Comprehensive Physiology最新文献

Preeclampsia (PE) is a complex hypertensive disorder of pregnancy characterized by placental dysfunction, systemic inflammation, oxidative stress, and widespread maternal endothelial injury. Although multiple molecular pathways have been implicated in its pathogenesis, the regulatory mechanisms that integrate placental stress with vascular and immune maladaptation remain incompletely understood. Post-translational modifications (PTMs) have emerged as critical regulators of protein function, stability, localization, and signaling, positioning them as key molecular integrators of the pathological processes underlying PE. In this review, we synthesize current evidence linking PTM dysregulation to the major biological processes disrupted in PE, with a particular focus on SUMOylation, ubiquitination, S-nitrosylation, acetylation, and glycosylation. These modifications modulate trophoblast invasion, angiogenic balance, redox homeostasis, immune tolerance, and endothelial signaling across placental, and maternal vascular compartments. We highlight how hypoxia, inflammation, and metabolic stress converge to disrupt PTM-regulating enzyme systems, thereby amplifying placental dysfunction and maternal vascular injury. Emerging evidence supporting PTM crosstalk further underscores the existence of coordinated regulatory networks rather than isolated molecular events. Advances in proteomics, systems biology, and extracellular vesicle profiling have revealed PTM-enriched molecular signatures in maternal circulation that precede clinical disease onset, offering opportunities for early diagnosis and risk stratification. We critically address current limitations in the field, including the predominance of cross-sectional studies, challenges in cell type-specific and temporal resolution, and barriers to clinical implementation. This review positions PTMs as central molecular hubs linking placental stress to systemic vascular dysfunction and highlights their potential to inform future precision medicine approaches in PE.

Acute exposure to hypoxia affects the cardiovascular system, especially pulmonary circulation and right heart hemodynamics. However, the impact of normobaric hypoxia on the right heart chambers during exercise is still not clear. This study examined whether a single bout of high-intensity exercise to voluntary exhaustion under acute moderate normobaric hypoxia (~3000 m a.s.l.; FiO₂ = 14.4%) induces significant changes in right ventricular (RV) and right atrial (RA) dimensions or RV systolic function compared to normoxia in trained and untrained men. Twenty-four healthy males (12 trained cyclists, 12 untrained) completed randomized trials involving exhaustive exercise under normoxic and hypoxic conditions. Echocardiographic assessments were conducted at rest and post-exercise. While hypoxia was found to reduce total mechanical work, end-exercise heart rate and oxygen saturation in both groups, no differences were observed in the post-exercise RV response between normoxia and hypoxia. Only untrained men showed increased resting RV dimensions and fractional area change (FAC) in hypoxia. Both groups exhibited post-exercise declines in tricuspid annular plane systolic excursion (TAPSE), systolic tissue Doppler velocity (S' wave), and right atrial area (RAA), but no additive effect of hypoxia was observed. These results indicate that acute moderate normobaric hypoxia does not impose additional RV load during maximal exercise in healthy athletes and untrained men. Trial Registration: ClinicalTrials.gov: NCT06896773.

Despite advances in dietary and pharmacologic therapies, obesity rates continue to escalate globally. Emerging evidence implicates the gut-immune interface as a key determinant of metabolic dysfunction. This review highlights the prostaglandin E₂ (PGE₂) EP4 signaling axis as a pivotal mediator linking gut dysbiosis to systemic insulin resistance. In obesity, elevated COX-2-derived PGE₂ reprograms the gut microbiota, depleting short-chain fatty acid (SCFA)-producing taxa and reducing regulatory T cell (Treg) homeostasis. The ensuing loss of intestinal integrity promotes metabolic endotoxemia and chronic low-grade inflammation, culminating in insulin resistance. Targeting the PGE₂-EP4 microbiota Treg network through EP4 antagonists or microbiome restoration offers a promising therapeutic strategy to restore metabolic balance and prevent obesity associated complications.

Heat therapy is a historic modality that has been used as a source of lifestyle intervention and community for many different cultures. Over the last ~40 years, heat therapy has gained increasing popularity among scientists and clinicians as a potential therapeutic tool for aging and disease. Recently, several systematic reviews and meta-analyses have sought to encompass specific aspects investigated in the scientific literature surrounding this ancient therapeutic modality, with each review having a primary focus on one beneficial aspect of heat therapy. This review aimed to provide a more comprehensive review of the scientific literature on heat therapy. To accomplish this, we have included studies that demonstrate clear beneficial adaptations (and those that show no effect of heat therapy) on specific organs, crosstalk between different organs and tissues, and integrated physiological systems and pathways. Furthermore, we also discuss what forms of heat therapy confer beneficial adaptations and for which populations these benefits occur. Where possible, we identify specific signaling mechanisms through which heating a tissue or raising internal body temperature results in a multitude of beneficial adaptations. Lastly, this review also emphasizes those investigations that have shown little or no benefit of heat therapy. The overarching aim of this review was to provide scientists, clinicians, and the lay public with a current consensus on the benefits and limitations of heat therapy as a healthy lifestyle intervention for a variety of persons and health conditions.

Understanding communication between various organ systems is vital to understanding the pathophysiology of disease, and this assists in tailoring appropriate therapies. Pulmonary vein stenosis is an example of a multi-organ disease process that occurs in infancy and later throughout life. The organs involved may be at a distance from the heart and lungs or from within the thoracic cavity. In former preterm infants with bronchopulmonary dysplasia (BPD), this condition is associated with ongoing inflammation in other organ systems, including lung parenchyma as well as the gut. It is also associated with perturbation in blood flow due to intracardiac shunt lesions or external pressure from intrathoracic structures. In patients with congenital heart disease (CHD) associated with PVS at baseline or after surgery involving pulmonary veins, there may be a genetic component to the development of PVS as well as factors like flow and shear stress and other less understood instigators of tissue proliferation within the veins. Understanding these interactions has led to improved surveillance as well as the development of protocols for the evaluation of pulmonary veins in the setting of infection or inflammation of the other organs and in patients otherwise predisposed to developing PVS. This early surveillance has resulted in prompt diagnosis, targeted drug development tailored to the disease process, appropriate and timely intervention with improved outcomes.

The greater omentum, often described as a "plaster" of the abdominal cavity, exhibits remarkable regenerative and immunological properties. Its unique morphology-rich vasculature and a diverse cellular composition comprising adipocytes, endothelial cells, and leukocyte aggregates known as milky spots (MS)-facilitates immune surveillance, fluid uptake, and the secretion of neurotransmitters. Additionally, MS contribute to peritoneal immunity by capturing pathogens, promoting lymphocyte proliferation, and releasing cytokines and chemokines that recruit effector immune cells while limiting local inflammation. Structurally, this peritoneal extension shields visceral organs, prevents adhesions, and absorbs tumor secretions, yet paradoxically also provides a niche for metastatic spread. Moreover, the greater omentum is susceptible to various pathologies-vascular steal can deprive organs of blood, torsion and herniation threaten tissue viability, and ossification can transform the greater omentum into a rigid structure lacking protective properties. Notably, omentectomy has been associated with weakened antibacterial defense, underscoring its protective role. This review aims to explore the multifaceted nature of the greater omentum, emphasizing both its physiological benefits and the potential disadvantages associated with its alteration or removal.

Background: Chronic kidney disease and cognitive impairment are common in heart failure, but how changes in microcirculatory perfusion and oxygenation contribute to these complications remains unclear. We investigated how heart failure with mildly reduced ejection fraction (HFmrEF) affects renal and cerebral perfusion and oxygenation, renal blood flow (RBF), and renal function in adult female sheep (Ovis aries, Linnaeus 1758).

Methods: HFmrEF was induced in Merino ewes (n = 10) via progressive ligation of coronary artery branches. Sham-operated controls (n = 10) underwent thoracotomy without ligation. Three weeks later, fiber-optic probes were implanted in the renal cortex, renal medulla, and frontal cerebral cortex to measure tissue perfusion and oxygenation. Transit-time flow probes and vascular catheters enabled continuous assessment of systemic hemodynamics, left atrial pressure, and RBF. Bladder catheterization allowed urine output measurement, and plasma and urine samples were collected to calculate creatinine clearance. Systolic function was assessed by two-dimensional echocardiography.

Results: Animals with HFmrEF exhibited reduced left ventricular ejection fraction (50.6% ± 1.4% vs. 77.8% ± 0.9%; p < 0.0001), elevated left atrial pressure (7.5 ± 0.9 vs. 3.3 ± 0.8 mmHg; p = 0.003), and clinical signs of heart failure. Renal medullary oxygenation was significantly reduced (41.4 ± 4.3 vs. 54.7 ± 2.7 mmHg; p = 0.02), while renal cortical and cerebral oxygenation were preserved. Systemic hemodynamics, RBF, and creatinine clearance were similar between groups.

Conclusions: In this large mammalian model of HFmrEF, selective renal medullary hypoxia occurred despite preserved renal function and systemic hemodynamics. These findings underscore the vulnerability of the renal medulla and support the need for early markers and interventions targeting renal microcirculation in heart failure.

Objectives: This study aimed to identify metabolites and metabolic pathways associated with blood-brain barrier (BBB) dysfunction in human and animal metabolomic research.

Methods: PubMed, Scopus, Web of Science, and Embase were searched (last search: 24 November 2025) without date limits. Original studies applying metabolomic techniques (¹H-NMR, LC-MS, GC-MS) to CSF, serum, or plasma and reporting metabolites linked to BBB damage were included. Study selection, full-text assessment, and data extraction were performed independently by two reviewers, with disagreements resolved by a third. Risk of bias was evaluated using SYRCLE and ROBINS-I tools. Metabolites reported in ≥ 2 studies were mapped to metabolic pathways using MetaboAnalyst with hypergeometric testing and Holm-Bonferroni and FDR corrections.

Results: Of 12,182 records identified, eight studies (four human, four animal) met the inclusion criteria. Across these, 157 metabolites were identified, 25 of which were reported in more than one study. Frequently observed metabolites included glutamate, glutamine, alanine, choline, creatine, and branched-chain amino acids (valine, leucine, isoleucine). Pathway analysis revealed significant enrichment of alanine, aspartate and glutamate metabolism, nitrogen metabolism, and BCAA biosynthesis (FDR = 0.01). Glutamate and glutamine most consistently correlated with BBB dysfunction and neuroinflammatory processes. Substantial heterogeneity was observed, partly due to differences in analytical platforms, sample types, and reporting standards.

Conclusions: Metabolites and pathways related to glutamate, nitrogen metabolism, and BCAA may play key roles in BBB impairment. Metabolomics shows promise for identifying BBB biomarkers, but larger, methodologically standardized studies are required.

Trial registration: OSF identifier: dapu9.

Background: Pulmonary vascular disease (PVD) in patients with single ventricular heart disease following the partial cavalpulmonary connection (Glenn) is a significant source of morbidity. However, the etiology of pulmonary vascular endothelial cell (EC) dysfunction, an established precursor to PVD, is incompletely understood but may involve abnormal blood flow patterns, hypoxemia, and polycythemia.

Hypothesis: Utilizing an ovine Glenn model, we hypothesized that nonpulsatile pulmonary blood flow (PBF) induces pulmonary vascular EC dysfunction, independent of hypoxemia or polycythemia.

Methods: Seven lambs (6-8 weeks old) underwent a Glenn procedure. Eight weeks later, Glenn and age-matched controls were studied. The response to the endothelium-dependent vasodilator acetylcholine (Ach) was determined in isolated pulmonary arteries (PA). Nitric oxide (NO) and endothelin-1 (ET-1) signaling were determined in right lung tissues. Indices of cell proliferation, angiogenesis, and apoptosis were determined in PA endothelial cells (PAECs). Comparisons were made by unpaired t-test and ANOVA.

Results: There were no differences in age, hemoglobin, or oxygen saturation between groups. Mean PA pressure and left PA flow were higher, and right lung blood flow was lower in Glenn lambs compared to controls (p < 0.05). All other baseline hemodynamics were similar. Glenn PAs had impaired relaxation to Ach. Glenn lung NO metabolite levels (NOx) and eNOS protein were lower, and ET-1 levels and prepro-ET-1 protein were higher than controls (p < 0.05). Glenn PAECs had higher rates of proliferation and angiogenesis, and decreased apoptosis (p < 0.05).

Conclusions: The initiation of nonpulsatile PBF following the Glenn induces early EC dysfunction independent of hypoxemia and polycythemia.

Primary hepatocytes rapidly lose viability and function in conventional two-dimensional (2D) cultures due to the absence of a physiologically relevant extracellular matrix (ECM). The collagen sandwich method improves polarization and function but creates a diffusion barrier that limits nutrient and signal exchange. This study investigates whether daily supplementation of a diluted, non-gelling Geltrex layer can sustain hepatocyte function and viability in 2D culture, offering a practical alternative to the sandwich method. Primary rat hepatocytes were cultured for 15 days under four conditions: monolayer (ML), monolayer with Geltrex (ML + GT), sandwich (SW), and sandwich with Geltrex (SW + GT). Cell morphology, confluency, viability (CCK-8, live/dead staining), and functionality (urea synthesis, albumin production, CYP3A4 activity) were assessed. The ML group showed significant declines in confluency, viability, and functional markers over time. Geltrex supplementation preserved confluency (~97% at day 15), improved viability, and maintained higher albumin production and CYP3A4 activity compared to ML. Functional outputs in ML + GT were comparable to SW and SW + GT groups, without the diffusion limitations of the sandwich top gel. Daily supplementation with low-dose Geltrex creates a biochemically enriched, diffusion-permissive microenvironment that supports long-term viability and function of primary rat hepatocytes in 2D culture. This method represents a simple and effective alternative to traditional sandwich cultures for liver cell studies and drug testing applications.