Comprehensive Physiology最新文献

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.

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.

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.

Endothelial cells (ECs) are functionally heterogeneous, even in vascular beds within the same organ. As the key cell type lining the vascular lumen, ECs regulate vascular tone (control of blood vessel diameter), permeability of molecules, water, and ions across the vascular wall, vessel composition through cell-cell contacts, regulation of tissue redox status, and cytokine signaling. ECs are also influenced by mechanical stimuli such as blood flow. Many of these features can be analyzed in multi-cellular in vitro models that provide a controlled setting to investigate EC biology. Endothelial dysfunction (ED) has emerged as a central pathophysiological mechanism connecting different underlying cardiovascular diseases. Given that ECs are functionally heterogeneous, developing novel therapeutical approaches that target EC subtypes in specific tissues is anticipated to provide new diagnostic markers and therapeutic approaches for organ-specific treatment of cardiovascular disease.

Complement factor D (CFD, also known as adipsin) is a secreted serine protease classically known for activating the alternative complement pathway and regulating systemic metabolism. Although CFD is highly expressed in adipocytes, its roles in adipogenesis remain to be elucidated. Here, we show that intracellularly localized CFD promoted lipid droplet (LD) formation in its catalytic activity-independent manner. Using mammary adipose tissue-derived stem cells (mADSCs) isolated from wild-type (WT) and Cfd-knockout (Cfd-KO) mice, we demonstrated that the lack of CFD significantly reduced LD number in mature adipocytes. Lentiviral expression of the secretion signal sequence-deficient (SD) or catalytically inactive CFD mutant, as well as the cytosolic CFD3 splice variant, rescued LD formation to WT levels in Cfd-KO adipocytes. In contrast, exogenously supplemented CFD proteins were unable to restore LD formation in our culture system. These findings uncover a previously unrecognized intracellular function for CFD, revealing its regulatory role in LD biogenesis during adipocyte differentiation.