Clinical science最新文献

Fetal growth restriction (FGR) arises from chronic hypoxia and increases the risk of cardiovascular dysfunction following perinatal asphyxia, although underlying mechanisms remain unclear. We investigated whether cardiovascular responses to asphyxia are impaired in preterm FGR lambs and whether this arises from α1- and β1-adrenergic receptor dysfunction. Ewes underwent sterile fetal surgery at 89 days' gestation (d; term=148 d) to induce FGR (single umbilical artery ligation) or sham surgery (control). At 126 d, lambs were delivered, instrumented and randomised to immediate ventilation (ControlVENTn=6; FGRVENTn=6) or asphyxia (ControlASPHYXIAn=12; FGRASPHYXIAn=11) by umbilical cord occlusion until diastolic blood pressure (BP) decreased to 10 mmHg. Lambs were ventilated for 8 hours before baseline ex vivo cardiac function was assessed via Langendorff perfusion to measure left ventricular developed pressure (LVDP), heart rate (HR) and coronary perfusion pressure (CPP). Ex vivo α1- and β1-adrenergic responses were assessed via phenylephrine and dobutamine administration, respectively. FGRASPHYXIA lambs had lower BP during asphyxia and took longer to reach a diastolic BP of 10 mmHg (P<0.05 vs ControlASPHYXIA). FGRASPHYXIA lambs had lower BP in the first 5 minutes after return of spontaneous circulation due to impaired vascular contractility (P<0.05 vs ControlASPHYXIA). Baseline LVDP, HR and CPP were similar between groups. FGRASPHYXIA lambs had increased LVDP responses to phenylephrine and dobutamine (P<0.05 vs FGRVENT and ControlASPHYXIA), without significant changes to HR or CPP. Overall, FGR lambs exhibit impaired vascular contractility and heightened cardiac α1- and β1-adrenergic responsiveness after perinatal asphyxia, consistent with reduced autonomic regulation, potentially increasing susceptibility to cardiovascular dysfunction postnatally.

Klebsiella pneumoniae is a major pathogen responsible for severe pulmonary infections, yet the early mechanisms of infection remain incompletely understood. This study investigates the role of exosomes derived from K. pneumoniae in polarizing macrophages to the M1 phenotype, thereby facilitating early lung infections. Utilizing single-cell Raman spectroscopy, we rapidly detected K. pneumoniae within host cells and observed significant lipid expression changes. Metabolomic analysis of exosomes from infected epithelial cells uncovered an elevation of phosphatidylcholine, which disrupted endothelial tight junctions and promoted M1 macrophage recruitment and polarization. This process activated the NF-κB signaling pathway, increasing inflammatory responses and attracting neutrophils. Our findings, validated in infected tissue models, suggest that these exosomal mechanisms significantly contribute to the early stages of pulmonary infection by K. pneumoniae. This study offers crucial insights into potential therapeutic targets for controlling K. pneumoniae infections.

Preeclampsia, defined by hypertension and end organ damage after 20 weeks of gestation, remains a significant cause of maternal and fetal morbidity and mortality. This disorder has a diverse clinical presentation and is likely driven by several underlying mechanisms, many remaining poorly understood. However, there is emerging evidence that epigenetic regulators, including histone deacetylases (HDACs), may contribute to the pathophysiology of preeclampsia. Of the many HDACs, HDAC9 is particularly intriguing in the context of preeclampsia due to its decreased presence in preeclamptic placenta and prominent role in controlling trophoblast, vascular, and immune behavior, which are often dysregulated in this condition. This review focuses specifically on HDAC9, detailing its expression patterns, molecular properties, known and hypothesized targets at the maternal-fetal interface, and potential causes of dysregulation. Special emphasis is placed on its impact on trophoblast function, immune signaling, angiogenesis, and G-protein-coupled receptor pathways, which are frequently disrupted in preeclampsia. Although current evidence for altered HDAC9 expression in this disorder is confined to the placenta, its potential role in maternal physiology remains an open and important question. By integrating findings from placental biology and disorders with overlapping pathways such as cardiovascular disease and cancer research, this review aims to establish a framework for understanding how HDAC9 contributes to preeclampsia pathogenesis and to identify promising directions for future investigation and therapeutic development.

Mineralocorticoid receptor antagonists (MRAs) reduce hypertension, inflammation and tissue injury in human and experimental diabetes. Inflammation and injury in diabetic hearts and kidneys is also dependent on infiltrating macrophages. Therefore, we hypothesised that the tissue protective effects of MRAs in diabetes are dependent on mineralocorticoid receptor (MR) signalling in macrophages. To evaluate this hypothesis, transgenic mice with intact myeloid MR (MRflox/flox) or myeloid MR deficiency (MRflox/flox LysMCre) were developed on the hypertensive endothelial nitric oxide synthase deficient (Nos3-/-) mouse strain. Groups of these mice were made diabetic with streptozotocin and were assessed after 15 weeks for development of hypertension, cardiomyopathy and nephropathy. Nos3-/- mice with myeloid MR deficiency had equivalent diabetes and hypertension as myeloid MR intact controls but were protected against cardiac and renal function impairment. In diabetic hearts, myeloid MR deficiency reduced cardiomyocyte hypertrophy, capillary loss and fibrosis in association with reduced macrophage accumulation and a switch from an M1 to an M2 macrophage phenotype. In diabetic kidneys, myeloid MR deficiency reduced renal dysfunction (elevated plasma cystatin C) but did not protect against albuminuria, glomerulosclerosis or tubular damage; this was associated with a partial reduction in glomerular macrophages and an M1 to M2 macrophage phenotype switch. Therefore, MR signalling in macrophages promotes dysfunction in the diabetic heart and kidneys of Nos3-/- mice without affecting hypertension. Furthermore, abolishing macrophage MR signalling provides greater protection to hearts than kidneys during type 1 diabetes and hypertension, giving new insight into the mechanisms by which MRAs suppress tissue injury during diabetes.

The clinical hallmarks of osteogenesis imperfecta (OI), often referred to as 'brittle-bone disease', are bone fragility and skeletal deformities that are usually accompanied by extra skeletal manifestations. OI is a family of collagen I-related disorders, currently classified into 23 distinct types and 5 OI-like forms, with variable phenotypic severity ranging from mild to lethal. At the molecular level, the pathophysiology of OI is driven by alterations in collagen I structure, primarily caused by dominant mutations in collagen genes (affecting approximately 85% of patients). It can also result from dominant, recessive, or X-linked defects in proteins involved in collagen biosynthesis, extracellular matrix organization, mineralization, or bone forming cell differentiation and/or activity. This review illustrates the different OI forms from a collagen I perspective, its complex biosynthetic process is first described, followed by a classification of the OI and OI-like causative mutations grouped based on whether the resulting collagen molecule is overmodified, undermodified, or unaltered. The underlying molecular mechanisms and the consequences at cellular and extracellular levels leading to the OI phenotype are discussed. An overview is provided on how newly discovered molecular pathways altered in OI can guide the development of innovative therapies aiming at increasing bone mass and improving bone quality in OI patients.

Lauryl gallate (LG, E312) is an antioxidant with hydrophobic properties that contribute to its activity by increasing affinity for membranes and acting on the lipid phase transition and likely the lateral membrane organization. Here, we show that LG at a low concentration has the ability to spontaneously induce washed human platelet shape change, filopodia emission, granule secretion, and aggregation. LG was able to activate intracellular signaling pathways, including Akt, p38MAP kinase, inositol phosphate, and calcium responses, as well as to trigger cyclic adenosine monophosphate decrease and αIIbβ3 integrin activation. LG significantly potentiated platelet aggregation induced by low concentrations of agonists, and the addition of low doses of LG to human blood strongly increased the platelet thrombotic response under arterial flow on a collagen matrix. Morphological analysis by scanning electron microscopy indicated that contrary to low doses, high concentrations of LG induced dramatic platelet membrane modifications associated with calcium influx, lactate dehydrogenase leakage, and a slow platelet aggregation response. Interestingly, a local flash application of LG efficiently decreased the tail bleeding time in rats. LG action was rapid and significantly more efficient than tranexamic acid, an antifibrinolytic agent, pointing to its hemostatic potential. Overall, our results indicate that LG, likely through its capacity to modify membrane lateral organization, has important pro-aggregant and antihemorrhagic properties.

South Asians (SAs) in the UK are at an increased risk of cardiovascular disease (CVD), develop type 2 diabetes mellitus at a lower age and body mass index, and have a lower high-density lipoprotein cholesterol (HDL-C) concentration than their white European (EU) counterparts. The failure of HDL-C raising therapies for CVD risk reduction has turned attention to its composition and function. A previous study comparing the effect of moderate weight gain on SA and EU men found baseline and weight gain-induced ethnic differences in body composition, adipocyte function and insulin resistance (ClinicalTrials.gov registration: NCT02399423). This study investigated differences in HDL protein composition, subclass distribution and in vitro vascular functions at baseline and after weight gain in the same cohort of men. HDL protein composition was determined by nano liquid chromatography tandem mass spectrometry using label-free quantification. HDL subclass distribution was measured by native gel electrophoresis. HDL in vitro paraoxonase-1 (PON-1) activity was measured by monitoring the PON-1 mediated hydrolysis of phenylacetate. In vitro HDL anti-inflammatory function was assessed in an endothelial cell assay of adhesion molecule inhibition. SAs had higher levels of immunity- and inflammation-related proteins and a detrimental profile of lipid metabolism-related proteins at baseline and with weight gain (including lower apolipoprotein (apo) A-IV and apoF and higher apoC-III) compared with EU. HDL subclass distribution and in vitro vascular function were not different between EUs and SAs. HDL protein composition reflects systemic physiology and acts as a mechanistic marker of impaired lipid metabolism in SAs.

Salt-sensitive hypertension (SSHTN) promotes systemic inflammation, pro-inflammatory immune cell infiltration, and end-organ damage, including in the kidneys and gonads. However, its impact on uterine immune cell populations remains unclear. We hypothesized that SSHTN alters immune cell homeostasis, induces inflammation, and promotes lymphangiogenesis in the uterus, and that these effects can be mitigated by pharmacological blood pressure (BP) reduction and anti-inflammatory macrophage augmentation. To test the hypothesis, female C57BL6/J mice were given nitro-L-arginine methyl ester hydrochloride (0.5 mg/ml) in drinking water for 2 weeks, followed by a 2-week washout period. Mice were then subjected to a 4% high-salt diet (SSHTN) for 3 weeks. Another group of mice received either hydralazine (HYD; 250 mg/l in drinking water), a vasodilator (SSHTN+HYD), or AVE0991 (AVE; 0.58 µmol/kg body weight/day), a nonpeptide Mas receptor agonist, through daily intraperitoneal injections (SSHTN+AVE). Control mice received tap water and a standard diet for the entire treatment period. Flow cytometry data revealed a significant decrease in total uterine CD45+ immune cells, along with an increase in tissue macrophages, in all SSHTN groups compared with the control group. SSHTN mice had increased uterine pro-inflammatory macrophages, dendritic cells, natural killer cells, and CD4+ pro-inflammatory T cells, all of which were mitigated by HYD and AVE treatments. SSHTN promoted uterine inflammation, lymphatic vessel expansion, and altered hormone receptor expression, which were mitigated by pharmacological intervention, highlighting their therapeutic potential in preserving uterine homeostasis and improving reproductive health in women with SSHTN.

Mitochondria are dynamic, undergoing both fission and fusion. Evidence indicates that a balance between these two processes is necessary to maintain a healthy state. With ischemia/reperfusion (I/R) of the heart, fission is enhanced and is associated with mitochondrial swelling, depolarization, and production of reactive oxygen species, as well as apoptosis. Accumulating evidence indicates that blocking fission is effective in reducing I/R-induced tissue damage and contractile dysfunction. In theory, enhancing fusion should also serve to prevent I/R-related heart damage. In this perspective article, we present evidence from preclinical studies over the last several years supporting the conclusion that targeting mitochondrial dynamics is a promising pharmacological strategy to protect the heart. Such an approach has great value in limiting heart damage from not only myocardial infarction but also medical interventional reperfusion, alcohol consumption, chemotherapy, and sepsis.

Obesity has been described by the WHO as the largest health threat facing mankind. More than 55% of pregnancies in the United Kingdom occur in women who are overweight or living with obesity. Obesity in pregnancy increases the risk of developing gestational diabetes mellitus (GDM), a condition that affects one in seven pregnancies globally and is associated with short- and long-term risks for both mother and baby. Therefore, optimising treatment to effectively treat both obesity and GDM in the perinatal period could have wide-ranging benefits for mother and child. Stabilised analogues of glucagon-like peptide-1 (GLP-1) have revolutionised the treatment of metabolic disease and obesity as they promote weight loss and lower blood glucose. However, the wider action of these analogues, especially in the context of pregnancy, is underexplored. In the United States, the number of young female users of GLP-1 receptor agonists (GLP1RAs), such as Ozempic (semaglutide), increased 659% between 2020 and 2023. Ozempic is not currently licensed for use in pregnancy; however, increased semaglutide use in women of reproductive age has resulted in a rise in 'Ozempic babies', when women have unplanned pregnancies while using semaglutide. The potential for GLP1RA use prior to or during pregnancy to limit the transmission of obesity risk between mothers with obesity and their offspring by lowering maternal body weight or correcting maternal glycemia has not been explored. Rodent studies suggest that GLP1RA administration to the dam in pregnancy alters fetal growth, and GLP1RA administration directly to neonates alters development of the hypothalamus. However, recent emerging case reports of human pregnancies where exposure to GLP1RAs has occurred through unplanned pregnancies suggest no harm to the fetus. Given both the potential for GLP1RAs to improve health outcomes in pregnant women with obesity and GDM, and the rapidly rising incidence of fetal exposure, we review the current literature base on the effects of semaglutide use in pregnancy on maternal and offspring health and explore potential broader impacts of use of these agents during the perinatal period based on their known site of action.