Comprehensive Physiology最新文献

Low but biologically relevant levels of bile acids are found in the brain and are altered in patients with Alzheimer's disease (AD). However, the regulation of brain bile acid levels and what drives brain bile acid dynamics are poorly understood. Bile acids are synthesized in the liver and further metabolized by bacteria in the gut. Therefore, bile acids are mediators of the liver-brain axis and the gut-brain axis. Additionally, whether the bile acid profile differs between brain regions and whether the brain region-specific bile acid profile is impacted by disease, such as AD, is unknown. Therefore, we tested the hypothesis that the brain bile acid profile is influenced by peripheral bile acid metabolism, differs between brain regions, and that these dynamics change in AD. To this end, we assessed the bile acid profile in the cortex and hippocampus of wild-type mice maintained on different diets. To test the effect of AD, we used the TgF344-AD rat model. We found that the brain bile acid profile in mice was mildly altered by diet and, in both mice and rats, differs substantially between brain regions. For example, cholic acid and taurocholic acid are enriched in the cortex relative to the hippocampus in both mice and rats. Further, using a rat model of AD, we found that brain region differences in bile acid profiles are attenuated in AD. Together, these data demonstrate that both peripheral and central regulatory mechanisms maintain bile acid homeostasis in specific brain regions and that these homeostatic mechanisms are disrupted in AD.

There is scientific evidence that supports the association between aerobic exercise capacity and the risk of developing complex metabolic diseases. The factors that determine aerobic capacity can be categorized into two groups: intrinsic and extrinsic components. While exercise capacity is influenced by both the intrinsic fitness levels of an organism and the extrinsic factors that emerge during training, physiological adaptations to exercise training can differ significantly among individuals. The interplay between intrinsic and acquired exercise capacities represents an obstacle to recognizing the exact mechanisms connecting aerobic exercise capacity and human health. Despite robust clinical associations between disease and a sedentary state or condition, the precise causative links between aerobic exercise capacity and disease susceptibility are yet to be fully uncovered. To provide clues into the intricacies of poor aerobic metabolism in an exercise-resistant phenotype, over two decades ago a novel rat model system was developed through two-way artificial selection and raised the question of whether large genetic differences in training responsiveness would bring about aberrant systemic disorders and closely regulate the risk factors in health and diseases. Genetically heterogeneous outbred (N/NIH) rats were used as a founder population to develop contrasting animal models of high versus low intrinsic running capacity (HCR vs. LCR) and high versus low responsiveness to endurance training (HRT vs. LRT). The underlying hypothesis was that variation in capacity for energy transfer is the central mechanistic determinant of the divide between complex disease and health. The use of the outbred, genetically heterogeneous rat models for exercise capacity aims to capture the genetic complexity of complex diseases and mimic the diversity of exercise traits among humans. Accumulating evidence indicates that epigenetic markers may facilitate the transmission of effects from exercise and diet to subsequent generations, implying that both exercise and diet have transgenerational effects on health and fitness. The process of selective breeding based on the acquired change in maximal running distance achieved during a treadmill-running tests before and after 8 weeks of training generated rat models of high response to training (HRT) and low response to training (LRT). In an untrained state, both LRT and HRT rats exhibit comparable levels of exercise capacity and show no major differences in cardiorespiratory fitness (maximal oxygen consumption, VO_2max). However, after training, the HRT rats demonstrate significant improvements in running distance, VO_2max, as well as other classic markers of cardiorespiratory fitness. The LRT rats, on the other hand, show no gain in running distance or VO_2max upon completing the same training regime. The purpose of this article is to provide an overview of studies using LRT and HRT model

Background: Parkinson's disease (PD) manifestations involve respiratory dysfunction and motor disability. Previous research on PD has mainly focused on central dopamine (DA) deficits and their effect on ventilation.

Objectives: The purpose of the study was to analyze the function of carotid bodies (CB), sensors of blood O₂, by studying the hypoxic ventilatory response (HVR) and measuring biogenic amine content in the CB of a 6-hydroxydopamine (6-OHDA) induced PD model. We also investigated the effects of supplementation with the DA biosynthesis precursor L-DOPA on HVR and central DA depletion on hypoxic phrenic (PHR) and hypoglossal (HG) nerve activity.

Methods: After 6-OHDA intrastriatal injection, awake Wistar rats were tested in a plethysmographic chamber to study the HVR (8% O₂) before and after L-DOPA treatment. Registration of PHR and HG under acute hypoxia (8% O₂) was performed in anesthetized rats.

Results: The 6-OHDA rats showed reduced normoxic ventilation and HVR, eliminated by L-DOPA treatment. Increased HG activity during hypoxia in the form of increased amplitude and pre-inspiratory amplitude was observed. In addition to decreased striatal levels of DA, serotonin (5-HT) and noradrenaline (NA), reduced NA (42%) and 5-HT (52%) were found in CB of 6-OHDA rats. The open-field test showed a decrease in motor activity 2 weeks after the lesion.

Conclusions: Our results showed NA and 5-HT deficits in CB in the PD model, which may be responsible for impaired HVR. L-DOPA treatment, replenishing DA deficiency in the striatum, stimulated HVR. Increased pre-inspiratory HG activity indicates modifications to the central mechanisms controlling their activity.

Aim: Intermittent fasting or exercise could be used as an adjunct to regulating abnormal glucose metabolism. However, the mechanism of action of intermittent fasting and exercise to regulate normal glucose metabolism is still unclear. We want to investigate the regulatory effect and mechanism of action of intermittent fasting combined with exercise on glucose metabolism in normal mice.

Methods: All mice were randomized into six groups of 12 animals each. The effects of 6-week alternate-day fasting (ADF) or time-restricted fasting (TRF) combined with running exercise on blood glucose regulation in normal C57BL/6 male mice were evaluated. The expressions of the proteins involved, AMPK, SIRT1, BDNF, MAPK, and Nrf2 signaling pathways, were detected by western blot.

Results: Running exercise could increase muscle glycogen content in mice, and both types of fasting combined with running exercise could decrease glycated serum protein and hepatic glycogen content. Furthermore, we found that fasting and exercise up-regulated the expressions of AMPK, PGC-1α, Glut-4, SIRT1, and PPAR-γ protein, and down-regulated the expression of FoxO1 protein, modulating the ability of the liver and skeletal muscle to uptake glucose and convert glucose-lipid metabolism. Meanwhile, fasting and running exercise increase hippocampal BDNF, activating the MAPK and Nrf2/HO-1 pathways to enhance antioxidant capacity. The regulatory effect of TRF on the above proteins was significantly greater than ADF.

Conclusion: TRF was more effective than ADF in regulating glucose metabolism. Taken together, the regulatory effect of fasting combined with exercise on glucose metabolism was better than the effect of mono-fasting.

Acute lung injury can be a devastating ailment leading to death in patients of all ages. In preterm neonates, lung injury is unique and unlike what is seen in pediatric and adult populations. The physiology behind the acute lung injury endured in developing lungs and the chronicity of harmful stimuli vastly distinguish how bronchopulmonary dysplasia (BPD), the most common complication of prematurity, settles in as a chronic lung disease with lifetime sequelae. Despite being recognized for over 50 years, BPD continues to puzzle the world of neonatology with a shifting phenotype that parallels improvement in neonatal care. The improved understanding of BPD's far-reaching and long-term consequences on the lung and other organs highlights the need to find effective interventions, making it a priority of neonatal research. In this review, we provide an overview of BPD and its associated consequences. Then, we examine the biological premises for mesenchymal stromal cells as a promising therapy, reviewing current translational efforts, challenges, and future directions toward bringing mesenchymal stromal cell therapy to BPD patients.

Placental dysfunction is implicated in the pathogenesis of multiple pregnancy complications. Mitochondria are the powerhouse of the cell and are critical for placental metabolism and function. Several pregnancy complications are associated with oxidative stress and mitochondrial alterations. Mitochondrial function is also essential for epigenetic modifications, which are pivotal in regulating gene expression during pregnancy. Extracellular vesicles (EVs) carry and transfer a variety of biological molecules, including intact mitochondria and mitochondrial components, and act as modifiers of epigenetics in recipient cells. Changes in the EV profile may serve as biomarkers for pregnancy complications. In the present review, we summarize the associations of mitochondrial dysfunction, epigenetic alterations, and changes in EVs that are associated with pregnancy complications. We also describe the link between mitochondria and epigenetics, mitochondria in EVs, and EVs in epigenetic modifications, which provide insight into the possible implications of crosstalk among mitochondria, epigenetics, and EVs in regulating placental function and adverse pregnancy outcomes.

Adipose tissue serves not only as a storage organ but also plays an active role in maintaining the body's homeostasis as an endocrine component. Mainly made up of adipocytes that store energy as triglyceride droplets, this tissue also contains fibroblasts, immune cells, neuronal cells, and endothelial cells. Collectively, these non-adipocyte cells are known as the stromal vascular fraction. Evidence suggests that both the quantity and quality of adipose tissue are crucial in regulating vascular physiology by influencing lipid metabolism and secreting important signaling molecules called adipokines. This review aims to systematically explore the complex effects of adipose tissue on vascular regulation with a particular focus on two well-characterized adipokines-leptin and adiponectin-whose receptors are abundantly expressed in the vasculature. We further aim to provide an overview of both classical and recent research to emphasize the significance of the interplay between adipose tissue and vascular biology.

Emerging evidence highlights the pivotal role of gut microbiota in regulating cardiovascular health and disease. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, interacts with its host through metabolites, immune modulation, and systemic signaling pathways, collectively shaping cardiovascular physiology. Dysbiosis, or an imbalance in gut microbial composition, has been linked to various cardiovascular diseases (CVDs), including hypertension, heart failure and atherosclerosis. Key microbial metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO) and lipopolysaccharides (LPS) have been implicated in mechanisms involving endothelial, cardiac fibroblast, cardiomyocyte dysfunction, systemic inflammation, and metabolic dysregulation. This review explores the dynamic interplay between the gut and the heart, focusing on: gut microbiota composition and its alterations in CVD; microbial-derived metabolites and their mechanistic roles in cardiovascular pathophysiology; pathways linking gut dysbiosis to endothelial, cardiac fibroblast and cardiomyocyte dysfunction, inflammation, and immune responses; and therapeutic opportunities targeting the gut-heart axis, including dietary interventions, prebiotics, probiotics and emerging microbiota-based strategies. By unraveling these intricate relationships, we aim to provide a comprehensive understanding of how gut microbiota shape CVD pathophysiology and discuss potential avenues for novel therapeutics in precision medicine.

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.