Prior studies have identified atypical expression of protein tyrosine phosphatase receptor type E (PTPRE) in animal models of salt-sensitive hypertension (SSH). This study investigates PTPRE's role in SSH and clarifies its mechanism of action. Through gene knockdown and overexpression of PTPRE in DOCA-salt hypertensive mice, we assessed the vasomotor function of aortic rings. PTPRE-induced phenotypic changes in vascular smooth muscle cells (VSMCs) were identified using phenotypic markers and related functional parameters. The phosphorylation levels of the MAPK signaling pathway subfamilies were assessed using Western blot analysis. Upregulation of PTPRE was observed in the VSMCs of DOCA-salt-induced SSH mice. This upregulation was associated with impaired vasoconstriction and vasodilation of arteries, as well as increased blood pressure (BP) (all p < 0.01). Altering PTPRE expression via knockdown and overexpression markedly affected the expression of synthetic (OPN) and contractile (α-SMA and SM22α) phenotype markers in the aortic media and VSMCs of SSH mice (all p < 0.01). Moreover, PTPRE expression influenced the phosphorylation activation within the MAPK signaling pathway. Specifically, regulation of PTPRE expression in SSH modulated the phosphorylation of the JNK and p38 MAPK subfamilies, along with the upstream phosphorylation of MKK3 and MKK6 (all p < 0.05). Our findings indicate that PTPRE significantly contributes to vascular vasomotor dysfunction and the phenotypic transformation of VSMCs in SSH. This involvement in SSH development seems to occur mainly via modulation of the JNK and p38 MAPK pathways.

Atrial fibrillation (AF) is one of the most common arrhythmias with complex pathogenesis. Recent studies showed that gut microbiota and its metabolic products, especially short-chain fatty acids (SCFAs), are closely linked to the onset and progression of AF. In this review, the alterations about SCFAs in AF patients were primarily summarized, and the potential mechanisms of SCFAs on the onset and progression of AF were further outlined. For the alterations, the contents of SCFAs in the circulatory system of AF patients were reduced, mainly ascribed to the dysregulation of SCFAs-producing gut microbiota and/or the reduction of genetic expression involved in the synthesis of SCFAs in the gut microbiota. For the potential mechanisms, SCFAs alleviate AF by inhibiting inflammation, relieving endoplasmic reticulum (ER) stress, mitigating oxidative stress, and improving atrial remodeling. Specifically, (1) SCFAs suppress inflammatory responses in AF mainly via activating GPCR, inhibiting the NLRP3 inflammasome, inhibiting HDAC activity, regulating vascular endothelial function, and maintaining gut barrier integrity. (2) SCFAs relieve ER stress in AF by reducing the expression of ER stress markers pPERK and/or CHOP, and correct ion current and calcium homeostasis disorders caused by TMAO. (3) SCFAs mitigate oxidative stress in AF by reducing mitochondrial damage and regulating Nrf2 pathways. (4) SCFAs improve atrial remodeling in AF by alleviating atrial structural and electrical remodeling. This review explores the regulatory mechanisms of SCFAs in alleviating AF from the gut-heart axis perspective, providing novel insights into AF prevention and treatment strategies.

The study aimed to investigate the neuroprotective functions and the underlying regulatory mechanisms of Tabersonine in cerebral ischemia/reperfusion (I/R) injury. Oxygen-glucose deprivation/reoxygenation (OGD/R)-treated neural cells were used as a cell model under I/R context. Cell counting kit 8 (CCK8) assay and enzyme-linked immunosorbent assay (ELISA) were used to assess the cell viability and the release levels of inflammatory cytokines (interleukin-1β (IL-1β), IL-6 and tumour necrosis factor α (TNF-α)) of treated neural cells. The apoptotic proportions of treated neural cells were analysed by flow cytometry, and the intracellular levels of reactive oxygen species (ROS) and superoxide dismutase (SOD) were quantified by corresponding kits. In this study, molecular docking analysis identified solute carrier family 6 member 2 (SLC6A2) as a potential target of Tabersonine in cerebral infarction, demonstrating a high binding affinity of -7.4 kcal/mol. Tabersonine treatment increased neural cell viability, repressed apoptosis and reduced the release levels of IL-1β, IL-6 and TNF-α under OGD/R stress. Moreover, Tabersonine treatment reduced ROS levels and increased SOD expression in neural cells under OGD/R treatment. In contrast to the protective effect of SLC6A2 knockdown, its overexpression counteracted the neuroprotection conferred by Tabersonine. Tabersonine also inactivated the NF-κB pathway partially via SLC6A2. Furthermore, Tabersonine pretreatment demonstrated significant neuroprotective effects in MCAO/R rats, as evidenced by reduced brain edema and attenuated neural inflammation and apoptosis. In conclusion, Tabersonine can alleviate neural impairment in cerebral I/R injury partially by inactivating the NF-κB pathway through SLC6A2.

Thrombosis is a common complication in paroxysmal nocturnal haemoglobinuria (PNH) patients, but primary prevention remains controversial. Identifying high-risk individuals could enable risk-stratified prophylactic anticoagulation strategies.

We analyzed clinical data from PNH patients with or without thrombosis, including MUC4 mutation status and serum complement C5b-9 levels. Complement deposition assays and a murine lower limb deep vein thrombosis model were used to investigate the role of MUC4 mutation in thrombotic risk and explore the underlying mechanism involving terminal complement activation in PNH patients. Therapeutic interventions with low molecular weight heparin (LMWH) were tested in vivo.

We found that PNH patients with MUC4 mutations have a higher incidence of thrombotic events (TEs) and MUC4 mutation is an independent risk factor for TE in PNH patients. Additionally, PNH patients with acute thrombosis had elevated serum complement C5b-9 levels, and complement deposition experiments further confirmed the abnormal activation and excessive deposition of C5b-9 as the basis for the thrombotic tendency in PNH patients. By constructing a mouse model of lower limb deep vein thrombosis, we confirmed the thrombotic tendency in a PNH mouse model and that MUC4 deficiency further promoted the thrombotic phenotype of the mice. Moreover, we found that MUC4 knockdown promoted the deposition of C5b-9 on the cell surface, indicating that a lack of MUC4 expression facilitates the deposition of C5b-9. Finally, in vivo drug administration experiments demonstrated that prophylactic anticoagulation with LMWH significantly reduced both the incidence of thrombosis and thrombus length in murine models.

MUC4 mutations promote the thrombotic phenotype in PNH patients by increasing the deposition of terminal complement. In PNH patients with concomitant MUC4 mutations, the risk of TEs is further elevated. The potential role of early complement inhibitor therapy in reducing this heightened thrombotic risk, as well as the value of prophylactic LMWH therapy as a potential option for patients who are unable to receive complement inhibitor treatment, warrants further study and prospective validation.

MUC4 gene mutation increases the deposition of abnormally activated terminal complement in patients with PNH, thereby promoting the thrombotic phenotype in these patients. Consequently, the risk of thrombosis is further elevated in PNH patients with concurrent MUC4 mutations. In patients with PNH who have concurrent MUC4 mutations, the potential role of early complement inhibitor therapy in reducing thrombosis risk, as well as the value of prophylactic LMWH therapy as a potential alternative for those who are unable to receive complement inhibitor treatment, may warrant further study and prospective validation.

This study investigated the protective effects of naringin, a flavanone glycoside with established antioxidant, anti-inflammatory, and anti-apoptotic properties, against testicular ischemia/reperfusion (I/R) injury in a mouse torsion/detorsion model. Forty adult male mice underwent a 720° torsion for two hours, followed by detorsion. Five groups (n = 8) received naringin (50, 100, or 200 mg/kg) administered intraperitoneally 30 min prior to detorsion: sham, T/D, and three T/D + naringin groups. After 30 days, sperm quality (concentration, motility, kinematics), oxidative stress markers, histological alterations, apoptotic markers (Bcl-2, Bax, caspase-3), hormonal profiles, and fertility outcomes were evaluated. The T/D group exhibited deteriorated sperm quality, reduced antioxidant levels (TAC, SOD, GPx), decreased hormones (testosterone, FSH, LH), elevated MDA and apoptotic markers, and impaired fertility. Notably, FSH levels decreased after T/D - in contrast to the typical increase in chronic damage models - possibly due to acute-phase pituitary suppression in this short-term mouse model. Naringin (particularly 100 and 200 mg/kg) dose-dependently improved sperm parameters, antioxidant status, testicular histology, hormonal levels, and fertility. The 50 mg/kg dose showed limited efficacy. Naringin inhibited apoptosis by upregulating Bcl-2 and downregulating Bax and caspase-3. These results indicate that intraperitoneal naringin, especially at 100-200 mg/kg, exerts significant protective effects against testicular I/R injury and may warrant further investigation as a potential adjunctive therapy in the clinical management of testicular torsion.

Hypertension is a major global health burden, affecting nearly half of the adult population and contributing significantly to morbidity and mortality. While traditionally viewed through its hemodynamic effects, growing evidence implicates immune dysregulation as a central driver of hypertension and its associated end-organ damage. Immune cells, including T cells, dendritic cells, and macrophages, infiltrate target organs and release mediators such as cytokines, reactive oxygen species, and metalloproteinases, promoting inflammation, fibrosis, and dysfunction. The discovery of isolevuglandin (IsoLG)-adducted neoantigens has advanced our understanding of antigen-dependent T cell activation in hypertension, revealing the roles of antigen-presenting cells, immune memory, and co-stimulatory pathways. Further, endothelial cells have emerged as non-professional antigen-presenting cells, orchestrating immune responses by modulating leukocyte recruitment and activation under mechanical and oxidative stress. Studies using experimental models and humans highlight the contributions of CD8⁺ T cells, immune memory formation, and altered sympathetic tone in perpetuating hypertension. Translational work has identified IsoLG-adducted peptides and their processing by the immunoproteasome as critical mechanisms driving immune activation. Collectively, these findings underscore the interplay between the immune system and hypertension, offering novel therapeutic opportunities to target immune-mediated mechanisms, mitigate blood pressure elevation, and reduce end-organ damage. This review highlights these advances while recognizing the growing body of literature in this evolving field.

This study evaluated the clinical significance of miR-567 in atherosclerosis and its regulatory effect on PDGF-BB-induced VSMCs, aiming to identify a novel biomarker for the risk and progression of atherosclerosis. The study enrolled 113 atherosclerosis patients and 126 non-atherosclerosis patients. Serum miR-567 level was compared between the two groups and its significance in disease severity was assessed. T/G human VSMC was induced with PDGF-BB, and based on this cell model, the regulatory effect and potential mechanism of miR-567 was estimated. miR-567 was upregulated in atherosclerosis patients and showed diagnostic significance (AUC = 0.875). miR-567 was positively correlated with homocysteine, total cholesterol, and low-density lipoprotein, and negatively correlated with high-density lipoprotein (r > 0.7, P < 0.0001). miR-567 was upregulated in PDGF-BB-induced VSMCs, and silencing miR-567 showed protective effect on PDGF-BB-induced VSMCs. CSF1R was negatively correlated with miR-567. Silencing CSF1R reversed the protective effect of miR-567 silencing on PDGF-BB-induced VSMCs.

Hypertension is a major contributor to cardiovascular diseases, being the most common comorbidity and the biggest risk factor in heart failure with preserved ejection fraction. Angiotensin II (Ang II) is a known hypertension and heart failure inducer in mice, but its role in the causality in phenotype development remains unclear. Here, hypertension was induced with low (LowA) or high (HighA) pressor doses of Ang II in mice. Both LowA and HighA groups demonstrated equal levels of hypertension with aortic dilatation and decreased aortic wall strain, but only HighA developed left ventricular hypertrophy with advanced cardiac dysfunction, demonstrating the hypertension-independent effects of Ang II on myocardial remodeling. Alterations in electrical conductivity occurred similarly in both groups, with prominent ECG waveform aberrations. The study demonstrates two distinct hypertensive heart disease phenotypes induced by Ang II, providing a valuable preclinical framework that emphasizes the critical role of Ang II in diastolic dysfunction and vascular remodeling beyond its effects on the regulation of blood pressure.

Postprandial hyperglycemia transiently impairs endothelial function. Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction and impaired glucose tolerance - both risk factors for cardiometabolic diseases - but the effects of hyperglycemia on endothelial function have yet to be assessed in PCOS. Exogenous ketone monoester (KME) supplementation lowers blood glucose and improves endothelial function in individuals predisposed to cardiometabolic diseases but has yet to be assessed in PCOS. Thus, we investigated whether oral glucose tolerance test (OGTT)-induced hyperglycemia impairs endothelial function in PCOS, and whether acute KME mitigates these impairments. Ten females with PCOS (age: 27±5yr, BMI: 23.8±2.7kg/m²) and 10 age- and BMI-matched controls (CTRL; age: 27±4yr, BMI: 23.7±2.0kg/m²) completed a randomized, double-blind, placebo controlled, crossover study. In the overnight post-absorptive state, participants consumed KME ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 482mg/kg) or a taste-matched placebo 30-min prior to a 75g OGTT. Endothelial function was assessed via flow-mediated dilation (%FMD) pre-OGTT and at 0, 60, and 120-min post-bolus. Following placebo, %FMD was lower in PCOS than CTRL (effect of group, P<0.01). %FMD declined from baseline to 60-min post-OGTT bolus in both groups (PCOS: 6.3±0.4 vs. 4.2±0.4%, P<0.01; CTRL: 9.7±0.9 vs. 6.6±0.9%, P<0.01), with sustained impairments at 120-min in PCOS only (6.3±0.4 vs. 4.0±0.5%, P<0.01). In both groups, KME reduced plasma glucose AUC (P<0.01) and improved %FMD across the OGTT (P<0.01). These data indicate that OGTT-induced endothelial dysfunction is exacerbated in PCOS, and that acute KME improved endothelial function during the OGTT. Overall, these data KME supplementation as a potential means of reducing cardiometabolic risk in PCOS.

Atherosclerosis is a chronic inflammatory disease driven by immune cell interactions within plaques. Nanotherapeutics targeting immune regulation offer potential for atherosclerosis treatment. However, current nanotherapies mainly focus on modulating individual immune subsets and rarely examine cross-cell anti-atherosclerotic mechanisms. Here, we develop an inorganic nanoparticle platform (PEGylated violet phosphorus nanosheets [VPNS@P]) that efficiently accumulates in the immune microenvironment of atherosclerotic plaques, particularly in macrophages and monocytes and partly T/B cells, with minimal off-target uptake. The VPNS@P platform substantially reduces plaque areas and improves plaque stability in atherosclerotic mice without observed side effects. Importantly, we unravel the underlying mechanisms of VPNS@P in atherosclerosis treatment through single-cell RNA sequencing (scRNA-seq) and experimental verification to suppress inflammation and enhance immunity, demonstrating that it effectively modulates four key immune cell populations within plaques. Additionally, VPNS@P reshapes intercellular communication among immune cells, revealing therapeutic targets for atherosclerosis. This study reveals an immune-modulating nanotherapy for atherosclerosis, highlighting the potential in treating inflammatory diseases.