Cardiovascular diseases (CVDs) remain the leading global cause of morbidity and mortality, imposing an increasing clinical and socioeconomic burden. Despite significant therapeutic advances, optimal control of risk factors and long-term outcomes remain challenging, particularly in patients with complex comorbidities. This narrative review provides a comprehensive and up-to-date synthesis of pharmacological options across major cardiovascular domains, with a specific focus on hypertension, heart failure, arrhythmias, and hypertrophic cardiomyopathy, conditions in which hemodynamic, neurohormonal, and electrophysiological pathways play central roles. We summarize mechanisms of action, clinical evidence, safety profiles, and guideline-based indications of established therapies, highlighting their relevance to vascular tone regulation, neurohormonal modulation, endothelial signaling, and myocardial function, the mechanistic axes that intersect with pathways implicated in pulmonary vascular disease (PVD). In addition, we discuss emerging therapeutic targets and innovative agents such as renin-angiotensin-aldosterone system silencers, endothelin pathway modulators, SGLT2 inhibitors, soluble guanylate cyclase stimulators, myosin inhibitors, and other mechanism-based approaches. Current challenges and unmet clinical needs are examined in the context of translational relevance for PVD and the broader goal of advancing individualized pharmacotherapy. Continued therapeutic innovation targeting shared vascular, metabolic, and neurohormonal pathways holds promise for improving outcomes across both systemic and pulmonary vascular diseases.
Atherosclerosis (AS) contributes to cardiovascular diseases (CVDs) through inflammation and oxidative stress, with inflammation-associated cell death pathways as drivers of vascular injury. This study aimed to investigate the protective effects of colchicine on diet- induced vascular remodeling, focusing on caspase-1-dependent inflammatory signaling, caspase-3/gasdermin E (GSDME)-mediated cell death pathways, and toll-like receptor 4 (TLR4) signaling modulation. Forty adult male C57BL/6 mice were categorized into four groups: control, colchicine-treated (0.25 mg/kg/day, i.p.), hypercholesterolemic, and hypercholesterolemic plus colchicine (0.25 mg/kg/day, i.p.). Mice were sacrificed after 12 weeks, and blood samples were collected. Thoracic aortic specimens were prepared for subsequent biochemical, molecular, histological, and ultrastructural analysis. Colchicine administration significantly improved serum lipid profiles and modulated tissue oxidative stress by decreasing (1.8-fold) malondialdehyde (MDA) levels and increasing (1.75-fold) superoxide dismutase (SOD) levels. Colchicine significantly downregulated the mRNA expression levels of caspase-1 (2.4-fold), interleukin-1 beta (IL-1β) (3.6-fold), specificity protein 1 (SP1) (3.0-fold), signal transducer and activator of transcription 3 (STAT3) (2.4-fold), GSDME (3.3-fold), and TLR4 (2.6-fold) in the aortic samples, accompanied by near-normal immunohistochemical expression of caspase-3 and IL-1β. Furthermore, colchicine effectively preserved aortic wall structure, diminished fibrosis, and attenuated ultrastructural damage associated with inflammatory cell death. Colchicine displays protective effects against diet-induced vascular remodeling in mice, associated with the modulation of inflammatory and cell death pathway markers, alongside ultrastructural improvements. These findings support its therapeutic potential for mitigating vascular injury relevant to atherosclerosis, though further mechanistic validation is required.
Vascular diseases remain a leading cause of global mortality, yet the dietary and lifestyle factors that contribute to them are not fully understood in Central Anatolian populations. This study aimed to quantify the dietary and lifestyle predictors of vascular disease status in a case-control cohort from a tertiary care setting in Yozgat province. A total of 1452 adults were enrolled from Yozgat Bozok University Research Hospital: Cardiovascular Surgery (CVS; cases, n = 720) and Primary Care (PC; controls, n = 732). All participants completed a 43-item questionnaire on diet, lifestyle, and sociodemographic characteristics. Binary logistic regression was used to identify independent predictors of case status, with age, sex, education, and income being included in the model. Chronic comorbidities were present in 33.9% of the control group and 80.3% of the case group. Use of olive oil was most strongly associated with control status (odds ratio [OR] = 0.17; 95% confidence interval [CI]: 0.11-0.27), followed by use of butter (OR = 0.25). Paradoxically, fast food (OR = 0.24) and junk food (OR = 0.31) consumption were more frequent among controls. The use of sunflower oil (OR = 2.30), diabetes (OR = 5.22), and elevated serum ferritin (OR = 1.04 per 10 ng/mL) independently predicted a higher likelihood of being in the case group. The model explained 54.8% of the variance (Nagelkerke R2 = 0.548). The apparently higher prevalence of unhealthy dietary behaviours among controls is most plausibly attributed to post-diagnosis dietary modification among cases (an 'illness effect'), underscoring the window for intervention before disease onset. As this case-control design precludes causal inference, these associations are hypothesis-generating. Promoting olive oil and reducing sunflower oil represent practical, culturally feasible dietary targets for cardiovascular risk counselling in Central Anatolia, pending prospective confirmation.
To explore the complex molecular mechanisms of Naoshuantong capsule (, NST), a Traditional Chinese Medicine formula, against ischemic stroke (IS) using network pharmacology and various experimental verifications. This study employed an integrative approach that combined network pharmacology with experimental validation. Specifically, a network pharmacology model was developed to clarify the fundamental mechanisms and essential NST targets against IS. The core targets and pathways were verified using molecular docking and animal experiments. Additionally, the predicted effects of NST were confirmed by a series of experimental techniques, including hematoxylin-eosin staining, platelet aggregation, flow cytometry, and Western blotting. A total of 299 targets for overlap of compounds-disease targets were predicted. Protein-protein interaction (PPI) network analysis revealed that the top 30 core targets. Subsequent molecular docking analysis demonstrated that serine-threonine protein kinase 1 (AKT1), phosphoinositide 3-kinase (PI3K), and vascular endothelial growth factor A (VEGFA) have significant binding abilities with these compounds. Gene ontology (GO) enrichment analysis indicated that NST mechanisms against IS involved anti-apoptosis, antiplatelet-aggregation, and angiogenesis ability, confirmed by animal experiments. GO pathway analysis further showed that the mechanism of NST in treating IS was associated PI3K-AKT signaling. Ultimately, this study determined that NST downregulated cleaved-caspase-3 expression while upregulated phosphorylated AKT (P-AKT)/AKT, phosphatidylinositol-4,5-Bisphosphate 3-kinase/PI3K, B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein, and VEGFA expressions. The analysis utilizing multiple approaches manifested that NST has anti-apoptotic, antiplatelet-aggregation, and pro-angiogenic properties in managing IS, offering a systemic outlook for investigating the impact of NST on IS.
Ischemic stroke is associated with increased risk of subsequent cardiac ischemic events, yet mechanisms linking cerebral ischemia to coronary dysfunction remain unclear. We hypothesized that ischemic stroke directly impairs coronary microvascular function through circulating factors released after cerebral ischemia. We found that the vasodilator function of coronary arterioles (CA) was reduced in patients with prior ischemic stroke. In rats, transient middle cerebral artery occlusion impaired CA vasodilator function. Extracellular vesicles (EVs) isolated after cerebral ischemia and delivered into the rat CA lumen also impaired vasodilation. Moreover, we found that luminal delivery of RGD peptide attenuated flow-induced vasodilation in rat CA, an effect that was prevented by BQ-123, an endothelin ETA receptor antagonist. We propose that ischemic stroke directly induces coronary microvascular dysfunction via circulating EV-mediated, RGD-motif-dependent activation of endothelin signaling. This brain-heart vascular axis provides a mechanistic basis for increased post-stroke coronary risk and identifies EV-mediated pathways as potential therapeutic targets.
Insulin resistance is a core metabolic abnormality driving the progression of cardiovascular-kidney-metabolic (CKM) syndrome. However, the gold-standard hyperinsulinemia-euglycemic clamp remains challenging for routine clinical use. The Single-Point Insulin Sensitivity Estimator (SPISE) index, calculated from HDL-C, triglycerides, and BMI without requiring insulin measurement, offers a simple and noninvasive alternative. However, its prognostic value for incident cardiovascular disease (CVD) in early-stage CKM syndrome (stages 0-3) has not been established. This prospective cohort study included 391,793 participants from the UK Biobank with CKM stage 0-3. Participants were followed for a median of 7.6 years. Cox proportional hazards regression, and restricted cubic spline regression analyses were employed to examine the association between SPISE and incident CVD and coronary heart disease (CHD), adjusting for demographic, lifestyle, and clinical covariates. Subgroup analyses and sensitivity analyses were also conducted. During follow-up, 66,577 participants (17%) with stage 0-3 CKM syndrome experienced incident CVD, including 31,597 cases (8%) of CHD. SPISE demonstrated a significant L-shaped, inverse association with CVD risk, with an inflection point at 5.81 (P for nonlinearity < 0.001).Compared with the lowest tertile, the second and highest tertiles of SPISE were associated with 21% (HR 0.79, 95% CI 0.77-0.80) and 31% (HR 0.69, 95% CI 0.67-0.70) lower risk of incident CVD, respectively. The protective association was stronger for CHD, with corresponding HRs of 0.73 (95% CI 0.71-0.75) and 0.54 (95% CI 0.52-0.55). Subgroup analyses revealed more pronounced benefits among younger participants (< 45 years; HR 0.71, 95% CI 0.68-0.74 for CVD) and never/previous smokers (P for interaction < 0.005). In this large population-based study, higher SPISE index was independently and nonlinearly associated with lower risk of incident CVD and CHD in patients with early-stage CKM syndrome. The SPISE index may serve as a practical, cost-effective tool for cardiovascular risk stratification and early prevention in this high-risk population.
Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated "redox-dead" DRP1-C631A knock-in mutant (Drp1C/A) BM exhibited markedly reduced limb perfusion recovery and CD31+ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G+ neutrophil accumulation, pro-inflammatory F4/80+CD80+ M1-like macrophages and reduced anti-inflammatory F4/80+CD206+ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD.
Retinal neurovascular unit (RNVU) dysfunction underlies major blinding and neurodegenerative conditions including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal ischemia-reperfusion (RIR) injury, and Alzheimer's disease (AD)-associated retinopathy. Within the RNVU, calcium ions coordinate neurotransmission, glial activation, vascular tone, and blood-retinal barrier maintenance, and calcium dysregulation is emerging as a unifying pathogenic hub across these conditions. Although upstream triggers differ, including mechanical stress in glaucoma, hyperglycemia in DR, oxidative damage in AMD, ischemic energy failure in RIR, and amyloid-β-driven endoplasmic reticulum stress in AD, all converge on disruption of intracellular calcium homeostasis, producing shared downstream consequences including excitotoxic injury of retinal ganglion cells (RGCs), Müller cell reactive gliosis, and pericyte hypercontraction. Broad-spectrum calcium channel blockade has shown limited clinical success, underscoring the need for cell-type-specific and pathway-selective approaches. This review therefore catalogs key interventional nodes, including transient receptor potential (TRP) channel antagonists, T-type calcium channel inhibitors, calcium/calmodulin-dependent protein kinase II (CaMKII) suppressors, and mitochondrial permeability transition pore (mPTP) inhibitors, and discusses how precision targeting of these pathways may restore RNVU homeostasis and open a therapeutic window into central nervous system (CNS) degenerative disorders.
Pituitary adenylate cyclase-activating polypeptide (PACAP) functions as an anti-atherogenic neuropeptide. Maxadilan, a PAC1 receptor agonist, offers atheroprotection by acting downstream of vascular inflammation caused by hypercholesterolemia. This study aims to explore how PACAP and Maxadilan influence migration and apoptosis in human coronary artery smooth muscle cells (HCASMCs). To investigate the role of PACAP deficiency in the pathogenesis of atherosclerosis under standard chow (SC) in vivo, PACAP-/--mice were crossed with ApoE-/--mice to generate PACAP-/-/ApoE-/--mice. The whole aorta was isolated and stained with OilRedO (ORO). Atherosclerotic lesions and lumen stenosis in the brachiocephalic trunk were quantified using ImageJ 1.54p (Fiji). To further investigate the role of PACAP and Maxadilan in the pathogenesis of atherosclerosis with special respect to HCASMC under a lipid-enriched environment, HCASMCs were treated with oxLDL, with or without PACAP or Maxadilan. Uptake and accumulation of oxLDL were analyzed using BodipyTM493/503, and cell viability was assessed with PrestoBlue®. Cell migration was evaluated using the scratch assay and the MRI wound-healing tool in ImageJ (Fiji). Mitochondrial morphology was examined with MitoTracker Green and the MiNA tool in ImageJ (Fiji). Apoptotic processes were analyzed by Western blot, immunocytofluorescence staining, and ELISA. In vivo, PACAP-/-/ApoE-/--mice showed increased lumen stenosis and decreased plaque burden compared with ApoE-/--mice. In vitro, PACAP enhanced the viability of oxLDL-treated HCASMCs, while neither PACAP nor Maxadilan influenced lipid content in HCASMCs, regardless of oxLDL presence. Both oxLDL and PACAP slowed cell migration, but Maxadilan increased migration in oxLDL-treated HCASMCs. The protein level of the proliferation marker Ki67 was reduced in cells treated with oxLDL and Maxadilan. Additionally, BAX, which promotes intrinsic apoptosis, was elevated in HCASMCs stimulated with Maxadilan and oxLDL. Investigations of mitochondrial morphology indicated that oxLDL and PACAP increased the individual and network structures, with a decrease in branches per network. Our data highlight the complex role of the PACAP/PAC1 system in vascular pathology and suggest that selective modulation-such as targeted PAC1 activation or PACAP supplementation-could lead to new strategies for stabilizing atherosclerotic plaques. In the long term, this could improve the balance between plaque formation and vascular function.
Current treatments for choroidal neovascularization (CNV) and its associated subretinal fibrosis (SRF), major causes of vision loss, are limited by the need for frequent intravitreal injections and the emergence of drug resistance. This study evaluated the safety and efficacy of the intravitreal administration of engineered humanized anti-vascular endothelial growth factor Nanobodies, including a wild-type Nanobody (WHNb) and two mutated variants (MHNb136 and MHNb256), in a rat model of laser-induced CNV and associated SRF. Safety was assessed through in vivo electrophysiological and histopathological analyses following intravitreal injection of Nanobodies at doses of 12.5, 25, 50, and 100 µg. Efficacy was evaluated in rat models of laser-induced CNV and SRF using double immunohistochemistry for isolectin B4 and anti-collagen type I on sclerochoroidal flat mounts. Mean CNV and SRF areas in Nanobody-treated groups were compared with those in bevacizumab-treated and sham control groups. None of the Nanobodies showed retinal toxicity in safety assessments. Compared with bevacizumab, MHNb136 and MHNb256 reduced the CNV area by 1.72-fold and 1.8-fold, respectively (both p < 0.0001), whereas WHNb showed an effect nearly identical to that of bevacizumab. In addition, 12.5 µg MHNb136 and 100 µg MHNb256 reduced the SRF area by 1.3-fold (p = 0.047) and 1.6-fold (p = 0.0007), respectively, relative to bevacizumab. For CNV reduction, 12.5 µg MHNb136 was comparable to 25 µg MHNb256; both outperformed bevacizumab. For SRF reduction, 12.5 µg MHNb136 was more effective than bevacizumab and comparable to 100 µg MHNb256. These findings suggest that 12.5 µg MHNb136 may represent a cost-effective bioengineered Nanobody candidate for future clinical studies.
We report an in situ light-mediated reinforcement strategy for spatial microvascular patterning. Laser-patterned stiff zones in AlgMA/fibrin hydrogels suppress capillary formation by >81%. A linear stiffness-density relationship (R2 > 0.78) enables predictable engineering of heterogeneous tissue architecture.
The article presents the results of a structured literature review of the past decade and focuses on the crucial role of platelets in the pathogenesis of pulmonary arterial hypertension (PAH). It explores how endothelial dysfunction initiates early prothrombotic signals that activate platelets, which, in response, adopt a pro-inflammatory phenotype, release cytokines and chemokines, and form aggregates with leukocytes, thereby modulating their migration and activity. A key feature of PAH is the "platelet paradox," in which chronic in vivo activation coexists with reduced ex vivo reactivity due to functional exhaustion. Prolonged stimulation and disease progression lead to complex hemostatic dysregulation, characterized by heterogeneity in platelet phenotypes. At the same time, platelets undergo immunometabolic reprogramming, with a predominance of glycolysis, over oxidative phosphorylation, mitochondrial dysfunction, altered fatty acid oxidation (FAO), increased lactate production, and enhanced vesicle release. These phenomena sustain inflammation and promote pulmonary vascular remodeling. This study aims to review the current mechanisms of immunometabolic platelet activation in pulmonary arterial hypertension. It primarily focuses on platelet aspects as key elements in disease progression and as potential sources of new biomarkers and therapeutic targets.
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Atherosclerotic cerebral infarction (ACI) is a major cause of disability and mortality worldwide. Atorvastatin provides lipid-lowering and anti-inflammatory benefits, whereas herb-partitioned moxibustion (HPM) may improve circulation and vascular function. This study evaluated the effects of atorvastatin combined with HPM on oxidative stress, blood rheology, and vascular physiological function in patients with ACI. In this prospective randomized controlled trial, 100 patients with ACI admitted between December 2023 and October 2024 were randomly assigned to a research group receiving atorvastatin plus HPM (n = 50) or a control group receiving conventional Western medicine alone (n = 50). Treatment lasted 12 weeks. Primary outcomes were serum paraoxonase-1 (PON-1) and oxidized low-density lipoprotein (ox-LDL). Secondary outcomes included blood rheology indexes, vascular physiological function parameters, clinical efficacy, and adverse reactions. All patients completed the study. Compared with the control group, the research group showed significantly lower whole blood viscosity at high shear (5.10 ± 1.23 vs. 6.15 ± 1.02 mPa·s), low shear (8.10 ± 1.17 vs. 10.46 ± 1.09 mPa·s), and plasma viscosity (1.20 ± 0.28 vs. 1.88 ± 0.36 mPa·s) (all p < 0.05). PON-1 levels were higher (185.62 ± 56.28 vs. 162.20 ± 54.24 µg/L; p = 0.037) and ox-LDL levels were lower (448.24 ± 80.64 vs. 500.40 ± 85.20 kU/L; p = 0.002). In addition, vascular physiological function improved significantly, with higher peak A, stroke volume, and ejection fraction and lower peak E and MVCF (all p < 0.001). The total effective rate was higher in the research group (94.0% vs. 82.0%; p = 0.037), with comparable adverse-event rates. Atorvastatin combined with HPM improved oxidative stress, blood rheology, vascular physiological function, and clinical outcomes in ACI without increasing adverse reactions.
Background. This rat study reveals a new point: the considerable impact of unilateral adrenalectomy, severe vascular and multiorgan failure, occlusion/occlusion-like syndrome, and the stable gastric pentadecapeptide BPC 157 therapy. Based on the recent Fourier transform infrared (FTIR) spectroscopy vascular disturbance studies, particularly those after unilateral adrenalectomy in rats, the noted cytoprotective vascular recovery effect of the BPC 157 therapy may be useful. Methods. In rats, unilateral adrenalectomy (at 15 min, 5 h, 24 h) leads to integrated gross and morphological changes, vascular alterations, oxidative stress parameters, molecular markers and occlusion/occlusion-like syndrome and BPC 157 as useful therapy (/kg ig) (10 µg, 10 ng). Results. Peripherally and centrally, counteraction includes the lesions (adrenal, brain, heart, lung, liver, kidney, gastrointestinal tract), organ hemorrhage, and thrombosis. Attenuated/eliminated were arrhythmias, intracranial (superior sagittal sinus), portal, caval hypertension, and aortic hypotension. Significant resolution occurred via activation of collateral pathways, the azygos vein (direct blood flow delivery), and the recovered peduncle of the inferior suprarenal artery and superior suprarenal vein. Virchow's triad circumstances were reversed. Occlusion/occlusion-like syndrome was counteracted as a whole. Also, BPC 157 counteracted adrenal lesions (lipid depletion, congestion). There were higher cortisol values, but still very low, and a shift toward the left of the adrenal compensatory weight increase. For the indicative conclusion along with previous studies, mechanistically, BPC 157 therapy exhibits the NO-system modulation/oxidative stress balance, increases NO-level, counteracts oxidative stress (malondialdehyde (MDA)), upregulates NOS1-3, and VEGF-A expression. Conclusions. These effects of BPC 157 therapy and its easy applicability deserve further consideration.
Local immune cell activation and vascular remodelling are characteristic pathogenic features of pulmonary arterial hypertension (PAH). HIV and schistosome infections have been individually associated with PAH. However, whether co-infection with these pathogens has a distinct impact on the development of pulmonary vascular disease remains poorly understood, partly due to the lack of experimental animal models. In a novel non-infectious model of HIV and Schistosoma pulmonary co-exposure based on lung embolisation of S. mansoni eggs in HIV-transgenic (HIV) mice, we previously reported exacerbated endothelial remodelling and dysfunction, along with increased pulmonary arterial pressure; which were associated with a unique profile of pro-inflammatory cytokines in the lung. In the present study, we used flow cytometric analysis of isolated lung leukocytes and immunofluorescence staining to characterise the pulmonary immune cell landscape associated with individual or combined exposure to HIV and schistosome. Compared with mice exposed to HIV (untreated HIV mice) or schistosome (egg-treated wild-type mice), co-exposed (egg-treated HIV mice) animals showed significantly increased numbers of interstitial and alveolar macrophages, patrolling-type monocytes, NKT and γδ T cells, and reduced CD8+ αβ T cells. Other lung immune cells, including inflammatory-type monocytes, eosinophils/neutrophils, dendritic cells, CD4+ αβ T cells, NK cells and B cells were not significantly affected in the co-exposure condition. Taken together, these results show for the first time that combined pulmonary exposure to HIV and Schistosoma, as it may occur in co-infected individuals, alters the local immune cell landscape in a manner distinct from that of individual exposure. Furthermore, these findings may contribute to a better understanding of the complex inflammatory processes involved in the pathogenesis of PAH, thereby supporting the development of therapies targeting pathogenic immune cells in pulmonary vascular disease associated with HIV and Schistosoma co-morbidity.
Proteins can be actively packaged into extracellular vesicles (EVs) through mechanisms dependent on the stimulus that activated the cells. Identifying proteins released in endothelial EVs in response to stimuli relevant to cardiovascular disease (CVD) may therefore reveal potential biomarkers that provide information about the vascular endothelium. This study aimed to identify differentially expressed proteins in EVs released from human umbilical vein endothelial cells (HUVEC) in response to stimuli relevant to vascular endothelium activation. HUVEC were stimulated with tumour necrosis factor alpha (TNFα) (10 ng/mL) or oxidised low-density lipoprotein (oxLDL) (10 µg/mL). Apoptosis was assessed using a flow cytometric DNA fragmentation protocol and caspase-3/7 activity assay. Size distributions of EVs were examined by nanoparticle tracking analysis. Isolated EVs were examined using tandem liquid-chromatography-mass spectrometry (LC-MS/MS). While treatment of HUVEC with TNFα or oxLDL resulted in non-significant elevations in levels of EVs, only TNFα increased apoptosis. Mass spectrometry quantified 1355 proteins and revealed significant differences in the proteome of EVs from TNFα-treated HUVEC compared to EVs from oxLDL-treated or untreated cells. Several candidate biomarkers were significantly and differentially expressed in response to TNFα, including E-selectin and dual specificity phosphatase 7. This study further associated E-selectin on endothelial-derived EVs with endothelial apoptosis and may offer a biomarker of endothelial damage in patients with CVD.
Background: Diabetic retinopathy (DR) is one of the major complications of diabetes mellitus. EJPs (Erjing Pills) are believed in Traditional Chinese Medicine to have the effects of a nourishing essence and a brightening of the eyes, but the specific effect on DR remains unclear. This study aims to investigate the therapeutic effects and underlying mechanisms of EJPs on DR. Methods: The chemical profile of EJPs was characterized by UHPLC-MS. Network pharmacology and molecular docking were employed to predict its active ingredients and potential targets. A DR rat model was induced by streptozotocin. Retinal morphology and function were assessed by OCT, FFA, and H&E staining. The expressions of proteins and mRNAs related to the AGE-RAGE pathway, oxidative stress, inflammation, and tight junctions were detected by Western blot, qPCR, and ELISA. Results: LC-MS and network pharmacology analysis identified 638 common targets between EJPs and DR, with core targets including SRC, AKT1, and MAPK1, primarily enriched in the AGE-RAGE signaling pathway. Molecular docking confirmed strong binding (binding energy < -5.0 kcal/mol) between key EJP constituents and core targets. In vivo, EJP treatment significantly alleviated retinal vascular leakage, improved retinal thickness, and alleviated histopathological damage. In addition, EJPs downregulated the AGEs-RAGE/NF-κB axis and pro-inflammatory cytokines while enhancing antioxidant defenses and tight junction proteins in the retinas of DR rats. Conclusions: EJPs ameliorate DR by protecting the blood-retinal barrier and modulating the AGE-RAGE/oxidative stress/inflammation network, demonstrating a multi-component, multi-target, and multi-pathway mechanism. This study provides a mechanistic basis for the potential application of EJPs in DR management.
Vascular endothelial cells form a selective barrier that regulates the passage of substances and leukocytes between the bloodstream and surrounding tissues, thereby maintaining vascular homeostasis. Although endothelial barrier dysfunction is implicated in numerous diseases, the molecular mechanisms that protect against such dysfunction remain incompletely defined. Thrombin, an inflammatory mediator, increases endothelial permeability by inducing myosin light chain (MLC) phosphorylation through Rho/Rho-associated kinase (Rho-kinase)-mediated inhibition of myosin phosphatase. This process disrupts vascular endothelial cadherin (VE-cadherin)-based junctions and promotes radial stress fiber formation. Here, we demonstrate that the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) reduces phosphorylation of the myosin phosphatase regulatory subunit MYPT1 at inhibitory sites and suppresses Rho-kinase signaling in endothelial cells. Together, these EGCG-mediated effects reduce MLC phosphorylation, inhibit radial stress fiber formation, and preserve VE-cadherin-mediated cell-cell adhesion, thereby maintaining endothelial barrier integrity.