As the core molecular chaperones of the cellular stress response, the heat shock protein (HSP) family has gained extensive attention for its role in the occurrence, development, and target organ damage of hypertension. This review aimed to comprehensively summarize the research progress of the HSP family in the field of hypertension, and to analyze its key roles in the pathogenesis of hypertension, including its regulatory effects on key pathological processes such as endothelial dysfunction, proliferation and migration of vascular smooth muscle cells, oxidative stress, and inflammatory responses. It also summarized the potential value of HSPs as biomarkers in the early diagnosis, condition monitoring, and prognostic evaluation of hypertension. Moreover, it discussed in depth the efficacy and safety of intervention strategies targeting HSPs, including the regulation of HSPs by gene editing, the targeted effects of small-molecule inhibitors, and the modulatory effects of natural products. We need to strengthen interdisciplinary collaboration mechanisms, accelerate the transformation of basic research results into clinical applications, carry out large-scale clinical trials, and develop specific modulators in the future, so as to ultimately provide solid scientific theoretical support and a practical clinical basis for the precise prevention and treatment of hypertension. The findings of this review not only provide novel insights into the pathogenesis of hypertension but also lay a theoretical foundation for the development of HSP-based biomarkers and targeted therapeutic strategies.

Vascular smooth muscle cell (VSMC) senescence contributes importantly to atherosclerotic plaque progression, yet the upstream mechanisms remain incompletely understood. Here, by integrating single-cell RNA sequencing analysis with human plaque validation, we found that TGFBR1 is enriched in senescent VSMCs in atherosclerotic lesions and correlates with senescence-associated markers. In vivo, VSMC-specific TGFBR1 knockin in Apoe-deficient mice accelerated plaque development and increased VSMC senescence. Mechanistically, we identified the deubiquitinase USP5 as a previously unrecognized stabilizer of TGFBR1. USP5 directly interacted with TGFBR1 and selectively removed K48-linked polyubiquitin chains at lysine 213, thereby preventing proteasomal degradation. Stabilized TGFBR1 suppressed the mitochondrial enzyme IDH2, driving a metabolic shift toward glycolysis that sustained apoptosis resistance in senescent VSMCs. Conversely, VSMC-specific knockdown of USP5 reduced TGFBR1 expression, restored IDH2 expression, attenuated glycolytic remodeling, and mitigated atherosclerosis in vivo. Our findings reveal a USP5-TGFBR1-IDH2 axis in which site-specific deubiquitination at K213 links receptor stability to metabolic remodeling and VSMC senescence, identifying USP5 as a potential therapeutic target for atherosclerosis.

BACKGROUND:Baduanjin, a traditional Chinese exercise, is commonly used in China as a rehabilitation intervention for patients who have undergone percutaneous coronary intervention (PCI) following an acute myocardial infarction (AMI) (AMI-PCI). However, current evidence supporting its application remains limited. OBJECTIVES:To assess the clinical benefits and safety of Baduanjin in the rehabilitation of patients with AMI-PCI. METHODS:PubMed, the Cochrane Library, CNKI, VIP, and Wanfang were systematically searched for randomised controlled trials (RCTs) assessing the therapeutic effects and safety of Baduanjin in patients with AMI-PCI. The search was conducted up to 18 January 2025. Data were analysed using RevMan 5.4. For dichotomous outcomes, effect sizes were expressed as risk ratios (RRs) with 95% confidence intervals (CIs); the number needed to treat (NNT) was calculated where appropriate. For continuous outcomes measured on the same scale, the mean difference (MD) with 95% confidence interval (CI) was used. When outcomes were assessed using different instruments or scales, results were synthesised descriptively. RESULTS:Thirteen studies involving 1293 participants (870 males and 423 females) were identified. Baduanjin significantly improved left ventricular ejection fraction (LVEF [MD = 6.20%, 95% CI (3.14, 9.25), Z = 3.98, P < 0.0001, 1003 participants] and 6-minute walk distance (6-MWD) [MD = 60.21 m, 95% CI (17.96, 102.46), Z = 2.79, P = 0.005, 589 participants]. It also led to clinically meaningful improvements in quality of life (QOL), as measured by the Seattle Angina Questionnaire [MD = 11.36, 95% CI (7.66, 15.06), Z = 6.02, P < 0.00001, 150 participants], the Angina Pectoris Quality of Life Questionnaire [MD = 3.71, 95% CI (0.92, 6.50), Z = 2.61, P = 0.009, 92 participants], and the WHOQOL-BREF [MD = 91.40, 95% CI (90.59, 92.21), Z = 220.28, P < 0.00001, 60 participants]. Significant reductions in anxiety and depression symptoms were observed across multiple instruments: on the Hamilton Anxiety Rating Scale, the mean reduction from baseline was greater in the Baduanjin group by 1.40 points [95% CI (0.47, 2.33), Z = 2.95, P = 0.003]; on the Generalized Anxiety Disorder-7 scale, post-intervention scores were lower in the Baduanjin group by 2.67 points [95% CI (2.20, 3.14), Z = 11.14, P < 0.00001]. Similarly, for depression, the mean reduction from baseline on the Hamilton Depression Rating Scale was greater by 2.80 points [95% CI (1.63, 3.97), Z = 4.71, P < 0.00001], and post-intervention scores on the Patient Health Questionnaire-9 were lower by 2.73 points [95% CI (2.25, 3.21), Z = 11.11, P < 0.00001]. Baduanjin did not appear to increase the risk of adverse events and may even reduce the incidence of certain cardiovascular adverse events [15/133 vs. 40/133, RR = 0.40, 95% CI (0.25, 0.65), Z = 3.75, P = 0.0002, NNT = 5]. CONCLUSIONS:The evidence suggests that Baduanjin may provide therapeutic benefits for patients with AMI-PCI, including improvements in cardiac function (LVEF), exercise capacity (6-MWD), QOL, and mental health. Moreover, the practice appears to be safe and may reduce the incidence of certain cardiovascular adverse events. These findings highlight the potential role of Baduanjin in the management and rehabilitation of patients with AMI-PCI, although further well-designed studies are warranted to confirm its efficacy. PROSPERO REGISTRATION NUMBER:CRD 42025634145 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42025634145).

BackgroundCurrent diagnostic and prognostic biomarkers for acute myocardial infarction (AMI) remain limited. Protein succinylation may provide novel biomarker candidates for AMI.MethodsWeighted gene co-expression network analysis (WGCNA) was applied to GSE66360 to identify AMI-related modules, and succinylation-annotated genes were retrieved from GeneCards. Using GSE66360 as the training set and GSE48060, GSE60993, and GSE59867 as validation sets, we evaluated 107 predefined machine-learning pipelines and assessed hub genes by differential expression and ROC analysis. Immune infiltration and gene-cell correlations were assessed with CIBERSORT. Single-cell transcriptomics examined hub-gene expression across monocyte subsets in plaque rupture (PR) and non-plaque rupture (NPR) cases, and exploratory pseudotime analysis assessed monocyte-state heterogeneity. ELISA was used to measure circulating protein levels.ResultsIntegrating WGCNA with GeneCards yielded 18 succinylation-annotated AMI genes. Among the evaluated pipelines, Stepglm[both] + plsRglm and Stepglm[backward] + plsRglm showed relatively favorable external validation performance. ROC and differential expression analyses prioritized ASGR2 and NPL as exploratory candidate biomarkers. Both genes correlated positively with monocytes, particularly classical monocytes. Classical monocytes were more abundant in NPR than PR samples. ASGR2 and NPL showed exploratory expression trends along an inferred pseudotime axis. ELISA showed elevated plasma levels of ASGR2 and NPL in AMI patients compared with control individuals.ConclusionASGR2 and NPL were identified as hypothesis-generating candidate biomarkers associated with acute myocardial infarction. Given the limited training sample size and the high number of evaluated machine-learning pipelines, these findings remain exploratory and require independent prospective validation before clinical translation. Their enrichment in monocytes, particularly classical monocytes, suggests a potential association with monocyte-related inflammatory remodeling.

The efficient enrichment and simultaneous detection of trace levels of angiotensin (Ⅰ, Ⅱ, Ⅲ) and aldosterone in plasma pose certain technical challenges. Herein, we propose a novel strategy where a cationic covalent organic framework (Py-BPy2+-COF) was served as an attractive adsorption material for efficient enrichment of angiotensin (Ⅰ, Ⅱ, Ⅲ) and aldosterone. Adsorption experiments and model fitting revealed that Py-BPy2+-COF exhibited adsorption capacities ranging from 5.02 to 26.12 μg g−1 for the four target analytes. The Hirshfeld partition analysis elucidated that the interaction forces of angiotensin and aldosterone with Py-BPy2+-COF originated from electrostatic interactions, π-π stacking and hydrophobic interactions. Py-BPy2+-COF was employed as the sorbent packing in a 96-well plate coupled with liquid chromatography-tandem mass spectrometry, achieving high sensitivity, excellent reproducibility, high recoveries (80.1

Trace amounts of mycotoxins present in food and herbal medicine are raising significant safety concerns, garnering widespread attention. Accurate, sensitive, and swift detection and control methods for mycotoxins suitable for the complex matrices found in these materials must be developed to ensure public-health protection. Through interdisciplinary advancements, innovative detection strategies have been developed and combined with nanotechnology to address the challenges associated with mycotoxin analysis. This review highlights the methodological advances achieved by utilizing nanomaterials for mycotoxin analysis. It elaborates the integration of their multifunctional roles (as adsorbents, carriers, and signal sources) into a comprehensive technical framework for detection. Focuses on explaining the governing mechanisms linking material properties to detection performance while concurrently revealing the practical bottlenecks inherent in the applied technologies. Furthermore, the challenges and potential opportunities of nanomaterials for detecting mycotoxin in food and herbal medicine are also highlighted.

Longan (Dimocarpus longan Lour.) is a traditional fruit with both nutritional and medicinal value, rich in various bioactive metabolites such as polysaccharides, phenolic acids, flavonoids, proanthocyanidins, triterpenoids, and adenosine. Following PRISMA 2020 guidelines, this narrative review systematically synthesizes the multi-target protective effects of longan’s bioactive metabolites on the vascular endothelial system, drawing on a systematic literature search of PubMed and Web of Science Core Collection (January 2015–July 2026) that employed Boolean combinations of keywords spanning plant nomenclature, vascular endothelium, and cardiovascular pharmacology, supplemented by manual screening of reference lists. Extensive studies using cellular and animal models have revealed that longan extracts and their metabolites effectively alleviate endothelial oxidative damage by directly scavenging free radicals. They downregulate the MAPK/NF-κB pathway, inhibit the expression of pro-inflammatory factors, and remodel the inflammatory microenvironment of the vascular wall. Regarding the regulation of vascular tone, longan metabolites exhibit bidirectional regulation of nitric oxide homeostasis. By inhibiting angiotensin-converting enzyme (ACE) activity, they reduce angiotensin II production and synergistically lower blood glucose, regulate blood lipids, and modulate immune balance. These findings suggest that longan and its bioactive metabolites hold significant potential for functional intervention in vascular diseases.

INTRODUCTION:Shexiang Xintongning (SXN) is a Chinese medicinal compound used to treat cardiovascular diseases and has been formulated into a commercial tablet. Based on Traditional Chinese Medicine (TCM) theory, SXN has anti-atherosclerotic effects. Despite its clinical application, the mechanism of action of SXN remains poorly understood. This research seeks to clarify the molecular pathways and active constituents through which SXN combats atherosclerosis. METHODS:In this study, network pharmacology was used to predict potential targets and biological processes involved in SXN's treatment of atherosclerosis (AS). AS was induced in ApoE⁻/⁻ mice by feeding them a high-fat diet (HFD). The anti-atherosclerosis effects of SXN were observed in the aorta, aortic root, and serum. Based on the screening pathways and targets, experimental analyses were conducted to elucidate the mechanisms underlying its pharmacological action. RESULTS:The chemical constituents of SXN were identified using UPLC/MS-MS analysis. The main components, including Muscone, Jasmone, Tetramethylpyrazine, Ferulic acid, trans-Cinnamic acid, and Senkyunolide H, were identified. Network pharmacology analysis revealed that the antiatherosclerotic effects of SXN were closely associated with the HIF-1 signaling pathway and the key factor HIF-1α. SXN significantly reduced atherosclerotic plaque formation, improved lipid profiles, suppressed inflammation, and alleviated oxidative stress in a dose-dependent manner. Mechanistically, SXN downregulated HIF-1α/HIF-2α while upregulating GPX4 and SLC7A11, indicating inhibition of ferroptosis. DISCUSSION:These findings suggest that SXN exerts anti-atherosclerotic effects mainly by modulating the HIF-1 signaling pathway, improving lipid metabolism, attenuating inflammation and oxidative stress, and inhibiting ferroptosis, thereby providing mechanistic support for its traditional use in cardiovascular disease. CONCLUSION:SXN demonstrates significant anti-atherosclerotic efficacy by targeting the HIF- 1α/SLC7A11/GPX4 signaling axis, thereby elucidating novel mechanistic paradigms underlying cardiovascular therapeutic applications of Traditional Chinese Medicine and establishing ferroptosis as a critical molecular target for atherosclerotic disease intervention.

Vascular endothelial cells play a crucial role in maintaining the structural integrity and microcirculatory function of the coronary microvasculature. Endothelial dysfunction, a critical pathological process in various cardiovascular diseases including myocardial infarction (MI), leads to reduced myocardial blood flow due to a lack of nitric oxide gas inside blood vessel walls that ultimately causes inflammation, thrombosis and coronary artery obstruction. Therefore, the identification of molecular mechanisms that protect against endothelial cell injury is necessary for effective MI treatment. In this study, we identified a novel interaction between TEK receptor tyrosine kinase (TEK) and signal transducer and activator of transcription 3 (STAT3), promoting the phosphorylation and nuclear translocation of STAT3. In particular, the upregulation of STAT3 and p-STAT3 could be prevented by inhibiting the binding of STAT3 to TEK using specific STAT3 domain inhibitors. Additionally, chromatin immunoprecipitation (ChIP) analysis revealed that STAT3 acts as a transcription factor, binding to the promoter region of lysyl oxidase (LOX) and LOX propeptide (LOX-PP) and inhibiting their transcription. Notably, excessive LOX-PP has been shown to induce endothelial cell injury, leading to reduced nitric oxide synthesis, increased permeability, and impaired functionality in terms of proliferation, migration, and tube formation. These novel findings reveal a new mechanism of endothelial cell injury after myocardial ischemia and may offer new insights for developing future therapeutic approaches.

Background Ba-Wei-Chen-Xiang San (BWCX), a classic formula in Traditional Tibetan Medicine (TTM), has been historically employed for preventing and treating “Chalong” disorders, which correspond to cardiovascular diseases in modern medicine. Previous literature mainly describes BWCX as a cardioprotective agent that can improve myocardial hypertrophy by regulating cardiac energy metabolism pathways. But the specific pharmacological mechanism by which it regulates the systemic metabolic drivers of essential hypertension still needs to be studied. Aim of the study This study aimed to systematically investigate the antihypertensive efficacy of BWCX and decipher its mechanism of action by identifying bioactive components and metabolic targets. Materials and methods The chemical composition characterization and blood-absorbed components of BWCX were characterized using Ultra Performance Liquid Chromatography-Quadrupole-Exactive Orbitrap Mass Spectrometry (UPLC-Q-Exactive Orbitrap-MS). Antihypertensive efficacy was evaluated in spontaneously hypertensive rats (SHR) by monitoring blood pressure, body weight, and liver histopathology. SHR were administered BWCX at low (0.27 g/kg), medium (0.54 g/kg), and high (1.08 g/kg) daily doses via intragastric gavage for 8 weeks. Valsartan (14.28 mg/kg) was used as a positive control. Serum and liver lipid metabolomics were performed to identify key biomarkers and pathways. Finally, the interaction between screened blood-absorbed components and the core target, choline-phosphate cytidylyltransferase α (CCTα), was predicted by molecular docking and validated by cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and surface plasmon resonance (SPR). Results UPLC-Q-Exactive Orbitrap-MS identified 191 chemical components and 37 blood-absorbed components from BWCX. BWCX significantly reduced systolic and diastolic blood pressure in SHR rats. Importantly, unlike known cardiocentric mechanisms, metabolomics analysis revealed that BWCX exerts its therapeutic effect primarily by reprogramming hepatic glycerophospholipid metabolic pathways. Lipid droplets in hepatocytes were reduced after BWCX administration compared with the SHR model group. BWCX regulated the abnormal levels of serum Ang II, Ren, and Ald in SHR rats. Metabolomics analysis revealed that 19 potential biomarkers, mainly linked to primary bile acid, sphingolipid, arachidonic acid, and glycerophospholipid metabolism pathways. Liver lipid metabolomics identified 11 potential biomarkers, primarily restoring the glycerophospholipid metabolism pathway. Specifically, BWCX reversed abnormal phosphatidylcholine (PC) biosynthesis. Three bioactive chromone components (DMPEC, MPEC, and DPEC) were predicted by molecular docking and confirmed by biophysical assays that they exhibited strong binding affinity to CCTα, the rate-limiting enzyme in PC synthesis. Conclusion This study provides new insights for future research on BWCX: in addition to its known cardioprotective effects, it also acts as a systemic metabolic regulator. BWCX exerts significant antihypertensive effects and ameliorates liver lipid metabolism disorders in SHR rats. The mechanism involves the modulation of the CCTα-mediated glycerophospholipid metabolic pathway by specific bioactive chromones. These findings provide a scientific basis for the clinical application of BWCX in hypertension management.

ObjectiveTo evaluate the long-term efficacy and safety of the Astragalus-Salvia miltiorrhiza (ASM) botanical drug pair as an adjunctive therapy for stable coronary artery disease (SCAD) and to develop a prognostic nomogram for frequent readmissions.MethodsThis real-world retrospective cohort study included 686 SCAD patients (343 receiving ASM plus standard care and 343 receiving standard care alone). Inverse probability of treatment weighting (IPTW) was applied to balance covariates. After a 5-year follow-up, biochemical parameters, primarily low-density lipoprotein cholesterol (LDL-C), and safety profiles were compared. Furthermore, multivariable logistic regression was used to construct a nomogram predicting frequent readmissions (≥3 times), and symptom networks were analyzed via the Apriori algorithm to evaluate symptom alleviation.ResultsAt the 5-year follow-up, compared to controls, the ASM group exhibited significantly reduced LDL-C, total cholesterol (TC), triglycerides (TG), heart rate, and monocytes, alongside elevated high-density lipoprotein cholesterol (HDL-C), free triiodothyronine (FT3), and free thyroxine (FT4) (all P < 0.05). Hepatic and renal functions remained unaffected (P > 0.05). Notably, stroke history emerged as the primary independent risk factor (P < 0.001) for frequent readmissions. The nomogram integrating stroke history, age, diastolic blood pressure, FT3, and hemoglobin demonstrated excellent calibration. Symptom network analysis identified “chest tightness” as the core symptom alleviated by ASM.ConclusionASM adjunctive therapy safely improves lipid profiles, stabilizes heart rate, and alleviates chest tightness in SCAD. The proposed nomogram offers a reliable tool for risk stratification, providing real-world evidence to optimize the integrative management of SCAD.Clinical Trial Registrationhttps://itmctr.ccebtcm.org.cn/mgt/dashboard, identifier TMCTR2025000058.

The mechanical cation channel Piezo1 has been confirmed as a key membrane mechanical protein that can convert physical forces into biological signals, serving as a molecular hub linking hemodynamic stimulation with thrombotic diseases. Studying mechanical sensitive channels in the cardiovascular system is helpful for understanding the working mechanism of these channels and providing new therapeutic targets for thrombotic diseases. This article systematically summarizes the expression and functional roles of the Piezo1 channel in cell types involved in thrombosis, including platelets, endothelial cells, red blood cells, immune cells, etc. This article also discusses the mechanical gating structural basis of Piezo1 and its activation mechanism and downstream signaling pathways in the thrombosis-related mechanical microenvironment. Based on the existing evidence, Piezo1 has significant pathological significance in the occurrence and development of thrombotic diseases, and targeting Piezo1 may provide new strategies for anti-thrombotic treatment. Future research needs to further clarify the differential regulatory mechanisms of the Piezo1 channel in different hemodynamic environments and evaluate its safety and efficacy as a drug target.

Purpose: This study aims to elucidate the molecular mechanism underlying the therapeutic effect of AS-IV in combination with Tan IIA in ameliorating cardiac fibrosis by inhibiting excessive collagen cross-linking following myocardial infarction (MI). Methods: MI model mice were administered AS-IV and Tan IIA for a duration of four weeks. After the treatment was completed, serum and cardiac specimens were collected from the mice to assess cardiac collagen fiber deposition, collagen cross-linking, cardiac function, copper homeostasis, lysyl oxidase (LOX) content, and the expression of related molecules. Meanwhile, utilizing an in vitro model of myofibroblasts and employing CTR1 overexpression or siRNA-mediated CTR1 silencing and recombinant LOX, we systematically investigated the effects of AS-IV and Tan IIA on key phenotypic features in myofibroblasts, including cross-linking and copper levels. Results: Our results demonstrate that AS-IV and Tan IIA significantly inhibited excessive collagen cross-linking in infarcted hearts, reduced cardiac collagen deposition, and consequently attenuated adverse cardiac remodeling while preserving cardiac function. Mechanistically, AS-IV and Tan IIA suppress intracellular copper accumulation by downregulating the CTR1/ATOX1 axis in the copper transport pathway within myofibroblasts. This downregulation subsequently reduces both the expression and enzymatic activity of LOX, a copper-dependent enzyme, thereby inhibiting excessive collagen cross-linking in these cells. Moreover, AS-IV and Tan IIA demonstrate potential in restoring abnormal copper homeostasis after myocardial infarction and modulating copper distribution within myofibroblasts. Conclusion: AS-IV and Tan IIA attenuate collagen cross-linking in myofibroblasts by downregulating the CTR1/ATOX1/LOX axis, thereby reducing aberrant collagen cross-linking and deposition in the infarcted heart and ultimately inhibiting cardiac fibrosis.

Autoimmune factor XIII (FXIII) deficiency is a rare hemorrhagic disease characterized by severe bleeding and a high mortality rate. However, the pathogenesis of this disease remains unclear. FXIII consumption caused by infections is becoming increasingly common. Our clinical investigation, combined with in vivo experiments, revealed that patients and mice with autoimmune FXIII deficiency displayed complement dysfunction and that pathogenic infection and autoantibody generation were positively correlated. Further analysis revealed the presence of combined FXIII-C3 autoantibodies in patients with autoimmune FXIII deficiency. These combined autoantibodies neutralize FXIII, cause bleeding, and form a complex with C3, inhibiting complement activation and complement-mediated adaptive immune responses. Therefore, compromised immune responses increase host susceptibility to pathogenic Candida albicans infections. Consequently, uncontrolled exogenous fungal infections further activate platelets and cause platelet-related CD40 ligand (CD40L) release. By interacting with the CD40 on the B cell surface, the released CD40L further promotes autoreactive B cell activation to produce more autoantibodies, thereby forming a self-amplification loop for the progressive consumption of FXIII. We believe this study provides a perspective on disease pathogenesis and therapeutic guidance for better treatment of autoimmune FXIII deficiency.

Atherosclerosis is a chronic inflammatory disease. Inhibition of macrophage inflammatory secretion is the key to the prevention and treatment of atherosclerosis. Ershen Dan (ESD) has been shown to be effective in treating atherosclerosis; however, its pharmacological mechanisms remain unclear. This study elucidated the mechanism of action of ESD by investigating its relationship with macrophages. The chemical composition of ESD was analyzed using ultra performance liquid chromatography (UPLC)-Q-Exactive-tandem mass spectrometry (MS/MS). In the in vivo experiments, serum levels of low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC) in ApoE−/− mice were measured using a biochemical analyzer. The serum levels of key inflammatory factors were quantified using an enzyme-linked immunosorbent assay (ELISA). The aortic lipid plaque area was assessed using Oil Red O staining, while plaque characteristics were evaluated using hematoxylin and eosin (H E), Masson trichrome, and Sirius Red staining techniques. Network pharmacology analyses in conjunction with molecular dynamics simulations was used to screen the active components of ESD and their target proteins. By integrating database resources, the key target genes related to inflammatory responses in atherosclerosis were identified. The expression levels of neurogenic locus notch homolog protein 1 (NOTCH1), hairy and enhancer of split-1 (HES1), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), and nuclear factor (NF)-κB in mouse aortic tissue were detected using western blot analyses. CD86 levels in mouse aortas were quantitatively analyzed by immunohistochemistry. In the in vitro experiments, RAW264.7 cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Macrophage phenotypic changes were evaluated using immunofluorescence analyses. Intracellular levels of reactive oxygen species (ROS) were measured using dichloro-dihydro-fluorescein diacetate (DCFH-DA) probes. The expression levels of key proteins and genes were validated by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). Twenty bioactive chemical components were identified in ESD. In vivo studies demonstrated that ESD inhibits macrophage secretion of inflammatory factors through the NOTCH1/NF-κB/NLRP3 signaling pathway, indicating its therapeutic potential for atherosclerosis. In vitro studies further revealed that ginsenoside Rg1 and tanshinone IIA, which are active constituents of ESD, exert anti-inflammatory effects by suppressing the NOTCH1/NF-κB/NLRP3 pathway and reducing intracellular ROS levels in macrophages, supporting their role in atherosclerosis treatment.

BACKGROUND AND PURPOSE:Mitochondrial dysregulation of endothelial progenitor cells (EPCs) has been implicated in endothelial destruction and hypertension. Regulation of silent information regulator 3 (sirtuin 3; SIRT3) in mitochondrial damage of EPCs and the underlying molecular mechanisms remain unclear, and evidence of selective SIRT3 agonists for the treatment of hypertension also is lacking. EXPERIMENTAL APPROACH:Here, we discovered a potent SIRT3 agonist, rhynchophylline (Rhy), and explored its underlying action on mitochondrial damage of EPCs and endothelial dysfunction. KEY RESULTS:In spontaneously hypertensive rats, Rhy reduced blood pressure and ameliorated vasomotion, paralleling improved EPC function in the peripheral circulation. Moreover, Rhy alleviated mitochondrial damage and inhibited apoptosis via the mitochondrial apoptotic pathway. SIRT3 knockdown interrupted the regulation of mitochondrial homeostasis induced by Rhy, thus abolishing its antagonizing effect on EPC dysfunction and endothelial damage, suggesting that Rhy protection of EPC mitochondria is mediated via the activation of SIRT3. Rhy restrained the production of mitochondrial ROS and improved the activity of superoxide dismutase 2 (SOD2) in a SIRT3-dependent manner, whereas silencing SOD2 eliminated the inhibition by Rhy of oxidative stress and apoptosis, reflecting that SOD2 was indispensable for the regulation of Rhy on mitochondrial dysfunction and the mitochondrial-mediated apoptosis pathway. CONCLUSION AND IMPLICATIONS:SIRT3-dependent mitochondrial homeostasis contributes to attenuating hypertension-related EPC dysfunction and endothelial injury, and Rhy itself is a potent and targeted SIRT3 agonist that prevented mitochondrial dysfunction by regulating the SIRT3/SOD2 pathway, which may provide new clues for drug candidates for hypertension therapeutics.

Inflammation has become a major residual risk factor for atherosclerotic cardiovascular disease (ASCVD). Certain lipid mediators, known as specialized proresolving mediators (SPMs), are mainly derived from polyunsaturated fatty acids (PUFAs) and can promote inflammation resolution while maintaining host autoimmunity. This review investigates the synthesis and ligand action pathways of these lipid mediators, as well as their regulatory mechanisms in the microenvironment of atherosclerotic plaques. Furthermore, it explores their clinical therapeutic potential, aiming to offer new insights into novel anti-inflammatory drug targets for the treatment of ASCVD. Reduced levels of SPMs are associated with the progression of atherosclerosis. SPMs inhibit inflammatory responses in the plaque microenvironment by limiting immune cell infiltration, reducing oxidative stress, and promoting the clearance of apoptotic cells, all of which contribute to plaque stabilization. Tyrosine-protein kinase Mer (MerTK), TRIF-related adaptor molecule (TRAM), and high mobility group box 1 (HMGB1) play crucial roles in the modulation of SPM production. Clinical use of ω-3 PUFAs has been shown to reduce the incidence of fatal cardiovascular events. Furthermore, aspirin not only initiates the synthesis of specific SPMs but also extends their activity within the body. The enhanced production of SPMs promotes inflammation resolution in the plaque microenvironment without inducing immunosuppression. This characteristic highlights MerTK, TRAM, and HMGB1 as potential targets for the development of anti-inflammatory drugs. Investigating targets and compounds that enhance the production of SPMs presents a promising strategy for developing future anti-inflammatory agents.

Objective To investigate the causal relationship between various lipid-modifying drugs and new-onset diabetes, as well as the mediators contributing to this relationship. Methods Mediation Mendelian randomization was performed to investigate the causal effect of lipid-modifying drug targets on type 2 diabetes (T2D) outcomes and the proportion of this association that is mediated through ectopic fat accumulation traits. Specific sets of variants in or near genes that encode 11 lipid-modifying drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, ABCG5/ABCG8, LPL, PPARA, ANGPTL3, APOC3, and CETP; for expansion of gene symbols, use search tool at www.genenames.org) were extracted. Random effects inverse variance weighted were performed to evaluate the causal effects among outcomes. Mediation analyses were performed to identify the mediators of the association between lipid-modifying drugs and T2D. The study was conducted from November 10, 2023, to April 2, 2024 Results The genetic mimicry of HMGCR and APOB inhibition was associated with an increased T2D risk, whereas the genetic mimicry of LPL enhancement was linked to a lower T2D risk. Gluteofemoral adipose tissue volume was a mediator for explaining 9.52% (P=.002), 16.90% (P=.03), and 10.50% (P=.003) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Liver fat was a mediator for explaining 21.12% (P=.005), 12.28% (P=.03), and 9.84% (P=.005) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Conclusion Our findings support the hypothesis that liver fat and gluteofemoral adipose tissue play a mediating role in the prodiabetic effects of HMGCR and APOB inhibition, as well as in the antidiabetic effects of LPL enhancement.