Tailored polysaccharide entrapping metal-organic framework for RNAi therapeutics and diagnostics in atherosclerosis.

Metal-organic frameworks (MOFs) hold promise as theranostic carriers for atherosclerosis. However, to further advance their therapeutic effects with higher complexity and functionality, integrating multiple components with complex synthesis procedures are usually involved. Here, we reported a facile and general strategy to prepare multifunctional anti-atherosclerosis theranostic platform in a single-step manner. A custom-designed multifunctional polymer, poly(butyl methacrylate-co-methacrylic acid) branched phosphorylated ß-glucan (PBMMA-PG), can effectively entrap different MOFs via coordination, simultaneously endow the MOF with enhanced stability, lesional macrophages selectivity and enhanced endosome escape. Sequential ex situ characterization and computational studies elaborated the potential mechanism. This facile post-synthetic modification granted the administered nanoparticles atherosclerotic tropism by targeting Dectin-1+ macrophages, enhancing in situ MR signal intensity by 72 %. Delivery of siNLRP3 effectively mitigated NLRP3 inflammasomes activation, resulting a 43 % reduction of plaque area. Overall, the current study highlights a simple and general approach for fabricating a MOF-based theranostic platform towards atherosclerosis conditioning, which may also expand to other indications targeting the lesional macrophages.

Mechanism of Xue-Jie-San treating Crohn's disease complicated by atherosclerosis: Network pharmacology, molecular docking and experimental validation.

BACKGROUND: Crohn's disease (CD), as a chronic systemic inflammatory disease, is strongly associated with the development of premature atherosclerosis (AS). Atherosclerotic cardiovascular disease, including coronary heart disease, myocardial infarction and stroke, is a lethal complication of CD. Nowadays, there is a lack of effective monotherapy for CD complicated by AS. PURPOSE: To explore the underlying effects and mechanisms of Xue-Jie-San (XJS) on treating CD complicated by AS via network pharmacology and experimental validation. METHODS: The targets of XJS components were obtained from TCMSP, ETCM and PubChem databases as well as the disease genes of CD and AS from GeneCards, DisGeNET and OMIM databases. The core targets were screened out from the drug-disease common targets identified by protein-protein interaction (PPI) network analysis and then analyzed with GO and KEGG enrichment. The interaction between core target and XJS component was detected by molecular docking and molecular dynamics simulation. Subsequently, the core targets were validated via GEO datasets and their biological functions were confirmed in vitro. Nile red staining was used to evaluated lipid accumulation in human umbilical vein endothelial cells (HUVECs) challenged by lipopolysaccharide (LPS) combined with oxidized low-density lipoprotein (ox-LDL). Levels of pro-inflammatory cytokines were examined by enzyme-linked immunosorbent assay. Chemokine CCL2 and CXCL8 were detected by immunofluorescence staining. The activity of the TLR4/Myd88/NF-κB signaling pathway was assessed using Western blot. RESULTS: In total, 26 common target genes of XJS, CD and AS were found. Among them, 11 core genes were identified by PPI network analysis. The effects of XJS treating CD complicated by AS were mainly mediated by the lipid and atherosclerosis pathway, inflammatory bowel disease pathway and toll-like receptor signaling pathway. Molecular docking and molecular dynamics simulation displayed strong binding affinity between XJS component and the core target. Six core genes including TLR4, IL-1ß, TNF, ICAM1, CCL2 and CXCL8 were validated by GEO datasets. In vitro, the effects of XJS on reducing lipid accumulation, secretion of IL-1ß, IL6, TNF-α, CCL2 and CXCL8, and the protein expressions of TLR4, Myd88, p-p65 and ICAM1 were verified. CONCLUSION: XJS is a potential candidate drug for the treatment of CD complicated by AS. The underlying mechanisms involve mitigation of lipid accumulation-mediated endothelial dysfunction and blockage of immune inflammatory response by targeting TLR4.

Osteocalcin and Chinese visceral adiposity index are associated with the risk of ASCVD and arterial stiffness in patients with T2DM.

This study aims to discover the association between serum osteocalcin, the Chinese visceral adiposity index (CVAI), and atherosclerotic cardiovascular disease (ASCVD) risk, and their impact on arterial stiffness in T2DM patients. We included 639 T2DM patients aged 30 and older who received the assessment of ASCVD risk using the China-PAR equation, Osteocalcin and arterial stiffness in this cross-sectional study. We found that osteocalcin and CVAI as independent risk factors for both medium-high-risk ASCVD (osteocalcin: men, OR,0.96, 95% CI 0.92, 1.00; women, OR, 0.93, 95% CI 0.8, 1.08, respectively)(CVAI: men, OR,1.01,95% CI 1.00,1.02; women: OR, 1.08, 95% CI 1.02,1.14, respectively) and arterial stiffness (osteocalcin: men, OR, 0.98, 95% CI 0.94,1.01; women, OR, 0.98, 95% CI 0.90,1.06, respectively)(CVAI: men, OR,1.0, 95% CI 0.99,1.01; women, OR, 1.02, 95% CI 1.00,1.04, respectively) in both men and women patients with T2DM. Combining osteocalcin levels and CVAI improved the prediction accuracy of arterial stiffness in men patients with T2DM (difference of AUC(Model 4 vs. Model 1):1.5%, NRI: 0.06 [0.0,0.4]). All P-values were < 0.05. The results suggested that osteocalcin levels and CVAI are independent risk factors for ASCVD risk and arterial stiffness in T2DM. Combining osteocalcin and CVAI can enhance the early detection of atherosclerosis through male patients with T2DM.

Endothelial dysfunction in prediabetes and diabetes mellitus in patients with normal coronary arteries.

BACKGROUND: Diabetes mellitus (DM) is a global health issue associated with increased cardiovascular disease risk. Endothelial dysfunction is a known precursor to atherosclerosis and cardiovascular disease, and its role in the pathogenesis of DM complications is well-documented. There is limited information in the evaluation of endothelial function in prediabetic patients using flow-mediated dilation (FMD), and studies have not excluded patients with known atherosclerosis or coronary artery disease. Thus, in this study, we aimed to evaluate the endothelial functions using FMD from the brachial artery of DM and prediabetes patients who had normal coronary arteries. METHODS: This study included 73 participants: 25 with DM, 25 with prediabetes, and 23 normoglycemic controls, all with normal coronary arteries on angiography. FMD measurements were conducted following established protocols, and statistical analysis was performed using standard methods to compare FMD levels among groups. RESULTS: The groups were comparable in clinical and demographic characteristics, except for fasting plasma glucose levels. Significant differences in FMD levels were observed: 10.1% in the DM group, 16.5% in the prediabetes group, and 14.8% in the control group (P = 0.004). Diabetic patients had significantly lower FMD levels than both prediabetic and normoglycemic individuals. No significant difference in FMD was found between prediabetic and control groups. CONCLUSIONS: Diabetic patients exhibited significant endothelial dysfunction compared to normoglycemic individuals, while prediabetic patients did not show similar dysfunction. These findings suggest a window of opportunity in the prediabetic stage for early intervention to prevent advanced endothelial dysfunction. TRIAL REGISTRATION NUMBER: ISRCTN Registry ISRCTN15351014. Registry date: 23/09/2024. Retrospectively registered.

The double-edged role and therapeutic potential of TREM2 in atherosclerosis.

Atherosclerosis is a chronic lipid-driven inflammatory disease characterized by infiltration of large numbers of macrophages. The progression of the disease is closely related to the status of macrophages in atherosclerotic plaques. Recent advances in plaque analysis have revealed a subpopulation of macrophages that express high levels of triggering receptor expressed on myeloid cells 2 (TREM2). Although TREM2 is known to play a critical role in inflammation, lipid metabolism, and tissue repair, its role in atherosclerosis is still not fully understood. Recent studies have shown that TREM2 promotes macrophage cholesterol uptake and efflux, enhances efferocytosis function, regulates inflammation and metabolism, and promotes cell survival, all of which are significant functions in atherosclerosis. In early plaques TREM2 promotes lipid uptake and increases lesion size. In advanced plaques TREM2 promotes macrophage survival and increases plaque stability. The dualistic nature of TREM2 in atherosclerosis, where it can exert both protective effect and a side effect of increased lesion size, presents a complex but crucial area of study. Understanding these dual roles could help in the development of new therapeutic strategies to modulate TREM2 activity and utilize its atheroprotective function while mitigating its deleterious effects. In this review, we discuss the roles and mechanisms of TREM2 during different stages of atherosclerotic plaques, as well as the potential applications of TREM2 in the diagnosis and treatment of atherosclerosis.

Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice.

Leukotrienes are potent mediators of the inflammatory response and 5-lipoxygenase, the enzyme responsible for their synthesis, is dependent on its interaction with 5-lipoxygenase activating protein for optimum catalysis. Previous studies had demonstrated that macrophage infiltration into adipose tissue is associated with obesity and atherosclerosis in LDLR-/- mice fed a high fat-high carbohydrate. The present study was undertaken to determine whether inhibition of 5-lipoxygenase activating protein is efficacious in attenuating adipose tissue inflammation in LDLR-/- mice fed a high fat-high carbohydrate. 10-week old male LDLR-/- mice were fed a high fat-high carbohydrate diet for 22-weeks, with or without MK886 (40 mg/kg/day, ad libitum) a well-established 5-lipoxygenase activating protein inhibitor. All mice had an approximate 2-fold increase in total body weight, but a 6-week course of MK886 treatment had differential effects on adipose tissue size, without affecting macrophage accumulation. MK886 exacerbated the dyslipidemia, increased serum amyloid A content of high-density lipoproteins and caused a profound hepatomegaly. Dyslipidemia and increased serum amyloid A were concomitant with increases in atherosclerosis. In conclusion, MK886 paradoxically exacerbated hyperlipidemia and the pro-inflammatory phenotype in a mouse model of diet-induced atherosclerosis, possibly via a disruption of hepatic lipid metabolism and increased inflammation.

Targeting mitochondria by lipid-selenium conjugate drug results in malate/fumarate exhaustion and induces mitophagy-mediated necroptosis suppression.

Atherosclerosis (AS) is a chronic vascular disease primarily affecting large and medium-sized arteries and involves various complex pathological mechanisms and factors. Previous studies have demonstrated a close association between atherosclerosis and inflammatory damage, metabolic disorders, and gut microbiota. It is also closely linked to several cellular processes, such as endothelial cell pyroptosis, ferroptosis, mitophagy, mitochondrial dynamics, and mitochondrial biogenesis. Mitophagy has been recognized as a previously unexplored mechanism contributing to endothelial injury in atherosclerosis. Our study aims to further elucidate the potential relationship and mechanisms between AS-induced mitophagy dysfunction and the interaction of TMBIM6 and NDUFS4. Data from the study demonstrated that atherosclerosis in AS mice was associated with substantial activation of inflammatory and oxidative stress damage, along with a marked reduction in endothelial mitophagy expression and increased pathological mitochondrial fission, leading to mitochondrial homeostasis disruption. However, under pharmacological intervention, mitophagy levels significantly increased, pathological mitochondrial fission was notably reduced, and oxidative stress and inflammatory damage were suppressed, while necroptotic pathways in endothelial cells were significantly blocked. Interestingly, the deletion of TMBIM6 or NDUFS4 in animal models or cell lines markedly impaired the therapeutic effects of the drug, disrupting its regulation of mitophagy and mitochondrial fission, and leading to the re-emergence of inflammatory responses and oxidative stress damage. Metabolomics analysis further revealed that autophagy plays a pivotal regulatory role during drug intervention and after genetic modification of TMBIM6 and NDUFS4. The activation of autophagy (macroautophagy/mitophagy) alleviated the negative effects of mitochondrial fission and inflammatory damage induced by lipid stress in endothelial cells, a regulatory mechanism likely associated with the TMBIM6-NDUFS4 axis. Subsequent animal gene modification experiments demonstrated that knocking out TMBIM6-NDUFS4 negates the therapeutic effects of the drug on lipid-induced damage and metabolic function. In summary, our research reveals a phenotypic regulatory mechanism of endothelial cell stress damage through mitophagy, influenced by the interaction of TMBIM6 and NDUFS4. Pharmacological intervention can restore mitochondrial homeostasis in endothelial cells by regulating mitophagy via the TMBIM6-NDUFS4 pathway. This novel insight suggests that TMBIM6-NDUFS4 may serve as a key therapeutic target for atherosclerosis.

Phosphate overload via the type III Na-dependent Pi transporter represses aortic wall elastic fiber formation.

Objectives: Phosphate (Pi) induces differentiation of arterial smooth muscle cells to the osteoblastic phenotype by inducing the type III Na-dependent Pi transporter Pit-1/solute carrier family member 1. This induction can contribute to arterial calcification, but precisely how Pi stress acts on the vascular wall remains unclear. We investigated the role of extracellular Pi in inducing microstructural changes in the arterial wall. Methods: Aortae of Pit-1-overexpressing transgenic (TG) rats and their wild-type (WT) littermates were obtained at 8 weeks after birth. The thoracic descending aorta from WT and TG rats was used for the measurement of wall thickness and uniaxial tensile testing. Structural and ultrastructural analyses were performed using light microscopy and transmission electron microscopy. Gene expression of connective tissue components in the aorta was quantified by quantitative real-time polymerase chain reaction. Results: Aortic wall thickness in TG rats was the same as that in WT rats. Uniaxial tensile testing showed that the circumferential breaking stress in TG rats was significantly lower than that in WT rats (p<0.05), although the longitudinal breaking stress, breaking strain, and elastic moduli in both directions in TG rats were unchanged. Transmission electron microscopy analysis of the aorta from TG rats showed damaged formation of elastic fibers in the aortic wall. Fibrillin-1 gene expression levels in the aorta were significantly lower in TG rats than in WT rats (p<0.05). Conclusions: Pi overload acting via the arterial wall Pit-1 transporter weakens circumferential strength by causing elastic fiber malformation, probably via decreased fibrillin-1 expression.

Atherosclerotic Risk Factor Prevalence in Adults With Congenital Heart Disease: A Meta-Analysis.

Background: The risk of atherosclerotic cardiovascular disease (ASCVD) in adults with congenital heart disease (ACHD) is comparable to that of the general population and is driven by traditional ASCVD risk factors. Objectives: The aim of the study was to estimate the prevalence of traditional ASCVD risk factors (hypertension, dyslipidemia, diabetes mellitus [DM], obesity, smoking, and physical inactivity) in ACHD and compare it with the general population. Methods: A systematic literature search was conducted up to May 15, 2024, to identify studies (with or without control group) reporting the prevalence of ASCVD risk factors in ACHD. Meta-analyses were conducted to synthesize the prevalence of risk factors and compare it with that of the general population, where applicable. Results: We identified 62 studies (30 controlled) encompassing 110,469 ACHD (mean age 39 years; 52% males, 88% with simple/moderate congenital heart disease complexity). Of these, 54% (45%-63%) reported lack of regular exercise, 33% (26%-40%) had hypertension, 18% (14%-22%) were obese, 17% (11%-25%) had dyslipidemia, 12% (9%-14%) were current smokers, and 7% (5%-9%) had DM. The prevalence of ASCVD risk factors was similar in ACHD and controls, with the exception of DM (higher prevalence in ACHD) and smoking (lower prevalence in ACHD). Significant heterogeneity was observed among the included studies, partially explained by differences in age, congenital heart disease complexity, and the presence of cyanosis. Conclusions: Except for DM and smoking, the prevalence of traditional ASCVD risk factors is similar in ACHD compared to the general population. Further research is needed to determine whether interventions applied in the general population are also effective in ACHD.

Lipoproteins and lipoprotein lipid composition are associated with stages of dysglycemia and subclinical coronary atherosclerosis.

BACKGROUND: Dyslipidaemia in patients with diabetes contributes to the risk of atherosclerotic cardiovascular disease. We aimed to identify a dyslipidemic profile associated with both dysglycemia and subclinical coronary atherosclerosis. METHODS: Study participants (n = 5050) were classified in three groups: normoglycemia, pre-diabetes, and diabetes. A coronary artery calcium score (CACS) > 0 defined subclinical coronary atherosclerosis. Two independent methods were used to identify, among 225 lipid biomarkers, those that were associated with pre-diabetes and diabetes and had to be further tested for association by zero inflated Poisson regression with CACS and CACS burden in those with CACS>0. Estimates were adjusted for cardiovascular risk factors with an interaction term for dispensed lipid lowering drugs. RESULTS: Thirty-two biomarkers associated with prediabetes and diabetes were further investigated for association with CACS. HDL diameter [multi-adjusted OR of 0.85 and 95 %CI (0.78-0.92)] as well as free cholesterol, phospholipids and total lipids in extra large HDL were inversely associated with CACS. There was a borderline significant interaction between small HDL and dispensed lipid lowering drugs on the presence of CACS, with and multi-adjusted OR of 0.53 and 95 %CI (0.36-0.77). None of the 32 glycemic profile-related lipid biomarkers associated with the relative increase of CACS in those with CACS>0. No consistent association was observed between non-HDL lipoproteins and CACS. CONCLUSIONS: Changes in composition and relative concentration of HDL associated with both dysglycemia and subclinical coronary atherosclerosis. Treatment with lipid lowering drugs may contribute to reduce the risk associated with high circulating levels of small HDL.

Adherence to the 2019 ESC/EAS guidelines for dyslipidaemia management in a large rheumatoid arthritis cohort: Data from the CORDIS Study Group of the Italian Society of Rheumatology.

BACKGROUND/AIM: Lipid-lowering therapy prescription is low in rheumatoid arthritis (RA) patients, often not achieving lipid threshold target despite treatment. However, evidence derives from small, monocentric cohorts. We assessed adherence to lipid-lowering treatment for primary cardiovascular (CV) prevention in a RA cohort according to international guidelines. METHODS: A cross-sectional analysis of an Italian RA cohort was performed. Disease-related features and traditional CV risk factors were collected. The 10-year CV risk was estimated by Systematic COronary Risk Evaluation 2 (SCORE-2) algorithm. The primary preventive dyslipidaemia strategy was assessed according to 2019 European Society of Cardiology/European Atherosclerosis Society guidelines. RESULTS: 1.133 RA patients (78.2% female, aged 60.6±10.2 years) free from CV events were included. According to SCORE-2, 42.9% of patients were at moderate risk (1-5-%), 33.3% at high risk (5-10%) and 23.7% at very high risk (>10%). In the whole cohort, 12.9% of patients with <5%, 23.6% with 5-10% and 32.3% with >10% risk were on statin, respectively (p<0.001). According to 2019 ESC/EAS guidelines, 51.5% of patients had LDL-c at target. Among patients with LDL-c not at target, 76% were not on lipid-lowering treatment. At multivariate analysis, patients with higher CV risk had significantly lower probability of LDL-c at target. CONCLUSION: In a wide Italian RA cohort, more than 50% of patients had high or very high CV risk. In these, lipid-lowering treatment prescription is suboptimal leading to not achievement of LDL-c target. Physicians should improve lipid screening and primary prevention therapy to reduce CV risk and improve CV comorbidity in RA patients.

Atherogenic Effect of Homocysteine, a Biomarker of Inflammation and Its Treatment.

Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. Ischemic stroke and heart disease, coronary heart disease, and cardiovascular disease are events resulting from long-lasting and silent atherosclerosis. This paper deals with the synthesis of homocysteine (Hcy), causes of HHcy, mechanism of HHcy-induced atherosclerosis, and treatment of HHcy. Synthesis and metabolism of Hcy involves demethylation, transmethylation, and transsulfuration, and these processes require vitamin B 6 and vitamin B 12 folic acid (vitamin B 9 ). Causes of HHcy include deficiency of vitamins B 6 , B 9 , and B 12 , genetic defects, use of smokeless tobacco, cigarette smoking, alcohol consumption, diabetes, rheumatoid arthritis, low thyroid hormone, consumption of caffeine, folic acid antagonist, cholesterol-lowering drugs (niacin), folic acid antagonist (phenytoin), prolonged use of proton pump inhibitors, metformin, and hypertension. HHcy-induced atherosclerosis may be mediated through oxidative stress, decreased availability of nitric oxide (NO), increased expression of monocyte chemoattractant protein-1, smooth muscle cell proliferation, increased thrombogenicity, and induction of arterial connective tissue. HHcy increases the generation of atherogenic biomolecules such as nuclear factor-kappa B, proinflammatory cytokines (IL-1ß, IL-6, and IL-8), cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selection), growth factors (IGF-1 and TGF-ß), and monocyte colony-stimulating factor which lead to the development of atherosclerosis. NO which is protective against the development of atherosclerosis is reduced by HHcy. Therapy with folic acid, vitamin B 6 , and vitamin B 12 lowers the levels of Hcy, with folic acid being the most effective. Dietary sources of folic acid, vitamin B 6 , vitamin B 12 , omega-3 fatty acid, and green coffee extract reduce Hcy. Abstaining from drinking coffee and alcohol, and smoking also reduces blood levels of Hcy. In conclusion, HHcy induces atherosclerosis by generating atherogenic biomolecules, and treatment of atherosclerosis-induced diseases may be by reducing the levels of Hcy.

Role of C-Reactive Protein, An Inflammatory Biomarker in The Development of Atherosclerosis and Its Treatment.

This article deals with the role of c-reactive protein (CRP) in the development of atherosclerosis and its treatment. CRP has a predictive value in ischemic heart disease, restenosis, coronary artery disease, aortic atherosclerosis, and cerebrovascular disease. This article deals with the synthesis and mechanism of CRP-induced atherosclerosis and its treatment. CRP increases the formation of numerous atherogenic biomolecules such as reactive oxygen species (ROS), cytokines (interleukin [IL]-1ß and IL-6), cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, activated complement C 5 , monocyte colony-stimulating factor, and numerous growth factors [insulin-like growth factor, platelet-derived growth factor, and transforming growth factor-ß]). ROS mildly oxidizes low-density lipoprotein (LDL)-cholesterol to form minimally modified LDL which is further oxidized to form oxidized LDL. The above atherogenic biomolecules are involved in the development of atherosclerosis and has been described in detail in the text. This paper also deals with the treatment modalities for CRP-induced atherosclerosis which includes lipid-lowering drugs, antihypertensive drugs, antioxidants, aspirin, antidiabetic drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, regular physical activity, weight reduction, and stoppage of cigarette smoking. In conclusion, CRP induces atherosclerosis through increases in atherogenic biomolecules and the treatment modalities would prevent, regress, and slow the progression of CRP-induced atherosclerosis.

Percutaneous Coronary Intervention for Atherosclerotic Coronary Artery Disease After Arterial Switch Operation: A Case Report.

Late coronary complications after an arterial switch operation (ASO) may occur due to vessel kinking, compression resulting from growth of the great vessels, ostial fibro-intimal thickening after reimplantation or possibly secondary to accelerated atherosclerosis. Given that many of these patients are asymptomatic, adult ASO survivors require special attention and an individualised approach to the early detection of coronary artery disease. Most previously reported cases of coronary artery disease after an ASO have been managed surgically. Owing to the complex anatomy of the aortic sinuses and abnormal coronary origin, percutaneous coronary intervention may be challenging with difficult catheter engagement and/or support. Pre-procedural multi-slice CT coronary angiography can be used for proper planning and guidance. A case is described here for percutaneous coronary intervention in an adult patient who presented with coronary artery disease 33 years after an ASO.

Exosomal miR-155-5p promote the occurrence of carotid atherosclerosis.

Periodontitis is a significant independent risk factor for atherosclerosis. Yet, the exact mechanism of action is still not fully understood. In this study, we investigated the effect of exosomes-miR-155-5p derived from periodontal endothelial cells on atherosclerosis in vitro and in vivo. Higher expression of miR-155-5p was detected in the plasma exosomes of patients with chronic periodontitis (CP) and carotid atherosclerosis (CAS) compared to patients with CP. Also, the expression level of miR-155-5p was associated with the severity of CP. miR-155-5p-enriched exosomes from HUVECs increased the angiogenesis and permeability of HAECs and promoted the expression of angiogenesis, permeability, and inflammation genes. Along with the overexpression or inhibition of miR-155-5p, the biological effect of HUVECs-derived exosomes on HAECs changed correspondingly. In ApoE-/- mouse models, miR-155-5p-enriched exosomes promoted the occurrence of carotid atherosclerosis by increasing permeable and angiogenic activity. Collectively, these findings highlight a molecular mechanism of periodontitis in CAS, uncovering exosomal miR-155-5p derived periodontitis affecting carotid endothelial cells in an 'exosomecrine' manner. Exosomal miR-155-5p may be used as a biomarker and target for clinical intervention to control this intractable disease in future, and the graphic abstract was shown in Figure S1.

Differences in IgG afucosylation between groups with and without carotid atherosclerosis.

BACKGROUND: A previous study demonstrated that N-glycosylation profiles of IgG are associated with subclinical atherosclerosis in a British population. However, the generalisability of this finding to other ethnic groups remains to be investigated, and it has yet to account for additional traditional atherosclerotic risk factors. The present study, thus, aims to explore IgG N-glycosylation profiles in Han Chinese with atherosclerosis, and their potential role in atherosclerosis, while controlling for traditional atherosclerotic risk factors. METHODS: Data of this case-control study were obtained from an established umbrella Health Examination Cohort Study (registration number: ChiCTR2100048740). The investigation was conducted at the Health Care Centre of the First Affiliated Hospital of Shantou University Medical College in China, from August 1, 2021, to July 31, 2022. A sample of 69 carotid atherosclerosis (CAS) cases was recruited from the umbrella cohort, along with 69 controls without carotid atherosclerosis, matched by traditional atherosclerosis-related risk factors, including gender, age, smoking, alcohol consumption, hypertension, diabetes, dyslipidemia and obesity. Subsequently, serum IgG N-glycosylation was profiled using Ultra-Performance Liquid Chromatography. RESULTS: After propensity score matching, the relative abundance of IgG fucosylation in CAS cases was significantly lower than that in controls [95.32 (92.96, 95.99) vs. 95.96 (94.70, 96.58), P = 0.022]. The traditional atherosclerosis-related risk factors showed no statistically significant difference between CAS cases and controls (P > 0.05). CONCLUSIONS: The reduced fucosylation of IgG in CAS cases underscores the pivotal role of afucosylation in CAS. Enhancing the inflammatory capability of IgG via initiating antibody-dependent cell-mediated cytotoxicity could be the potential mechanism behind this, which should be further verified by functional studies.

Glucose-lowering medications and glucose levels as the major determinants of progression of carotid atherosclerosis in middle-aged adults and elders: a community-based prospective study.

Background: Few prospective studies explored the incidence and determinant of carotid atherosclerosis (CA) progression (CAP). This community-based prospective study focused on the effects of diabetes mellitus (DM) treatments and glucose levels on CAP risks. Methods: We followed up a group of 657 CA-positive middle-aged adults and elders for CAP. CAP was defined as an increase in the total number of carotid plaque and/or an increase in diameter stenosis by at least 10%. Results: After 4.05 years of followed-up, CAP was detected in 364 (55.4%) subjects. The multivariable-adjusted hazard ratios (HRs) were 1.805 (95% confidence interval [CI]: 1.374-2.358) and 0.694 (95% CI: 0.510-0.944) for elevated fasting plasma glucose (eFPG; FPG≥100 mg/dL) and glucose-lowering medications (GLM), respectively. As compared to GLM-negative+eFPG-positive subjects, the multivariable-adjusted HRs were 0.497 (95% CI: 0.373-0.662), 0.537(95% CI: 0.306-0.942), and 0.586 (95% CI: 0.412-0.833) for GLM-negative+eFPG-negative, GLM-positive+eFPG-negative, and GLM-positive+ eFPG-positive subjects, respectively. The multivariable-adjusted risks of CAP were similar between GLM-negative+eFPG-negative and GLM-positive+ eFPG-positive subjects (p=0.77). Stratified analyses showed that the multivariable-adjusted HRs per 5.0 mg/dL increase in FPG were significantly increased among GLM-negative subjects (HR=1.131; 95% CI: 1.094-1.171) and non-significantly decreased among GLM-positive subjects (HR=0.985; 95% CI: 0.957-1.013). Conclusion: We found that more than 50% of CA-positive subjects had CAP in 4 years and higher FPG significantly increased and GLM significantly decreased the risks of CAP. Additionally, GLM and FPG demonstrated an interactive effect on CAP risks. It seems possible that GLM may induce effects beyond lowering glucose levels and subsequently lowers CAP risks.

Anti-atherosclerotic effect of incretin receptor agonists.

Incretin receptor agonists (IRAs), primarily composed of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs), work by mimicking the actions of the endogenous incretin hormones in the body. GLP-1RAs have been approved for use as monotherapy and in combination with GIPRAs for the management of type 2 diabetes mellitus (T2DM). In addition to their role in glucose regulation, IRAs have demonstrated various benefits such as cardiovascular protection, obesity management, and regulation of bone turnover. Some studies have suggested that IRAs not only aid in glycemic control but also exhibit anti-atherosclerotic effects. These agents have been shown to modulate lipid abnormalities, reduce blood pressure, and preserve the structural and functional integrity of the endothelium. Furthermore, IRAs have the ability to mitigate inflammation by inhibiting macrophage activation and promoting M2 polarization. Research has also indicated that IRAs can decrease macrophage foam cell formation and prevent vascular smooth muscle cell (VSMC) phenotype switching, which are pivotal in atheromatous plaque formation and stability. This review offers a comprehensive overview of the protective effects of IRAs in atherosclerotic disease, with a focus on their impact on atherogenesis.

Transient changes in L-arginine, asymmetric and symmetric dimethyl arginine in triathletes following Norseman Xtreme Triathlon.

Arterial vasodilation is dependent on nitric oxide synthesized from L-arginine by endothelial nitric oxide synthase. Triathletes are reported to display altered serum concentrations of nitric oxide metabolites such as L-arginine, asymmetric dimethyl arginine (ADMA) and symmetric dimethyl arginine (SDMA) shortly after completing long-distance triathlon races. In other populations, similar changes to nitric oxide metabolites are established risk markers of cardiovascular disease. The objective of this study was to assess serum concentrations of metabolites for endothelial nitric oxide synthesis in triathletes one week following a long-distance triathlon race. In this prospective observational study, we used high-performance liquid chromatography to measure circulating concentrations of L-arginine, ADMA, and SDMA in triathletes. Venous blood samples were collected before, immediately after, day one, and one week following the triathlon race. Serum concentrations and L-arginine/ADMA ratio were determined for each time-point and compared to baseline. L-arginine/ADMA ratio was reduced on day one (147 ± 32 vs 163 ± 40, p < 0.02). ADMA was reduced immediately after and increased at day one and remained elevated at one week (0.29 ± 0.05 µM, p < 0.001, 0.44 ± 0.08 µM, p < 0.001 and 0.42 ± 0.07 µM, p = 0.04, respectively vs 0.40 ± 0.05 µM). SDMA was increased at all time-points when compared to baseline (0.48 ± 0.10 µM, p < 0.001, 0.53 ± 0.11 µM, p < 0.001 and 0.42 ± 0.08 µM, p = 0.048 vs 0.38 ± 0.05 µM). L-arginine was only decreased immediately after (46.0 ± 9.3 µM vs. 64.6 ± 16.1 µM, p < 0.001). Long-distance triathlon racing induces altered levels of metabolites for endothelial nitric oxide production that mostly normalizes within one week following racing. The clinical relevance of these transient changes has yet to be elucidated in the athletic population.

A cross-sectional study of factors associated with carotid atherosclerosis.

Objective: The aim of this work was to study the relationship between carotid atherosclerosis (CAS) and several indexes and provide a basis for the prevention and treatment of cardiovascular and cerebrovascular diseases. Methods: There were 11,028 adults who underwent physical examination at the Guangzhou Cadre and Talent Health Management Center from January 2023 to December 2023 and were selected as research subjects. Retrospective analysis was used to understand the carotid atherosclerosis of the examined population and analyze its relationship with sex, age, blood pressure, blood glucose, blood lipids, renal function, 25-hydroxyvitamin D, neutrophil to lymphocyte count ratio (NLR), platelet to lymphocyte count ratio (PLR), systemic immune inflammation index (SII), monocyte count to high-density lipoprotein cholesterol ratio (MHR), triglyceride glucose body mass index (TyG-BMI), insulin resistance metabolic index (METS-IR), and other indicators. Results: Among 11,028 subjects, the detection rate of carotid atherosclerotic thickening (CAT) was 12.00% and carotid atherosclerotic plaque (CAP) was 25.11%. The CAT and CAP detection rates in men were 13.32% and 28.78%, respectively, which were higher than the CAT detection rate of 8.28% and CAP detection rate of 14.80% in women, and the differences were statistically significant (both p < 0.001). Multivariate logistic regression analysis using TyG-BMI and METS-IR as two indicators was modeled separately, and the results showed that CAS was associated with men, increasing age, and systolic blood pressure. The area under the curve (AUC) was analyzed using the subject's work characteristic (ROC) curve in the descending order of METS-IR, TyG-BMI, and MHR. The combination of the three indexes of sex, age, and METS-IR predicted atherosclerosis with the highest AUC values. Conclusion: Carotid atherosclerosis is highly prevalent in men. Elevation of systolic blood pressure, fasting glucose, MHR, and TyG-BMI (or METS-IR) with age are independent influences on carotid atherosclerosis. The three indexes of MHR, TyG-BMI, and METS-IR, respectively, in combination with sex and age, can be used as a new and effective index to predict CAS.