Comprehensive Physiology最新文献

The integrative influence of heat acclimation (HA) protocol characteristics and approach on adaptation kinetics and exercise capacity/performance in the heat remains unclear. Bayesian multilevel regression models were used to estimate adaptations with the number of exposures, exposure duration, ambient temperature, water vapor pressure, and HA approach (e.g., constant workrate) as predictors. Data from 211 papers were included in meta-analyses with results presented as posterior means and 90% credible intervals. Mean protocol characteristics were as follows: 8 ± 4 exposures, 90 ± 36 min/exposure, 39.1°C ± 4.8°C, and 2.78 ± 0.83 kPa. HA decreased resting (-5 beats·min^-1 [-7, -3]) and end-exercise heart rate (-17 beats·min^-1 [-19, -14]), resting (-0.19°C [-0.23, -0.14]) and end-exercise core temperature (-0.43°C [-0.48, -0.36]), and expanded plasma volume (5.6% [3.8, 7.0]). HA also lowered exercise metabolic rate (-87 mL·min^-1 [-126, -49]), increased whole-body sweat rate (WBSR) (163 mL·h^-1 [94, 226]), time to exhaustion (49% [35, 61]) and incremental exercise time (14% [7, 24]), and improved time trial performance (3.1% [1.8, 4.5]). An additional HA exposure increased hemoglobin mass (1.9 g [0.6, 3.2]) and WBSR (9 mL·h^-1 [1, 17]), and an additional 15 min/exposure further lowered end-exercise core temperature (-0.04°C [-0.05, -0.03]) and expanded plasma volume (0.4% [0.1, 0.7]). A 5°C increase in ambient temperature further lowered end-exercise HR (-2 beats·min^-1 [-3, -1]) and a 1 kPa increase enhanced WBSR (37 mL·h^-1 [4, 72]). End-exercise heart rate and core temperature decreased similarly following controlled hyperthermia (-16 beats·min^-1 [-18, -14]; -0.43°C [-0.48, -0.36]) and constant workrate HA (-17 beats·min^-1 [-18, -16]; -0.45°C [-0.49, -0.42]). HA protocol characteristics influence the adaptive response and may be manipulated to optimize adaptations. A predictor for estimating HA adaptations based on protocol characteristics is available at: https://www.canberra.edu.au/research/centres/uc-rise/research/environmental-physiology/exercise-heat-acclimation-predictor.

Leukotrienes are potent inflammatory lipid mediators produced primarily by immune cells. Inflammation, being the center stone of two major disease conditions, namely, asthma and inflammatory bowel disease (IBD), has led researchers to study the role of leukotrienes (LTs) in both these disease settings extensively. Several studies indicate a crucial role for LTs in the development and progression of IBD, whereas LTs, especially cysteinyl leukotrienes (cys-LTs), have been identified as the major contributors to asthma initiation and progression for over three decades. Additionally, the lungs and the gut share several common characteristics, including their exposure to the external environment, similar microbiome composition, and inflammatory responses. These similarities suggest a bidirectional relationship, supported by the increased risk of IBD in asthma patients and vice versa. However, the specific role of LTs in this lung-gut connection remains unclear. This review will examine how several common factors, such as physiology, microbiome, environment, and inflammatory mediators, especially LTs, modulate this crosstalk. The review also highlights in detail how altered leukotriene biosynthesis and signaling contribute to the pathogenesis of both asthma and IBD. Furthermore, we will consider the therapeutic implications of targeting leukotriene pathways for patients with concurrent asthma and IBD in the hope of developing more efficient treatment outcomes for these interconnected conditions. Finally, this review will very briefly explore the involvement of neuronal connections in mediating the lung-gut crosstalk.

Pulmonary fibrosis is a complex pathophysiological process characterized by local pulmonary inflammation and fibrosis, along with systemic inflammation and distal organ damage. The acidic environment of lysosomes, as intracellular degradation and recycling centers, is important for cellular homeostasis and function. This review summarizes the potential role of lysosomal acidification in pulmonary fibrosis pathogenesis and its implications for cross-organ effects. Various proteins and ion channels, such as V-ATPase, ClC-7, CFTR, TRPML1, and NHE, regulate lysosomal acidification. Lung fibrosis involves many cells, including lung epithelial cells, endothelial cells, macrophages, fibroblasts, and myofibroblasts. Studies have shown that abnormal lysosomal acidification significantly contributes to the onset and progression of pulmonary fibrosis. Damaged epithelial cells activate inflammatory and fibrotic signals through lysosomal dysfunction; abnormal lysosomal acidification in endothelial cells causes tissue edema and inflammatory responses; macrophages exacerbate inflammatory responses due to impaired lysosomal acidification; and fibroblasts hyperproliferate and transform into myofibroblasts due to deficient lysosomal acidification. Chronic pulmonary inflammation increases blood-gas barrier permeability, facilitating extravasation of inflammatory mediators (e.g., IL-6, TNF-α, and TGF-β) into the circulation, where they act as endocrine signals affecting distant organs. These findings provide a rationale for exploring novel therapeutic targets; future pharmacologic modulation of lysosomal acidification and inhibition of key inflammatory mediators may represent important strategies for preventing and treating pulmonary fibrosis and its systemic complications.

Long Covid is a post-viral syndrome characterized by persistent symptoms targeting multiple organ systems after initial SARS-CoV-2 infection. Current literature suggests that the mechanisms causing Long Covid involve viral persistence, immune dysregulation, systemic inflammation, endothelial dysfunction, and metabolic disturbances. By forming reservoirs in the tissues of various organs, SARS-CoV-2 may evade immunological clearances while triggering immune responses and contributing to chronic symptoms through cytokine imbalances, T-cell exhaustion, and systemic inflammation. These symptoms parallel other post-viral syndromes such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), suggesting similar mechanisms of pathology. The coronavirus has also been linked to neuroinflammation and endothelial dysfunction causing cognitive symptoms and cardiovascular complications. Furthermore, its ability to lower energy production links it to post-exertion malaise (PEM) and muscle pain. These symptoms may result from iron dysregulation and persistent oxidative stress due to Covid-impaired mitochondrial function. This review synthesizes current data on the mechanisms that drive Long Covid pathogenesis and explores potential therapeutic strategies to mitigate viral persistence, immune dysfunction, and metabolic disturbances. It is critical to understand these interactions to develop targeted interventions that address the long-term sequelae of SARS-CoV-2 infection and improve patient outcomes.

The maternal nutritional and/or metabolic environment is crucial for future offspring health outcomes, and impairments during critical periods of development can alter the development of brain circuits that regulate energy balance, predisposing individuals to metabolic disorders throughout life. Epigenetic changes, changes in cell number and/or organ structure, and cellular metabolic differentiation could be some of the fetal adaptations leading to the development of metabolic disorders later in life. Here, we review animal models showing that the nutritional environment to which the offspring are exposed during their perinatal life can influence the development of the hypothalamic melanocortin system, promoting increased feeding and fat deposition. Following maternal undernutrition, the development of obesity in the offspring may be related to decreased POMC neuronal function since birth. Similarly, maternal diabetes and obesity also induce hypothalamic changes that result in an imbalance in AgRP/NPY and POMC expression during adulthood. Widespread impairments in brain development may also induce a global downregulation of the melanocortin system. Furthermore, animal models highlight that the time and type of exposure are key to the offspring outcomes, as are their sex and age. Possible sex-specific differences remain unclear, as most studies have evaluated only the male offspring, despite females having an increased risk of developing obesity and gestational diabetes during their pregnancy, which imposes a transgenerational effect of metabolic disorders. Studies aiming at evaluating the long-term effects of the maternal nutritional environment in both males and females could help delineate how the susceptibility to metabolic disorders development worsens over time.

Epigenetic changes in gene expression due to DNA methylation regulate pulmonary vascular structure and function. Genetic or acquired alterations in DNA methylation/demethylation can promote the development of pulmonary arterial hypertension (PAH). Here, we performed epigenome-wide mapping of DNA methylation in whole blood from 10 healthy people and 19 age/sex-matched PAH patients from the PAH Biobank. Exome sequencing confirmed the absence of known mutations in PAH-associated gene variants identifying subjects with or without mutations of TET2, a putative PAH gene encoding the demethylating enzyme, TET2. DNA of patients with PAH and no TET2 mutation was hypermethylated compared to healthy controls. Patients with PAH and a TET2 mutation had greater DNA CpG methylation than mutation-free PAH patients. Unique Differentially Methylated Regions (DMR) were more common in patients with PAH with TET2 mutations (1164) than in PAH without mutations (262). We correlated methylome findings with a public PAH transcriptomic RNA dataset, prioritizing targets that are both hypermethylated in our cohort and downregulated at the RNA level. Relative to controls, functional analysis reveals enriched functions related to T cell differentiation in PAH patients with a TET2 mutation. We identified genes with downregulated expression that were hypermethylated in PAH patients (with or without a TET2 mutation). In both cases, a conserved T cell phenotype emerged. Pan-chromosomal hypermethylation in PAH is greatest in patients with TET2 mutations. Observed hypermethylation of genes involved in the pathogenesis of PAH, such as EIF2AK4, and transcription factors that regulate T cell development, such as TCF7, merit further study and may contribute to the inflammation in PAH.

Atherosclerosis is a lipid disorder where modified lipids (especially oxidized LDL) induce macrophage foam cell formation in the aorta. Its pathogenesis involves a continuum of persistent inflammation accompanied by dysregulated anti-inflammatory responses. Changes in the immune cell status due to differences in the lesional microenvironment are crucial in terms of plaque development, its progression, and plaque rupture. Ly6C^hi monocytes generated through both medullary and extramedullary cascades act as one of the major sources of plaque macrophages and thereby foam cells. Both monocytes and monocyte-derived macrophages also participate in pathological events in atherosclerosis-associated multiple organ systems through inter-organ communications. For years, macrophage phenotypes M1 and M2 have been shown to perpetuate inflammatory and resolution responses; nevertheless, such a dualistic classification is too simplistic and contains severe drawbacks. As the lesion microenvironment is enriched with multiple mediators that possess the ability to activate macrophages to diverse phenotypes, it is obvious that such cells should demonstrate substantial heterogeneity. Considerable research in this regard has indicated the presence of additional macrophage phenotypes that are exclusive to atherosclerotic plaques, namely Mox, M4, Mhem, and M(Hb) type. Furthermore, although the concept of macrophage clusters has come to the fore in recent years with the evolution of high-dimensional techniques, classifications based on such 'OMICS' approaches require extensive functional validation as well as metabolic phenotyping. Bearing this in mind, the current review provides an overview of the status of different macrophage populations and their role during atherosclerosis and also outlines possible therapeutic implications.

Emerging evidence has shown that gut-brain barrier dysfunction occurs at the early stages of ALS. Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA-approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h-SOD1^G93A, restores the gut-brain barrier function, and delays ALS progression. SOD1^G93A mice (9-10-week-old) were treated with Riluzole (10 mg/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6 weeks. The Riluzole/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate-only treatment. More reduction of h-SOD1^G93A aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate-only treatment. Tight junction proteins (ZO-1 and Claudin-5) significantly increased in the colon, spinal cord lumbar, and brain cortex of mice with Riluzole and sodium butyrate treatment. The Riluzole and sodium butyrate combination reduced serum lipopolysaccharides and h-SOD1^G93A aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate-only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate-only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut-brain axis for ALS.

Adipose tissue has varying distributions and metabolic properties between the sexes. Inherent sex-specific differences in adipocytes may heighten the risk of metabolic disease in males. Analysis of the adipocyte proteome can potentially provide important insight. To enable cell-type specific proteomic profiling in vivo, we genetically engineered a mouse line for cell-type specific production of a promiscuous biotin ligase (BirA*G3) facilitating the rapid isolation of biotinylated cell-type specific proteomes. Adipocyte-specific activation of cytoplasmic BirA*G3 led to robust biotinylation of adipocyte proteins across all major fat depots. Comparison of brown adipose tissue (BAT) and subcutaneous white adipose tissue (SAT) proteomes identified 229 brown adipose-enriched and 35 white adipose-enriched proteins. Regional comparison of white fat depots revealed additional differences across depots. Comparison of male and female depots identified sexually dimorphic adipose proteins: AHNAK predominating in the male and ACOT2 in the female. These findings validate the genetic model and highlight insights to be gained through targeted profiling of adipocytes. The genetic tool adds to existing approaches for in vivo proximity profiling of cell-type specific proteome programs.

The vagus nerve is the body's primary sensory conduit from gut to brain, traditionally viewed as a passive relay for satiety signals. However, emerging evidence reveals a far more complex system-one that actively encodes diverse aspects of meal-related information, from mechanical stretch to nutrient content, metabolic state, and even microbial metabolites. This review challenges the view of vagal afferent neurons (VANs) as simple meal-termination sensors and highlights their specialized subpopulations, diverse sensory modalities, and downstream brain circuits, which shape feeding behavior, metabolism, and cognition. We integrate recent advances from single-cell transcriptomics, neural circuit mapping, and functional imaging to examine how VANs contribute to gut-brain communication beyond satiety, including their roles in food reward and memory formation. By synthesizing the latest research and highlighting emerging directions for the field, this review provides a comprehensive update on vagal sensory pathways and their role as integrators of meal information.