsm/kgH₂O excluded AVP disorders. These new cutoffs can improve WDT accuracy and should be validated in prospective studies. No serious adverse effects (SAEs) were observed. The lower limit of 3% weight loss was the criterion for early WDT interruption in nine conclusive tests. The demonstrated safety encourages us to use weight losses greater than 5% as stopping intervals and also tolerate a more extended test duration when necessary. In conclusion, WDT in children and adolescents is safe and still necessary until better diagnostic tools are proven helpful in pediatric patients with polyuria-polydipsia syndrome.NEW & NOTEWORTHY This large pediatric cohort study confirms the safety of the water deprivation test but reveals its limited diagnostic accuracy. Updated diagnostic criteria can improve performance and reduce unnecessary testing. A baseline urinary osmolality (uOsm) > 279 mOsm/kgH₂O excluded arginine vasopressin (AVP) disorders with 100% sensitivity and 74% specificity and an interrupt uOsm > 533 mOsm/kgH₂O excluded them with 100% sensitivity and specificity. A weight loss >5% was a safe threshold. Prospective, multicenter studies are needed to generalize these findings.

Current therapeutics for hypoxic/ischemic brain damage can benefit from insights resulting from the study of hypoxia/anoxia-resistant organisms. Hypoxia resistance, however, is not a common feature in mammalian models. Being naturally exposed to hypoxic/anoxic conditions, the sea hare Aplysia californica could become a very useful model for the study of hypoxia resistance. Here, we experimentally exposed two cohorts of A. californica, resulting from crosses of adults with different environmental exposure histories, to daily 6 h pulses of hypoxic water conditions (<1.8 mgO₂/mL) for six consecutive days. The transcriptional response to hypoxia was evaluated in the abdominal and pleural/pedal ganglia through the exposure, during rapid reoxygenation, and after >12 h of recovery. Resistance to hypoxia was observed in the offspring of wild animals, with no significant changes in growth and reflex performance, compared with unexposed controls of the same cohort. Impairments were observed however in the offspring of lab-reared individuals. Transcriptional response to hypoxia was larger in the abdominal ganglia compared with the pleural/pedal for both cohorts, and significant differences between cohorts were observed for both ganglia. Overall, wild-cross animals displayed a significant reduction in the expression of metabolic genes, and an increased expression of genes involved in stress-response and immune system functions compared with the lab-cross cohort, both under control conditions and during hypoxia exposures. The resistant group displayed similar gene-level regulation as that described to be involved in hypoxia/ischemia preconditioning (HPC/IPC) in mammalian models, including the frontloading of HIF1-a orthologs and other neuroprotective genes like VEGF and HSP70.NEW & NOTEWORTHY Our results indicate that regular exposure to challenging natural conditions activates mechanisms involved in hypoxia resistance in Aplysia californica. This experience is passed to the next generation, fading in the absence of exposure for at least two generations. Gene expression and physiological responses varied significantly between resistant and sensitive sea hares under normoxic and hypoxic conditions, displaying clear evidence of preconditioning in core hypoxia response pathways like HIF.

Ulcerative colitis (UC) is a serious inflammatory bowel disease with a significantly increasing incidence globally. Current treatment options often exhibit unstable efficacy and notable side effects, making the exploration of alternative therapies particularly important. Peucedanum praeruptorum Dunn, a traditional Chinese medicine, contains various bioactive compounds, among which praeruptorin A (PA) has garnered attention for its anti-inflammatory potential. This study aimed to investigate the anti-UC effects of PA in a dextran sulfate sodium (DSS)-induced colitis mouse model and in Caco-2 cells and its underlying mechanisms. Preliminary results indicate that PA alleviates symptoms of DSS-induced ulcerative colitis, significantly reduces the expression of inflammatory factors, decreases colonic apoptosis, and repairs damaged intestinal barrier function in mice. PA also had protective effects on DSS-induced barrier dysfunction and inflammation in Caco-2 cells. Further research demonstrated that PA inhibits the phosphorylation of the STAT-1 and STAT-3 proteins, whereas AG490, an inhibitor of STAT-1 and STAT-3, effectively mimics the intestinal protective effects of PA. In addition, network pharmacology and molecular docking analyses were conducted to further elucidate the molecular targets and mechanisms of PA. These analyses revealed key pathways and potential interactions, supporting the hypothesis that PA exerts its protective effects through the modulation of inflammatory and apoptotic pathways. In summary, these findings support the protective role of PA in ulcerative colitis in vivo and in vitro and suggest its potential as an intervention for the prevention and treatment of this condition.NEW & NOTEWORTHY This study revealed that praeruptorin A (PA) alleviates symptoms of ulcerative colitis in a DSS-induced mouse model, reduces inflammatory factors levels, and promotes intestinal barrier repair in both DSS-induced colitis model mice and Caco-2 cells. The effects of PA are linked to STAT-1 and STAT-3 inhibition, highlighting its potential as a therapeutic intervention.

Insulin resistance has been associated with acute mountain sickness (AMS) risk, but the influence of active ascent is unclear. Thirty-two unacclimatized soldiers (23 ± 4 yr; 80 ± 14 kg) were tested at baseline residence (BLR), hiked ∼5 km (n = 16) or were driven (n = 16) to 4,300 m, and stayed for 4 days (∼66 h). Venous blood was taken each morning at BLR and during high altitude (HA) exposure days 2-4 (HA2-4) and the evening on day 1 at HA (HA1). Metabolites and hormones were measured, and insulin resistance (HOMA-IR) was calculated. AMS cerebral factor score (AMS-C) was measured daily and peak scores were calculated. Active ascenders had higher energy expenditure (1,265 ± 351 vs. 408 ± 208 kcal) and lower oxygen saturation ([Formula: see text]) (75 ± 3 vs. 82 ± 3%) during ascent. Norepinephrine and lactate were higher (P < 0.007) in active ascenders on HA1. All other data were combined due to lack of group differences. Glucose, insulin, and HOMA-IR were elevated (P < 0.05) on HA2 (105.9 ± 12.3 mg/dL; 12.1 ± 6.8 µIU/mL; 3.2 ± 2.1 au) and HA3 (101.8 ± 11.2 mg/dL; 10.2 ± 5.5 µIU/mL; 2.2 ± 1.4 au) vs. baseline and returned to normal on HA4. Epinephrine (P < 0.001) and cortisol (P = 0.004) were elevated on HA1 and HA2 vs. baseline, respectively. GLP-1 was higher on HA1 vs. HA2 and HA3 (P < 0.021). Glucose (r_rm = 0.42; P = 0.001), insulin (r_rm = 0.29; P = 0.001), HOMA-IR (r_rm = 0.27; P = 0.002), epinephrine (r_rm = 0.34; P < 0.001), and norepinephrine (r_rm = 0.20; P = 0.027) were significantly correlated with AMS-C. Transient perturbations to glucose metabolism during 4 days of HA exposure influences AMS severity without further impact from active ascent.NEW & NOTEWORTHY We demonstrate insulin resistance during 4 days of exposure at 4,300 m is positively correlated with acute mountain sickness (AMS) severity. This builds on previous data showing insulin sensitivity and carbohydrate metabolism at sea-level predict AMS. The blood glucose excursions appear at least partly mediated by cortisol and nocturnal hypoxemia.