Comprehensive Physiology最新文献

Previously, we showed that male mice subjected to Maternal Separation and Early Weaning (MSEW), a model of early life stress, exhibit heightened cardiovascular responses to hypertensive stimuli. This study aimed to determine whether MSEW increases blood pressure salt sensitivity. Male C57BL/6J mouse pups were separated daily from their dams for 4-8 h from postnatal Day 2-16. MSEW mice were weaned the following day, while control litters were normally reared and weaned at postnatal Day 21, after which all mice were placed on a low-fat, normal salt diet (LFNS, 10% kcal from fat, 0.4% NaCl) for 20 weeks. Subsequently, mice were randomized to either LFNS or a low-fat, high-salt diet (LFHS, 10% kcal from fat, 4.0% NaCl) for an additional 6 weeks. MSEW induced sympathetic overactivity in mice on the LFNS diet, evidenced by increased urinary NE excretion, reduced low-frequency heart rate variability, and downregulation of cardiac adrenergic receptors compared to control mice. Despite diminished cardiac parasympathetic activation compared to controls, MSEW mice showed enhanced water and electrolyte excretion in response to increased dietary sodium content during daytime hours. Taken together, MSEW increases the basal sympathetic tone and reduces the overall adaptability and responsiveness of the cardiovascular system to increases in dietary sodium content. This impaired autonomic regulation of blood pressure and heart rate variability may favor the development of cardiovascular dysfunction in settings of renal disease where the kidneys lack the capacity to compensate for the excess of sodium intake.

Background: The gut microbiome plays an important role in human health and disease. Kidney Precision Medicine Project (KPMP) is a well-phenotyped, kidney biopsy-proven cohort of AKI and CKD patients. Comprehensive profiling of gut microbiota can uncover novel mechanistic, diagnostic, and therapeutic strategies for CKD and AKI patients.

Methods: We performed metagenomic whole genome sequencing (mWGS; > 25 million reads) on KPMP stool samples. mWGS data of healthy controls from 4 published studies was used. Kraken2 and MetaPhlAn3 were used for taxonomic assignment, and HUMAnN3 for functional annotation.

Results: Kraken2 analysis showed significantly higher abundance of Ruminococcus bicirculans in CKD (6.47) compared to AKI (1.82) and healthy individuals (2.42; p = 0.01). Furthermore, the abundance of Gordonibacter pamelaeae increased in CKD (0.30) compared to AKI (0.07; p = 0.05) and healthy individuals (0.03). The percent mean abundance of genus Chryseobacterium was slightly higher in CKD (0.07) compared to AKI (0.05; p = 0.05) but reduced compared to healthy individuals (0.20; p < 0.001). MetaPhlAn3 identified alterations in Gordonibacter, Bacteroides, and Faecalibacterium with a significant increase in Clostridium asparagiforme in AKI (11.68) compared to CKD (0.03; p = 0.06) and healthy (0.01; p = 0.001) individuals. Roseburia hominis, Roseburia intestinalis, Dorea longicatena, and Gemmiger formicilis were significantly reduced in AKI compared to CKD and healthy individuals. LDA/HUMAnN3 analysis showed a significant correlation between several metabolites and bacterial species in this KPMP population.

Conclusion: Kidney biopsy-proven CKD and AKI patients show a distinct gut microbiota profile compared to healthy individuals. This high-quality dataset is a valuable resource for developing microbiome-based diagnostics and therapies for CKD and AKI.

An increasing body of evidence suggests that cellular senescence is a risk factor for the development of idiopathic pulmonary fibrosis (IPF). Cellular senescence is a permanent state by which cells cease to divide and adopt an irreversible cell cycle arrest, which is believed to contribute to aging and aging-related diseases. IPF is an age-related, chronic, progressive, and ultimately fatal interstitial lung disease of unknown etiology. IPF is characterized by repeated alveolar epithelial cell damage, fibroblast proliferation, excessive extracellular matrix (ECM) deposition, impaired gas exchange, and death. As an important transcription factor, p53 is critically involved in the regulation of senescence and fibrosis-related diseases. The mechanism of p53-mediated cellular senescence in IPF remains poorly understood, particularly regarding therapeutic strategies targeting p53. In this review, we summarize p53's structure, function, and signaling in senescence-driven IPF, and explore p53-targeted interventions for IPF. In conclusion, p53 may be a potential therapeutic target for senescence and IPF.

The pathophysiology of preeclampsia and HELLP syndrome relies on systemic vascular endothelial dysfunction, resulting from angiogenic imbalance due to abnormal uteroplacental vascular remodeling and placental ischemia/reperfusion. Recent studies demonstrated that HELLP syndrome falls within the spectrum of secondary microangiopathy due to abnormal complement activation. However, to date, the link between angiogenic imbalance, endothelial dysfunction, and complement activation remains unclear. Building upon current understanding of complement regulation, this paper proposes a novel pathophysiological approach, suggesting a new understanding of HELLP syndrome and preeclampsia, including the undebatable role of sFlt-1/PlGF and the knowledge of maternal systemic endothelial and renal diseases. We hypothesize that endothelial glycocalyx may be the missing link between angiogenic factors, inflammatory regulation, and endothelial maternal lesions. Targeting the glycocalyx-endothelium axis may enable novel therapeutic strategies that delay delivery and reduce maternal-neonatal morbidity in preeclampsia and HELLP syndrome.

The 'Cardiovascular-Kidney-Metabolic Syndrome' which is characterized by multi-organ dysfunction ultimately resulting in adverse cardiac outcomes, serves to highlight the importance of organ crosstalk in pathophysiology. The cellular metabolism of fructose, regulated by Ketohexokinase-C with associated inflammatory sequelae, is mechanistically linked with each component of this clinical entity. Fructose metabolism is confined to the Kidney, Liver, and Small Intestine under normal physiological conditions; however, in the context of ischaemia, HIF-1α induces cardiac expression of Ketohexokinase-C with consequent organ hypertrophy and dysfunction. This adverse effect of cardiac HIF-1α accumulation raises concerns over the potential pleiotropic effects of the 'HIF stabilizing' inhibitors of Prolyl Hydroxylase currently entering clinical practice for the treatment of anemia in Chronic Kidney Disease, particularly given the increased cardiovascular mortality observed in this patient group. We suggest that pleiotropic effects of 'HIF stabilization' on cardiac physiology warrant investigation and, furthermore, that pharmacological inhibition of Ketohexokinase-C, and therefore fructose metabolism, represents an opportunity to improve cardiac outcomes in the Cardiovascular-Kidney-Metabolic Syndrome.

The human microbiome is a unique organ and maintains host immunomodulation and nutrient metabolism. Structural and functional microbiome alterations are commonly known as dysbiosis, which is strongly associated with disease progression. Ferroptosis is a novel iron-dependent cell death mode characterized by intracellular iron accumulation, increased reactive oxygen species (ROS), and lipid peroxidation (LPO). Importantly, the complex crosstalk between the microbiome and ferroptosis in disease has attracted considerable research attention. The microbiome influences ferroptosis by regulating host iron homeostasis, mitochondrial metabolism, and LPO, among many other pathways. Thus, the in-depth analysis of microbiome-ferroptosis crosstalk and associated mechanisms could provide new strategies to treat human diseases. Therefore, understanding this crosstalk is critical. Here, we systematically explore the associations between gut microbiome and ferroptosis across multiple diseases. We show that the oral microbiome also influences disease progression by regulating ferroptosis. Furthermore, we provide a potential for certain disease therapies by targeting the crosstalk between the microbiome and ferroptosis.

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.