Clinical science最新文献

There is a fundamental knowledge gap regarding the effects of neonatal hyperoxia exposure on the systemic vasculature and its repercussions on the cardiopulmonary system. Neonatal hyperoxia exposure induces a pro-inflammatory profile. However, the role of inflammation in the developing vascular tree and cardiopulmonary system is poorly understood. Caspase-1 mediates activation of inflammatory cytokines (IL-1β and IL-18) and gasdermin D (GSDMD), causing pyroptosis and inflammation. We hypothesized that caspase-1 is a critical contributor in neonatal hyperoxia-induced systemic vascular and cardiopulmonary inflammation and that caspase-1 inhibition attenuates hyperoxia-induced vascular stiffness, cardiopulmonary inflammation, and bronchopulmonary dysplasia (BPD) phenotype in a neonatal rat model. Newborn rats randomized to room air (RA) or hyperoxia (85% O2) from postnatal day (P) 1 to 14 received caspase-1 inhibitor, VX-765, or placebo. Hyperoxia-exposed pups had increased cardiovascular inflammation and fibrosis, aortic stiffness, pulmonary vascular rarefaction and remodeling, alveolar simplification, and right ventricular hypertrophy. Administration of a caspase-1 inhibitor decreased IL-1β and GSDMD gene and protein expression in the aorta and left ventricle. This was accompanied by reduced aortic stiffness and cardiac fibrosis, improved alveolar structure, pulmonary vascular density and vascular remodeling, and attenuation of right ventricular hypertrophy. Together, our findings suggest that inhibition of the caspase-1 pathway leads to decreased cardiopulmonary inflammation and remodeling. In conclusion, targeting caspase-1 signaling may be a therapeutic strategy to prevent the consequences of vascular and cardiopulmonary inflammation associated with preterm birth and oxygen therapy.

Acute kidney injury (AKI) is recognized as a critical clinical problem, and pharmacological therapeutic options for AKI remain limited. Our previous study confirmed that Rac GTPase-activating protein 1 (RacGAP1) effectively promoted the repair of tubular epithelial cells in vitro. Further investigation is needed to determine whether boosting the expression of RacGAP1 in vivo helps protect against AKI. Herein, lipid-coated calcium phosphate (LCP) nanoparticles loaded with RacGAP1 plasmids (pRacGAP1-LCP) were generated and subsequently characterized based on their size, zeta potential, and morphological features. Animal models of AKI induced by ischemia/reperfusion (I/R) injury (IRI) were established in C57BL/6 mice, and pRacGAP1-LCP was injected into the tail vein to explore the role of RacGAP1 on renal IRI in vivo. The therapeutic efficacy of pRacGAP1-LCP against IRI was assessed through western blotting, real-time PCR, and histological analyses. The effects of RacGAP1 on mitochondrial homeostasis were further examined in mouse renal tubular epithelial cells (mRTECs). Serial administrations of pRacGAP1-LCP led to a significant increase in RacGAP1 expression in murine kidneys. This therapeutic intervention effectively attenuated AKI, as evidenced by down-regulation of AKI biomarkers, amelioration of renal histopathological damage, and suppression of both apoptosis and inflammatory responses. Characteristic mitochondrial abnormalities, diminished ATP production, and excessive lipid droplet accumulation were observed in tubular cells of IRI mice. Notably, pRacGAP1-LCP treatment reversed these pathological alterations and up-regulated the expression of PGC-1α and CPT-1α, indicating that RacGAP1 exerted its reno-protective effects through enhanced mitochondrial biogenesis and fatty acid oxidation (FAO). To further investigate the role of RacGAP1 in mitochondrial homeostasis, we employed an ATP depletion-repletion (ATP D-R) model in mRTECs. Crucially, RacGAP1 effectively restored ATP production, mtDNA copy number, and oxygen consumption rate (OCR) in mRTECs after ATP D-R treatment. RacGAP1 overexpression also suppressed mitochondrial depolarization, fragmentation, and reactive oxygen species (ROS) generation. Conversely, RacGAP1 knockdown exacerbated mitochondrial defects in mRTECs exposed to ATP D-R. In summary, this study uncovers that RacGAP1 overexpression protects against renal injury and mitochondrial dysfunction, highlighting its therapeutic promise for AKI. The LCP nanoparticle exhibits potential as a precise and efficient delivery platform and presents a viable option for AKI therapy.

Some types of dietary fibre undergo fermentation by the gut microbiome, producing microbial metabolites called short-chain fatty acids (SCFAs) - these are protective against cardiovascular disease (CVD). Emerging evidence suggests that maternal fibre intake also protects the offspring. Here, we aimed to determine whether delivery of SCFAs during pregnancy results in sex- and cell-specific molecular changes to the offspring's heart. Female mice were subjected to high or low-fibre diets during pregnancy and lactation, while all offspring received a standard-fibre diet. We then studied the single-cell transcriptome (scRNA-seq, n = 16) and immune composition (fluorescence-activated cell sorting, n = 27) of the hearts and gut microbiome profiles (16S rRNA, n = 28) of six-week-old male and female offspring. Maternal fibre intake induced significant changes in the cardiac cellular and immunological landscapes, revealing sex-specific signatures at the single-cell level. High-fibre intake reduced the number of monocytes in the hearts of male offspring and the number of B cells in both female and male offspring. Cardiac fibroblasts in both male and female offspring of high-fibre intake dams showed an anti-fibrotic transcriptome. In contrast, only male offspring showed an anti-inflammatory transcriptome in macrophages and endothelial cells. Our findings suggest that high-fibre intake during pregnancy may induce a CVD-protective transcriptome (i.e., anti-fibrotic and anti-inflammatory), especially in male offspring. These findings underscore the relevance of maternal dietary choices during pregnancy influencing cardiovascular health outcomes in the offspring.

Periodontitis is a chronic inflammatory condition that gradually destroys the tissues supporting the teeth, including the gingiva, periodontal ligament, and alveolar bone. Emerging evidence suggests that psychological stress plays a significant role in the initiation and progression of periodontal disease, primarily through its impact on immune regulation. Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticotropin-releasing hormone (CRH) from the hypothalamus and, in turn, adrenocorticotropic hormone (ACTH) from the pituitary gland. Activation of the HPA axis and the sympathetic-adrenal-medullary (SAM) system during stress triggers the systemic release of cortisol, epinephrine, norepinephrine, and cytokines. The HPA, SAM, and cytokines interact in both direct and indirect ways. Not only does stress induce interleukin-10 (IL-10), but IL-10 also helps regulate the stress response and cortisol levels. IL-10 can stimulate the release of CRH and ACTH, while concurrently inhibiting cortisol secretion from the adrenal glands. IL-10 has drawn increasing attention within the oral cavity owing to its dual role in modulating immune responses and maintaining periodontal tissue homeostasis. This review outlines the current understanding of stress-related neuroendocrine pathways and their relevance to periodontal health. It explores the involvement of HPA axis effectors-cortisol and IL-10-in modulating the inflammatory milieu associated with periodontitis. This includes recent insights into IL-10-expressing regulatory B cells and the potential role of IL-10 in mitigating alveolar bone loss. By integrating recent advances in neuroendocrinology, immunology, and oral biology, this review clarifies how systemic stress responses contribute to local inflammatory changes in the periodontium. Understanding the mechanisms linking psychological stress, cortisol dynamics, and IL-10-mediated regulation may offer new opportunities for early diagnosis and intervention in stress-exacerbated periodontitis.

Our previous studies, as well as other investigations, demonstrated that non-neuronal acetylcholine (ACh) produced by cardiomyocytes-that is, the non-neuronal cardiac cholinergic system (NNCCS)-is indispensable for sustaining the physiological functions and structural integrity of cardiomyocytes and for protecting the heart from ischemic/hypoxic insults, hypertrophic stress, and hypersympathetic conditions. These findings were supported by pharmacologically manipulated models in non-neuronal ACh systems and by gain- or loss-of-function models in the NNCCS. Nevertheless, the mechanisms underlying this phenomenon (i.e., sustention and protection) and the target of the NNCCS in cardiomyocytes remain to be fully elucidated. Our conditional murine model with heart-specific deletion of the choline acetyltransferase (ChAT) gene in the heart (hChAT KO mice) revealed cardiac dysfunction associated with heart failure symptoms. The representative culprit targets were the mitochondria with a disorganized appearance and dysfunction, accompanied by a reduction in mitochondrial DNA, membrane potential, and ATP production. Alternatively, malfunctioning mitochondria impaired cardiac energy metabolism and nicotinic receptor-mediated calcium responses in the mitochondria and down-regulated the mitochondrial calcium uniporter (MCU), leading to poor calcium handling by the mitochondria. The impaired cardiac function in hChAT KO mice induced systemic inflammatory responses and attenuated blood-brain barrier function, further influencing higher brain functions, including the aggravation of depression-like phenomenon. These specifically characteristic phenotypes indicate that the NNCCS principally plays a crucial role in sustaining mitochondrial functions through nicotinic receptors in the mitochondria and that the signal is indispensable for maintaining mitochondrial functions and integrity.

Lecithin cholesterol acyltransferase (LCAT) plays a pivotal role in acyl-esterifying cholesterol intravascularly, but its function in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) has remained uncertain both in murine models and humans for decades, which is largely attributable to the distinct differences in cholesterol metabolism between mice and humans. Previously, we created a novel golden Syrian hamster model deficient in LCAT activity. Herein, we explored the influence of LCAT on the development of MASLD and MASH. A cross-sectional clinical study of LCAT activity and free cholesterol (FC) levels in healthy and MASLD patients was performed. LCAT knockout (LCAT KO) hamsters were used to explore the characteristics of cholesterol homeostasis and MASLD and MASH development. Lipidomics, mRNA-seq, and qPCR were employed to investigate the underlying mechanisms involved. MASLD patients displayed reduced LCAT activity, elevated FC levels, and ratio of FC/TC. Serum FC levels were positively correlated with triglyceride (TG), total cholesterol (TC), and apoB100 levels. In hamsters, LCAT deficiency resulted in increased FC levels and decreased high-density lipoprotein levels. Apolipoprotein profiles revealed increased ApoB100/48 and apoE but decreased apoAI. Increases in serum FC levels were primarily observed in LCAT-deficient hamster. Interestingly, LCAT KO hamsters presented mild TG species deposition in the liver even when fed a chow diet indicated by lipidomics. These increased TG species included TG (16:0/18:1/18:2), TG (16:0/18:1/18:3), and TG (16:0/16:1/18:1). On a high-fat and high-cholesterol diet, LCAT-deficient hamsters developed severe liver ballooning, inflammation, and fibrosis. Using HepG2 cells and primary hepatocytes confirmed that FC increased intracellular lipogenesis and promoted inflammatory response, which was reversed by a NLRP3 inhibitor. In summary, LCAT deficiency in hamsters promotes liver lipid deposition and MASH progression, thus highlighting the therapeutic role of LCAT in MASLD and MASH.

Obesity continues to be a major global health crisis, contributing to the rising prevalence of metabolic disorders such as type 2 diabetes, cardiovascular disease, and certain cancers. Central to the regulation of energy homeostasis is the adipocyte-derived hormone leptin, which serves as a key afferent signal to the central nervous system to suppress food intake, enhance energy expenditure, and maintain glucose balance. Since its discovery over three decades ago, a wealth of research has illuminated the molecular, cellular, and physiological mechanisms through which leptin exerts its metabolic effects. These foundational studies have delineated the neural circuits, particularly within the hypothalamus and brainstem, that integrate leptin signaling to co-ordinate complex metabolic responses. This review provides a comprehensive synthesis of the current understanding of leptin's metabolic actions, with an emphasis on the intracellular signaling cascades that mediate leptin receptor activation. We also highlight the diverse neuronal populations and brain regions that contribute to leptin's regulatory roles.

In the United States, the alarming increase in opioid use disorder diagnoses during pregnancy in the last decade has increased the incidence of neonatal opioid withdrawal syndrome (NOWS). Although 8 per 1,000 newborns are diagnosed with NOWS each year, the lack of prospective studies is a roadblock in the development of approaches to reduce adverse health outcomes in this vulnerable population. This study used a preclinical model to assess short- and long-term effects of preconceptional and gestational fentanyl (FEN) exposure on morphometrics, hormonal plasma profile, and sensitivity to opioid re-exposure in the offspring. Sprague Dawley female rats self-administered FEN citrate [fixed-ratio 1 (FR1), 2.5 μg/kg] or vehicle (NaCl 0.9%) during preconception and until gestational day 21. In utero fentanyl exposure (IUFE) did not influence neonatal weight and morphometrics; however, IUFE pups exhibited a higher frequency of behaviors indicative of somatic withdrawal compared with controls (CTLs). In male and female weanlings, IUFE induced the dysregulation of endogenous opioid peptides (EOPs) and increased metanephrine levels compared with CTL counterparts. However, only adult females with IUFE showed increased EOPs and metanephrine levels, FEN-induced hyperalgesia, and greater FEN-induced hypotensive and bradycardic effects compared with CTL counterparts. This preclinical model suggests a long-lasting association between IUFE-induced neuroendocrine dysregulation and adverse effects of opioid re-exposure in female offspring.

Exercise training (ET) is increasingly recognized as a beneficial non-pharmacological intervention for cardiovascular diseases. Our previous results demonstrated that the thoracic perivascular adipose tissue (tPVAT) of heart failure (HF) rats underwent a phenotypic shift from brown to white adipose tissue, accompanied by impaired anticontractile function and oxidative stress. Thus, the present study aimed to investigate the effects of combined aerobic and resistance ET on the vasoactive properties of tPVAT in a HF rat model following myocardial infarction (MI). Wistar rats were subjected to either coronary artery ligation or sham operation (SO). Four weeks after surgery, the rats were divided into four groups: untrained (u) and exercise-trained (t) SO or HF. An 8-week ET program significantly improved running distance and maximum load lifting in the SO and HF groups, ameliorating tPVAT dysfunction and inducing browning only in the HF group. Additionally, ET enhanced the nitric oxide bioavailability, restored oxidative stress and pro-inflammatory cytokine levels (interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and increased anti-inflammatory interleukin-10 levels in tPVAT. Furthermore, it increased noradrenaline (NE) content and β3-adrenoceptor (AR) gene expression in tPVAT, optimizing the NE/β3-AR/ adiponectin/AMP-activated protein kinase (AMPK)/endothelial nitric oxide synthase pathway locally. These findings highlight the potential of ET as a non-pharmacological approach to managing PVAT and vascular adjustments in HF.

The relaxin family functions as pleiotropic hormones with various antioxidant, angiogenic, anti-apoptotic, anti-hypertrophic, anti-inflammatory, antifibrotic, and vasodilatory effects. To fully appreciate the potential therapeutic applications of relaxins and the pathophysiological implications, it is important to understand their multifaceted roles. This comprehensive review of current literature aims to elucidate the role of relaxins in modulating the biology and function of blood cells. It places special emphasis on the signaling pathways of relaxin family peptide receptor 1 (RXFP1) and the glucocorticoid receptor (GR) activated by relaxin-2. Relaxin-2 influences circulating blood cell counts and exerts inhibitory effects on megakaryocytes, thrombocytes, and mast cells. It also possesses immunomodulatory characteristics that affect granulocytes and agranulocytes, particularly regarding their morphology, differentiation, and function. Relaxin-1 regulates dendritic cell maturation and cytokine secretion. RXFP1 could play significant roles in blood malignancies and preeclampsia. The broad spectrum of activities demonstrated by relaxins significantly influences blood cell biology and highlights their therapeutic potential in a range of conditions, including hematological, cardiovascular, renal, pregnancy-related, and fibrotic disorders.