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: Inter-organ crosstalk, particularly between adipose tissue and vasculature, plays a key role in obesity-induced cardiovascular dysfunction. Our previous work showed that adipose-derived extracellular vesicles (adiposomes) from obese donors impair arteriolar vasodilation through endothelial dysfunction, but their impact on vascular smooth muscle cell (VSMC) function remains unclear.

Methods: Visceral adipose tissues were collected from 25 obese and 12 lean subjects undergoing bariatric and elective surgeries, and from high-fat diet-induced obesity (DIO) mice (n = 40). Adiposomes were isolated by ultracentrifugation, and arteriolar myogenic tone was assessed using pressure myography. Intracellular Ca²⁺, membrane potential, and reactive oxygen species (ROS) were measured in VSMCs.

Results: Obese arterioles exhibited greater myogenic tone than lean controls, a response also observed in healthy vessels exposed to obese adiposomes. Native VSMCs from obese subjects showed amplified acetylcholine-induced Ca²⁺ waves, a response also observed in cultured VSMCs exposed to adiposomes from obese humans or DIO mice. Membrane potential analysis showed that obese adiposomes impaired KATP channel function, attenuating pinacidil-induced hyperpolarization while enhancing glibenclamide-mediated depolarization. Obese adiposomes also elevated ROS levels in VSMCs, which were reduced by extracellular ROS scavenging, normalizing K_ATP channel function and Ca²⁺-influx, thereby ameliorating arterial hypercontractility in obese specimens. Furthermore, depleting ceramides in obese adiposomes diminished their ability to induce hypercontractility, highlighting ceramide as a key mediator of obesity-induced vascular dysfunction.

Conclusions: These findings underscore a pathogenic form of vascular-adipose crosstalk in obesity, where adiposome-mediated signaling alters VSMC excitability and vascular tone. Targeting this inter-organ communication axis may offer new strategies to reverse obesity-related vascular complications.

Biological sex profoundly impacts HIV acquisition, disease progression, and persistence. Beyond genetic differences, sex hormones such as estrogen play multifaceted roles in shaping immune responses to HIV. However, the precise effects of estrogen and other sex hormones on the various components of the immune system, and their implications for HIV progression and persistence, remain poorly understood. Addressing these gaps is essential for developing strategies to improve the management of chronic HIV, especially in post-menopausal cisgender women and transgender women. B cells are crucial for HIV control, primarily through the production of anti-HIV antibodies. Emerging evidence suggests that estrogen exerts significant, yet underappreciated, effects on B cell function. However, the interactions between estrogen and B cells during HIV remain poorly characterized. This review explores current insights into the estrogen-B cell axis, emphasizing its role in modulating immune responses critical to HIV. Specifically, it examines estrogen's effects on B cell activation, antibody production, and antibody functionality, all of which can influence HIV control and disease progression. We also highlight key research gaps, including the impact of differential estrogen levels on immune-mediated HIV control and the potential of estrogen modulators to enhance B cell-driven immunity during HIV.

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.