Clinical science最新文献

Background: Schistosomiasis is a major cause of pulmonary hypertension (PH) worldwide, and CD4 T cells are critical in disease pathogenesis. The role of dendritic cells (DCs) in Schistosoma-induced PH (SchPH) is unknown. There are two types of conventional DCs, cDC1 and cDC2, that prototypically activate CD8 and CD4 T cells, respectively.

Methods: We exposed wildtype, DC reporter, and DC knockout mice to Schistosoma mansoni and quantified PH severity by heart catheterization and cell density by flow cytometry.

Results: Experimental S. mansoni exposure increased the density of pulmonary DCs, particularly cDC2s. Deleting both cDC subsets did not significantly modify SchPH disease severity. Deleting only cDC1s caused more severe SchPH, associated with more Th2 CD4 and CD8 T cells. In contrast, deleting only cDC2s reduced SchPH disease severity.

Conclusions: cDC1s appear to be protective, whereas cDC2s promote disease in SchPH.

Vascular smooth muscle cell (VSMC) phenotypic switching, followed by enhanced proliferation and migration, is a key event in the development of intimal hyperplasia in diverse vascular diseases. While tetraspanin 4 (TSPAN4) is known to be expressed in the vasculature, its function in VSMC phenotypic switching and vascular disease is currently unknown. Here, we investigated the role of TSPAN4 using an in vitro model of platelet-derived growth factor BB (PDGF-BB)-induced phenotypic switching and an in vivo carotid artery ligation model in wildtype and TSPAN4-deficient mice. Our experiments, including EdU assays, Transwell assays, western blot analysis, and immunoprecipitation, revealed that TSPAN4 expression is elevated in human atherosclerotic arteries, ligated mouse carotid arteries, and PDGF-BB-stimulated VSMCs. Additionally, TSPAN4 overexpression promoted the switch from a contractile to a synthetic phenotype, accompanied by enhanced VSMC proliferation and migration. Conversely, TSPAN4 knockdown inhibited these effects, suppressing PDGF-BB-induced phenotypic switching. Mechanistically, TSPAN4 was found to interact with and influence the expression and localization of tropomyosin-1 (TPM1). This, in turn, affected cytoskeletal organization, ultimately driving phenotypic switching and functional alterations in VSMCs. Finally, we demonstrated that TSPAN4 deficiency in mice attenuated vascular neointimal formation following carotid artery ligation. These findings suggested that TSPAN4 is a promising novel therapeutic target for vascular remodeling and proliferative vascular diseases.

Pulmonary arterial hypertension (PAH) is a syndrome characterized by a mean pulmonary artery pressure >20 mmHg and elevated pulmonary vascular resistance >2 Wood Units in the absence of left heart disease, chronic lung disease or hypoxia, and chronic thromboembolic disease. PAH is an obliterative pulmonary arteriopathy that leads to morbidity and mortality, often due to right ventricular failure (RVF). Emerging evidence from preclinical research, using chemical inhibition or genetic depletion of inflammatory mediators, reveals a role for inflammation in the adverse pulmonary vascular remodelling in PAH. More recently, studies have also identified inflammation of the right ventricle (RV) as a potential contributor to RV decompensation and failure. While inflammation contributes to the pathogenesis of PAH, no approved PH-targeted therapies specifically target inflammation. Macrophages are myeloid cells that play a critical role in inflammation and PAH. Their cellular plasticity enables the acquisition of tissue-specific phenotypes and functions that may promote either resolution or exacerbation of inflammatory signalling. Macrophage plasticity in PAH is poorly understood. We examine how alterations in glucose metabolism, particularly the uncoupling of glycolysis from glucose oxidation-a notable feature of PAH observed in various cell populations-impact macrophage polarization and the inflammatory phenotype associated with PAH. The study of immune cell metabolism, known as immunometabolism, is an emerging field that has yet to be explored in PAH. Improving understanding of the inflammatory mechanisms in PAH, particularly novel pathways related to macrophage immunometabolism, may identify new targets for anti-inflammatory therapies for PAH.

Phosphoinositides and inositol phosphates (IPs) are integral to numerous cellular processes, including membrane trafficking, signal transduction and calcium dynamics. These lipid-derived signalling mediators orchestrate the spatial and temporal regulation of many signalling cascades, largely through interactions with specific effector proteins. Recent studies have highlighted their critical roles in metabolic homeostasis and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we examine the pathways important for phosphoinositide and IP synthesis, and the physiological functions of myo-inositol, d-chiro-inositol and phosphatidylinositol, as well as their phosphorylated inositol counterparts, including phosphoinositides (PI(3)P, PI(4)P, PI(3,4)P2, PI(3,5)P2, PI(4,5)P2, PI(3,4,5)P3) and IPs (inositol 1,4,5-trisphosphate (IP3), inositol 1,3,4,5-tetrakisphosphate (IP4), inositol pentakisphosphate (IP5), inositol hexaphosphate (IP6 or phytic acid) and inositol pyrophosphates (IP7 and IP8)), with an emphasis on their emerging significance in hepatic metabolism. We explore how perturbations in IP metabolism contribute to the development and progression of MASLD, liver inflammation, fibrosis and hepatic insulin resistance. We further highlight recent studies utilizing genetic models and pharmacological interventions that underscore the therapeutic potential of targeting inositol metabolism in MASLD. This review synthesizes current knowledge to provide a comprehensive understanding of how phosphoinositides and IPs integrate metabolic cues and contribute to hepatic pathophysiology, identifying knowledge gaps and offering novel insights for therapeutic innovation in the management of MASLD.

Inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and asthma, are driven by mitochondrial dysfunction and aberrant immune responses, yet the regulatory role of mitophagy-a selective autophagy eliminating damaged mitochondria-remains poorly defined. This review synthesizes evidence from in vivo and in vitro studies to dissect the molecular interplay between mitophagy and inflammation. Key fundings reveal that mitophagy exerts context-dependent effects: Protective mitophagy (via PTEN-induced putative kinase 1 [PINK1]-Parkin or FUN14 domain-containing protein 1 [FUNDC1] pathways) clears mitochondrial reactive oxygen species (mtROS)/mitochondrial DNA (mtDNA), suppressing NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation and pyroptosis, but excessive mitophagy exacerbates mitochondrial fragmentation and necroptosis. Notably, bidirectional cross-talk exists, and therapeutic strategies-genetic and pharmacological-could restore mitophagy flux, attenuating inflammation in preclinical models. However, challenges persist in targeting tissue-specific mitophagy (such as alveolar and bronchial epithelia). This work underscores mitophagy as a double-edged sword in lung inflammation and proposes precision interventions to balance mitochondrial quality control, offering novel avenues for inflammatory lung diseases.

Exacerbated inflammation is a major contributor to tissue damage and mortality in infectious diseases, including SARS-CoV-2. The resolution phase of inflammation is critical for restoring tissue homeostasis following an injury. Annexin A1 (AnxA1) is a ubiquitous protein that plays a fundamental role in the resolution of inflammation, including in preclinical models of infectious disease. Here, we investigated the role of AnxA1 in coronavirus infection and its potential as a host-targeted therapeutic strategy against SARS-CoV-2. Wildtype (WT) and AnxA1 knockout (AnxA1KO) mice were intranasally infected with the murine betacoronavirus MHV-3 to study the endogenous role of AnxA1. Immunohistochemistry and Western blot analyses in the lungs of MHV-3-infected mice revealed increased AnxA1 expression and its cleavage, which was associated with neutrophilic infiltration (Ly6G+ cells) mainly in peribronchiolar and perivascular regions. AnxA1-deficient mice exhibited higher neutrophilic infiltration and lung damage, alongside increased CXCL1 production in the lungs, when compared with WT-infected mice. In a murine model of SARS-CoV-2 infection in K18-hACE2 mice, we found increased AnxA1 cleavage associated with lung inflammation. Treatment of SARS-CoV-2-infected K18-hACE2 mice with the AnxA1-mimetic peptide, Ac2-26, reduced lung damage and lethality, without altering the host ability to deal with viral replication. Notably, Ac2-26-treated mice exhibited similar levels of protection to that afforded by the nucleotide analog Remdesivir, following SARS-CoV-2 infection. Our findings highlight the protective role of the endogenous AnxA1 in mitigating coronavirus-induced lung inflammation and underscore the therapeutic potential of AnxA1 mimetic Ac2-26 as a host-targeted therapy against SARS-CoV-2.

Circulating lipid levels are typically low in fetuses, and exposure to high lipid levels at developmental stages prior to term birth is sometimes associated with pathology. Experimentally, near-term fetuses tolerate one week of high lipid concentrations; it is unknown whether this brief exposure to elevated circulating lipids is pathological at an earlier developmental age. We studied the physiological response to intravenous lipid emulsion during mid-gestation. Fetal sheep received intravenous Intralipid 20® (n = 9) or Lactated Ringer's Solution (n = 8) from 85.0 ± 0.7 to 97.0 ± 0.7 days of gestation (term = 147 days). Intralipid was administered according to manufacturer's recommendations, with an initial dose of 0.5-1 g/kg/d that increased daily to a maximum of 3 g/kg/d. Hemodynamic and arterial blood parameters were assessed throughout the study. Fetal growth, liver function, and lipid droplet accumulation were measured on the final day. Fetal hemodynamics and blood gases did not change as a result of the treatment. Compared with Controls, Intralipid fetuses had lower blood lactate concentrations (1.3 ± 0.2 vs. 1.0 ± 0.2 mmol/l, P=0.009) after eight days of treatment. Conjugated (0.4 ± 0.1 vs. 0.6±0.1 mg/dl, P<0.001) and unconjugated (0.3 ± 0.1 vs. 1.2 ± 0.5 mg/dl, P<0.001) bilirubin levels were higher in Intralipid-infused fetuses than in Controls. Fetal somatic growth was unchanged, but heart weight was lower in fetuses receiving Intralipid (6.9 ± 0.7 vs. 6.1±0.7 g, P=0.008). Compared with Controls, Oil Red O staining was elevated in the liver and heart of Intralipid-infused fetuses (liver score: 18.9 ± 17.2 vs. 371.7±44.2, P<0.0001; heart score: 1.8 ± 2.8 vs. 97.6 ± 60.1, P=0.0006). Our findings suggest that mid-gestation fetal sheep can tolerate intravenous lipid emulsion. Lipid accumulation in the liver and heart may precede pathologies associated with ectopic lipid storage, but further research is needed to understand the long-term consequences of Intralipid infusion at this developmental stage.

The global prevalence of obesity has exerted a profound influence on human health. It has contributed to numerous obesity-related comorbidities, including metabolic dysfunction-associated steatotic liver disease (MASLD) and insulin-resistant diabetes. MASLD is diagnosed when there is substantial fat accumulation concomitant with five additional diagnostic criteria. If untreated, MASLD may progress to liver fibrosis and cirrhosis, conditions that can be life-threatening in the final stages. Nonetheless, the development and progression of MASLD are complex, and its underlying mechanisms remain incompletely elucidated. Typically, during fasting, adipose tissue releases fatty acids, which the liver subsequently uptakes for gluconeogenesis. However, this process, along with many others, is impaired in the liver and adipose tissue of individuals with MASLD. This review provides comprehensive details on the mechanisms underlying adiposity and insulin resistance associated with MASLD. We discuss the canonical pathways that promote lipogenesis and insulin sensitivity in the liver and adipose tissues, including bile acids, bilirubin, fatty acids, inflammation, de novo lipogenesis, oxidative stress, peroxisome proliferator-activated receptors (PPARs), fibroblast growth factor 21 (FGF21), glucagon-like peptide 1 (GLP1), and metabolism of fructose. The scope of the review is expanded to encompass biological responses to fasting and feeding, as well as their effects on fat accumulation and insulin sensitivity in these tissues. Additionally, the review elaborates on critical molecular mechanisms regulating MASLD progression, including hepatic insulin clearance, insulin degradation, bilirubin metabolism, nerve innervation, and the roles of cytokines and adipokines. Overall, this review examines the mechanisms driving MASLD and explores potential novel therapeutic strategies for its management.

Perimenopause is a transitional phase leading to female reproductive senescence, which can cause vasomotor symptoms and increase the risk of osteoporosis, obesity, and metabolic-related disturbances in middle-aged and older women. Nevertheless, little is known regarding the underlying mechanisms linked to menopausal transition, which could be of great value in designing new interventions addressed to improve the health of both perimenopausal and postmenopausal women. We used an ovarian-intact middle-aged model of rats resembling the characteristics of human perimenopause and applied liquid and gas chromatography quadrupole time-of-flight mass spectrometry approaches for the determination of polar and lipid-related metabolites to identify characteristic circulating signatures across perimenopause. The gradual loss of regularity in the estrous cycle occurring during the natural transition to reproductive senescence was associated with altered circulating levels of estradiol, progesterone, and luteinizing hormone (LH) and, in rats that were in an acyclic state, with ovary atrophy and with a lack of stromal luteinization and corpus luteum. These results were accompanied by progressively significant changes in the 144 lipid-related metabolites detected in serum as the estrous cycles were losing regularity. Furthermore, we identified 18 lipid-related metabolites-including 9 phosphatidylcholines, 4 lysophosphatidylcholines, 2 phosphatidylethanolamines, cholesterol ester (18:2), 5α-androstane-3,17-diol, and 17,18-dihydroxyarachidonic acid-that already changed with the transition from a regular to an irregular estrous cycle and anticipated the changes in blood progesterone, LH, and cholesterol levels that occurred in acyclic rats. These metabolites could be used as a potential multivariate biomarker of early perimenopause. The translational applicability of these findings deserves further research.