Physiological Reports最新文献

The endothelial glycocalyx (eGC) is a carbohydrate-rich layer on the vascular endothelium, and its damage can lead to endothelial and organ dysfunction. Heparanase (HPSE) degrades the eGC in response to cellular stress, but its role in organ dysfunction remains unclear. This study investigates HPSE's role in lung ischemia-reperfusion (I/R) injury. A left lung hilar occlusion model was used in B6 wildtype (WT) and HPSE genetic knockout (^-/-) mice to induce I/R injury in vivo. The left lungs were ischemic for 1 h followed by reperfusion for 4 h prior to investigations of lung function and eGC status. Data were compared between uninjured lungs and I/R-injured lungs in WT and HPSE^-/- mice. WT lungs showed significant functional impairment after I/R injury, whereas HPSE^-/- lungs did not. Inhibition or knockout of HPSE prevented eGC damage, inflammation, and cellular migration after I/R injury by reducing matrix metalloproteinase activities. HPSE^-/- mice exhibited compensatory regulation of related gene expressions. HPSE facilitates eGC degradation leading to inflammation and impaired lung function after I/R injury. HPSE may be a therapeutic target to attenuate graft damage in lung transplantation.

Excess body fat (BF) contributes to metabolic syndrome (MetS). The Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) is an equation-derived body fat estimator proposed to assess BF. However, its efficiency compared to the standard method is unknown. We aimed to compare the efficacy of CUN-BAE with the standard method in estimating BF in southern Indians. We included 351 subjects, with 166 MetS patients and 185 non-MetS subjects. BF was obtained from the standard bioelectrical impedance analysis (BIA) method and measured by CUN-BAE in the same subjects. We compared the efficacy of CUN-BAE in estimating BF with that of BIA via Bland-Altman plots, intraclass correlation coefficients, concordance correlation coefficients and the kappa index. The mean body fat percentage (BF%) values measured by BIA and CUN-BAE in all the subjects were 28.91 ± 8.94 and 29.22 ± 8.63, respectively. We observed significant absolute agreement between CUN-BAE and BIA for BF%. BIA and CUN-BAE showed good reproducibility for BF%. CUN-BAE had accuracy comparable to BIA for detecting MetS using BF%. Our findings indicate that CUN-BAE provides precise BF estimates similar to the BIA method, making it suitable for routine clinical practice when access to BF measurement devices is limited.

Hyperlactatemia is common during tumor craniotomy, but the underlying pathophysiology is unclear. This study measured simultaneous arterial and jugular-bulb lactate concentrations in patients undergoing brain tumor craniotomy to investigate the hypothesis that hyperlactatemia was associated with a net cerebrovascular lactate input. In 20 patients, arterial and jugular-bulb blood was collected hourly from the start of surgery to 6 h postoperatively for measurement of lactate, glucose, and oxygen concentration. For each marker, data were analyzed using a linear mixed-effects model with jugular-bulb concentration as dependent variable, arterial concentration as fixed effect, and patient as random effect. Furthermore, we generated regression lines between arterial and jugular-bulb concentrations. The slope of the regression line between arterial and jugular-bulb lactate was 0.95 (95% CI 0.93-0.97, R² = 0.98), indicating that increasing arterial lactate levels were associated with an increasingly positive net cerebrovascular balance (net input). The line crossed the identity line at 2.86 (95% CI 0.57-5.16) mmol/L, indicating that lower levels of lactate were associated with a negative net cerebrovascular balance (net output). This suggests a switch from net lactate output during normolactatemia towards net input during hyperlactatemia. Hyperlactatemia in tumor-craniotomy patients probably does not originate from the brain.

Hypertension drives the development of concentric left ventricular hypertrophy (LVH). However, the relative contribution of pentraxin-3 (PTX-3), a novel marker for inflammatory cardiovascular disease, in the hypertrophic response to pressure overload has not been adequately elucidated. We investigated the role of PTX-3 in the development of LVH in spontaneously hypertensive rats (SHR), untreated and treated with either captopril (an ACE inhibitor) or hydralazine (a non-specific vasodilator). Three-month-old SHR received either 20 mg/kg/day hydralazine (SHR + H, n = 6), 40 mg/kg/day captopril (SHR + C, n = 6), or plain gelatine cubes (untreated SHR, n = 7) orally for 4 months. Wistar Kyoto rats (WKY, n = 7) were used as the normotensive controls. Blood pressure (BP) was measured using the tail-cuff method. Cardiac geometry and function were determined using M-mode echocardiography. Circulating concentrations of inflammatory markers were measured in plasma by ELISA. LV fibrosis and cardiomyocyte width were assessed by histology. Relative mRNA expression of PTX-3 was determined in the LV by RT-PCR. Untreated SHR exhibited greater systolic BP and relative wall thickness (RWT) compared to WKY. Captopril and hydralazine normalized BP but only captopril reversed RWT in SHR. Circulating PTX-3 and VCAM-1 levels were elevated in untreated SHR and reduced with captopril and hydralazine. Circulating PTX-3 was positively associated with systolic BP but lacked independent relations with indices of LVH. LV relative mRNA expression of PTX-3 was similar between the groups. PTX-3 may not be involved in the development of LVH in SHR, but plausibly reflects the localized inflammatory milieu associated with hypertension.

Therapeutic development for skeletal muscle diseases is challenged by a lack of ex vivo models that recapitulate human muscle physiology. Here, we engineered 3D human skeletal muscle tissue in the Biowire II platform that could be maintained and electrically stimulated long-term. Increasing differentiation time enhanced myotube formation, modulated myogenic gene expression, and increased twitch and tetanic forces. When we mimicked exercise training by applying chronic electrical stimulation, the "exercised" skeletal muscle tissues showed increased myotube size and a contractility profile, fatigue resistance, and gene expression changes comparable to in vivo models of exercise training. Additionally, tissues also responded with expected physiological changes to known pharmacological treatment. To our knowledge, this is the first evidence of a human engineered 3D skeletal muscle tissue that recapitulates in vivo models of exercise. By recapitulating key features of human skeletal muscle, we demonstrated that the Biowire II platform may be used by the pharmaceutical industry as a model for identifying and optimizing therapeutic drug candidates that modulate skeletal muscle function.

This study compared cardiovascular and metabolic responses during concentric and eccentric stepping. Eight participants (5 m, 3f; 22 ± 2 years) performed maximal concentric and eccentric ramp incremental tests on a modified stepping ergometer. Subsequently, three randomized 15-min constant-power tests were performed (1) concentric stepping at 90% of the concentric lactate threshold (LT), (2) eccentric stepping at the same power, and (3) eccentric stepping at the same oxygen uptake (V̇O₂). At equivalent power (36 ± 6 W, p = 0.62), eccentric stepping resulted in 46 ± 8% lower V̇O₂, 16 ± 6% lower heart rate (HR), and 11 ± 5% lower mean arterial blood pressure compared to concentric (p < 0.01). Matching V̇O₂ required 65 ± 19% more power during eccentric stepping (p < 0.01). During this test, eccentric V̇O₂ and HR continued to increase, resulting in a 22 ± 29% higher V̇O₂ and 19 ± 16% higher HR in the final minute (p < 0.001). Reduced cardiorespiratory demand during eccentric stepping at the same power as concentric demonstrates a higher eccentric power is required to produce the same V̇O₂. However, despite being below the concentric LT, eccentric V̇O₂ and HR continued to increase past the predicted steady state, indicating a higher exercise intensity.

The overall objective was to determine how no extracellular glucose and/or low glycogen content affect fatigue kinetics in mouse flexor digitorum brevis (FDB) single muscle fibers. High glycogen content (Hi GLY), near normal in situ level, was obtained by incubating fibers in culture medium containing glucose and insulin while low glycogen content (Lo GLY), at about 19% of normal in situ level, was achieved by incubating fibers without glucose. Neither Lo GLY nor the absence of extracellular glucose (0GLU) affected tetanic [Ca²⁺]_i prior to fatigue. The number of contracting unfatigued fibers versus stimulus strength relationship of Lo GLY-0GLU fibers was shifted to higher voltages compared to Hi GLY fibers exposed to 5.5 mM glucose (5GLU). The relationship for Lo GLY-0GLU fibers was shifted back toward that of Hi GLY-5GLU fibers when glucose was reintroduced, whereas the removal of glucose from Hi GLY-5GLU fibers had no effect. Fatigue was elicited with one 200 ms long tetanic contraction every s for 3 min. Both Lo GLY and 0GLU increased the rate at which intracellular tetanic concentration ([Ca²⁺]_i) declined and unstimulated [Ca²⁺]_i increased during fatigue in the order of the least fatigue resistant > mid fatigue resistant > the most fatigue resistant fibers.

This study comprehensively validated the bleomycin (BLEO) induced mouse model of IPF for utility in preclinical drug discovery. To this end, the model was rigorously evaluated for reproducible phenotype and TGFβ-directed treatment outcomes. Lung disease was profiled longitudinally in male C57BL6/JRJ mice receiving a single intratracheal instillation of BLEO (n = 10-12 per group). A TGFβR1/ALK5 inhibitor (ALK5i) was profiled in six independent studies in BLEO-IPF mice, randomized/stratified to treatment according to baseline body weight and non-invasive whole-body plethysmography. ALK5i (60 mg/kg/day) or vehicle (n = 10-16 per study) was administered orally for 21 days, starting 7 days after intratracheal BLEO installation. BLEO-IPF mice recapitulated functional, histological and biochemical hallmarks of IPF, including declining expiratory/inspiratory capacity and inflammatory and fibrotic lung injury accompanied by markedly elevated TGFβ levels in bronchoalveolar lavage fluid and lung tissue. Pulmonary transcriptome signatures of inflammation and fibrosis in BLEO-IPF mice were comparable to reported data in IPF patients. ALK5i promoted reproducible and robust therapeutic outcomes on lung functional, biochemical and histological endpoints in BLEO-IPF mice. The robust lung fibrotic disease phenotype, along with the consistent and reproducible lung protective effects of ALK5i treatment, makes the spirometry-confirmed BLEO-IPF mouse model highly applicable for profiling novel drug candidates for IPF.

Human salivary amylase secretion increases in response to stress; the activity has been reported to rise significantly with high-intensity exercise. The human salivary amylase gene (AMY1) has copy number variation, with the copy number correlating with salivary amylase activity. However, the relationship between individual AMY1 copy number and salivary amylase activity in response to exercise remains unclear. In this study, we investigated AMY1 copy number and fluctuations in amylase activity in 42 healthy university students (25 males and 17 females). Participants engaged in intermittent round-trip interval training on a basketball court. Saliva samples were collected pre- and post-exercise to measure amylase activity. DNA was extracted from the oral mucosa, and AMY1 copy number was quantified using RT-PCR. Results showed a significant increase in amylase activity postexercise. Additionally, amylase activity pre- and post-exercise was positively correlated with AMY1 copy number. The generalize linear model showed that the exercise-induced increase in amylase activity per AMY1 gene was negatively related to the AMY1 copy number and aerobic fitness. Gender has no effect on amylase activity. These results suggest a different mechanism for the constitutive and exercise-induced amylase secretion, while aerobic fitness may be independently involved in the secretion.