Comprehensive Physiology最新文献

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.

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.

Cancer-associated fibroblasts (CAFs) interact with tumor cells in the tumor microenvironment (TME), enhancing glycolysis in CAFs and tumor malignancy. However, the regulatory mechanisms between hepatoblastoma (HB) cells and CAFs are unclear. This study aimed to elucidate the crosstalk mechanism between HB cells and CAFs and identify a new therapeutic target for HB. Exosomes were successfully extracted from Huh-6/HepG2 cells, and hepatic stellate cells (LX2) were treated with conditioned medium or exosomes from these cells. We found that HB cells may stimulate the differentiation of LX2 cells into CAFs through exosomes and enhance histone lactylation. Additionally, HB cell exosome-derived fatty acid synthase (FASN) promoted the transformation of LX2 cells into CAFs and histone lactylation. Mechanistically, FASN affected the transformation of LX2 cells into CAFs and histone lactylation by regulating hexokinase 2 (HK2). FASN regulated HK2 stability by competitively combining with MARCHF1. Activated fibroblasts promoted HB progression by secreting CXCL1/CXCL5. In vivo experiments have demonstrated that HB cell exosome-derived FASN affected the transformation of LX2 cells into CAFs and histone lactylation. Clinical sample analysis revealed that FASN protein expression was significantly positively correlated with the levels of HK2, lactate, and H3K18la, thereby validating the clinical relevance of this regulatory pathway. In conclusion, HB-derived exosomal FASN affected the transformation of LX2 cells into CAFs by regulating the stability of HK2 and mediating histone lactylation, providing novel insights into the crosstalk between HB cells and CAFs and highlighting exosomal FASN as a potential therapeutic target for HB.

Hypobaric hypoxia, a defining feature of high-altitude environments, poses a considerable physiological challenge to both humans and rodents. To withstand hypoxic stress, mammals have developed cellular and systemic adaptations that not only safeguard against acute and future episodes of oxygen deprivation but may also enhance overall resilience and functional capacity. A central aim of current research is to harness these health-promoting effects of hypoxic exposure as a therapeutic strategy for a range of medical conditions. To date, much of the evidence regarding the safety and efficacy of such interventions derives from rodent studies. In this review, we summarize current knowledge on hypoxia tolerance, oxygen transport, and oxygen consumption in humans, rats, and mice, and evaluate the extent to which findings from rodent models can be extrapolated to humans. While the anatomical, physiological, and molecular foundations of oxygen transport and utilization are broadly conserved across species, there are important quantitative differences-largely linked to body-mass variation-as well as qualitative distinctions. Mice that evolved in high-altitude environments, display remarkable hypoxia tolerance. Their physiological repertoire includes highly efficient pulmonary gas exchange, metabolic downregulation, and substantial plasticity of the mitochondrial electron transport system under hypoxic conditions. In contrast, rats exhibit heightened vulnerability in hypoxia, manifesting as right ventricular hypertrophy, excessive erythropoiesis, and myocardial injury. These interspecies differences highlight that the robust hypoxia tolerance of mice-and the potentially comparatively greater susceptibility of rats than humans-must be carefully considered when translating findings from rodent hypoxia research into human contexts.

Semaglutide (SEMA), a GLP-1 receptor agonist, effectively reduces body weight. Yet its mechanisms of action remain incompletely understood. It is unclear whether SEMA promotes weight loss solely through reduced food intake or also through intake-independent mechanisms, and whether these effects differ by sex. To address these questions, we used a pair-feeding design in diet-induced obese rats, comparing SEMA-treated rats with both ad libitum-fed controls and SEMA intake-matched groups over 4-week treatment. Analyses included sex-stratified outcomes, depot-specific brown and white adipose profiling, thermogenesis, locomotor activity, and circulating metabolic hormone measurements. SEMA reduced food intake of both hypercaloric, high-fat/high-sugar diet and chow and produced body weight loss beyond the effects of caloric restriction alone. SEMA also curbed the hunger hormone ghrelin. It reduced visceral adiposity and increased activity, albeit more potently in females compared to males. Across adipose depots SEMA promoted smaller adipocyte size, white adipose tissue browning, and enhanced sympathetic innervation, while these changes were largely absent in pair-fed rats. SEMA rescued caloric restriction-associated hypothermia and small reductions in circulating thyroid hormones; it also potentiated local thyroid input. SEMA induced sex-dependent, depot-specific adipose remodeling and sustained increases in locomotor activity independent of food intake. Our integrative approach provides new insight into SEMA's mechanisms and highlights the importance of evaluating sex as a biological variable in mechanistic studies of obesity therapies. Metabolic benefits of the SEMA treatment far outweighed those offered by comparable caloric restriction, indicating that its mechanism of action involves not only hypophagia but also adipose tissue remodeling and browning.

The kidneys and lungs are frequent sites of organ injury during critical illness. Acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS) are clinical syndromes resulting from kidney and lung injury respectively. Complex pathophysiologic mechanisms underlie the development of these two syndromes individually, and a substantial body of evidence now indicates that crosstalk between the lungs and the kidneys occurs after organ injury. Here we review the pathophysiology of AKI and ARDS, animal models of kidney and lung injury, and mechanisms of organ crosstalk after injury has occurred. We focus the discussion on how either kidney injury or lung injury may propagate damage in the other organ, which is relevant to multiorgan injury commonly encountered in the intensive care unit. The reviewed literature contains more mechanistic preclinical studies of lung injury after AKI compared with AKI after lung injury. Identified mechanisms of lung injury after AKI include leukocyte recruitment, inflammatory signaling, activation of pattern recognition receptors, formation of neutrophil extracellular traps, osteopontin signaling, metabolic dysfunction, and impaired alveolar fluid clearance. After lung injury, AKI is instigated by inflammatory signaling, the effects of mechanical ventilation, and consequences of fluid management.

Population aging poses a significant threat to quality of life and contributes to an increasing medical burden. The concept of healthy aging has emerged to represent an aging process that is relatively well controlled. However, due to the multifaceted hallmarks and complex mechanisms underlying aging, there is a need for novel therapeutic targets to promote healthy aging comprehensively. As a fundamental hormone regulating nutrient anabolism and cell proliferation, insulin plays a central role in the aging process. Insulin resistance (IR), which triggers compensatory insulin secretion, along with β-cell dysfunction and impaired insulin clearance, is an established aging phenotype. These alterations of insulin synergistically contribute to the decline in insulin level and sensitivity during aging, making hyperglycemia a prominent risk factor for healthy aging. The decline of insulin signaling with age is associated with pro-aging effects, particularly by promoting dysregulated nutrient sensing and cellular senescence. Current hypoglycemic agents necessitate careful consideration of their potential pro-aging effects due to the overactivation of insulin signaling. Thus, a critical challenge for targeted interventions is to preserve the hypoglycemic benefits of insulin signaling while mitigating its downstream pro-aging effects. Herein, we analyzed current evidence on the complex changes in insulin synthesis, function, and clearance during aging, concentrating on the roles of insulin in hepatocytes, skeletal muscle cells, and adipocytes in the aging process. Additionally, current anti-aging interventions and their mechanisms were discussed from the perspective of regulating insulin signaling, aiming to provide new strategies and pharmacological targets for promoting healthy aging.

Acute kidney injury (AKI) and acute lung injury (ALI) are common in critically ill neonates, children, and those with severe cardiac disease. Although kidney and lung dysfunction can occur independently, molecular signaling and organ crosstalk significantly influence the function of each organ. Additionally, there is a link between AKI and fluid balance disorders. A bidirectional and synergistic relationship exists between AKI and fluid imbalance, with fluid management potentially becoming compromised before or after AKI. Fluid accumulation can further worsen ALI by impairing gas exchange. Organ crosstalk involves both pro-inflammatory and anti-inflammatory cytokines, as well as other modulating factors. Both AKI and ALI have harmful effects in pediatric patients, and AKI can lead to long-term consequences, especially in premature neonates, who are at much higher risk for bronchopulmonary dysplasia and chronic lung disease following AKI. Unfortunately, supportive treatments for ALI, such as positive pressure ventilation, can increase right ventricular afterload and central venous pressure, which may worsen renal perfusion, creating a cycle of ongoing multiple organ dysfunction. Pediatric research has provided insights into potential treatment strategies for preventing ALI, even without AKI. Prophylactic peritoneal dialysis may help remove pro-inflammatory cytokines that contribute to AKI and ALI in children undergoing cardiac surgery. Future studies are necessary to explore interventions that can prevent or reduce the harmful effects of kidney and lung injuries in critically ill children.

Alzheimer's disease (AD), a leading cause of dementia in the elderly, is traditionally characterized by neurodegeneration driven by amyloid-beta plaques and tau tangles. However, emerging evidence reveals that AD's impact extends beyond the brain, significantly affecting skeletal health. This review integrates clinical and transgenic mouse model data to elucidate the mechanistic interplay between AD pathology and bone metabolism. AD patients exhibit increased risk for hip fractures and low bone mineral density (BMD), independent of cognitive impairment severity. We found altered calcium and alkaline phosphate levels in the blood of patients with mild cognitive impairment and AD, as assessed from the Alzheimer's Disease Neuroimaging Initiative data. Convergent risk factors-age, sex, APOE4 genotype, smoking, and vitamin D deficiency-contribute to both neurodegeneration and bone fragility. Key molecular pathways, such as Wnt/β-catenin signaling and TREM2-mediated osteoclast regulation, underscore shared mechanisms driving disease pathology in both systems. Mouse models of AD consistently demonstrate disrupted bone remodeling, impaired osteoblast function, and heightened osteoclast activity. Therapeutic strategies targeting overlapping pathways, including lithium, anti-FSH antibodies, and NF-κB inhibitors, show promise in mitigating both cognitive decline and bone loss. Collectively, these insights advocate for a more integrated view of AD that includes skeletal comorbidities, potentially guiding the development of dual-purpose interventions.