Abstract:N⁶-methyladenosine (m⁶A) modification is one of the most abundant epitranscriptomic modifications in eukaryotic mRNA, with dynamic and reversible properties. This modification process is coordinated by methyltransferases, demethylases, and related m⁶A binding proteins, which in turn affect mRNA metabolism and function. Increasing evidence has indicated that the m⁶A RNA modification plays an important role in the occurrence and development of atherosclerosis (As) and other related diseases. This paper provide a comprehensive review of the relationship between m⁶A RNA modification and As. The entire manuscript summarizes the m⁶A RNA modification mechanism and its roles in As-related cells including endothelial cells, macrophages, and smooth muscle cells, and discusses the association of m⁶A RNA modification with risk factors of As such as high-fat diet, ischemia/hypoxia, oscillatory stress, and hypertension. Finally, this review summarizes researches on drug intervention targeting m⁶A RNA methylation to mitigate As. These studies provide important references for exploring new targets for early diagnosis and treatment of As.

Abstract:Aim To explore the effect of Buyang Huanwu decoction on anti-atherosclerosis by regulating the phenotypic transformation of vascular smooth muscle cells and serum inflammatory response based on Wnt/β-catenin signaling pathway. Methods 50 ApoE－/－ mice were randomly divided into model group, Buyang Huanwu decoction modified (low, medium and high dose) groups, and atorvastatin group, with 10 mice in each group; 10 C57BL/6J mice with the same genetic background were set as the control group. The mice of control group were fed with regular forages, while the mice of other five groups were fed with high-fat forages for 8 weeks for model replication. From the 9th week, they were continuously gavaged for 4 weeks. After 12 weeks, the mouse aortic roots were isolated and paraffin sections were prepared. Oil red O staining was used to observe the lipid content of aortic sinus. Immunohistochemical method was used to detect the expression level of bone bridge protein (OPN). Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) in serum. Western blot was used to detect the protein expressions of Wnt1, β-catenin and c-myc in mice aorta. RT-PCR was used to detect the expressions of Wnt1 and β-catenin gene. Results Buyang Huanwu decoction modified (low, medium and high dose) could reduce the lipid content and OPN expression in the aortic sinus of As model mice, reduce serum levels of IL-6 and TNF-α, IL-1β and MCP-1 in mice, and downregulate the expression of Wnt1 and β-catenin protein and gene. Conclusion Buyang Huanwu decoction modified exerts an anti-atherosclerosis effect by regulating inflammatory response, and some of the mechanisms may be related to inhibiting the activation of the Wnt/β-catenin signaling pathway.

Abstract:Aim To explore the mechanism of oxiracetam promoting neurogenesis and migration in rats with cerebral infarction through stromal cell-derived factor-1α (SDF-1α)/C-X-C chemokine receptor 4 (CXCR4) pathway. Methods 100 SD rats were randomly divided into control group, cerebral ischemia (CI) group, oxiracetam (200 mg/kg) group, and oxiracetam (200 mg/kg)＋AMD3100 (5 mg/kg) group, with 25 rats in each group. Electrocoagulation was used to create rat model of local permanent cerebral infarction. After 1,7 and 14 days of modeling, neurological deficits were scored, TTC staining was used to detect the volume of cerebral infarction, Nissl staining was used to detect cell survival in the infarcted area, Western blot was used to detect SDF-1α and CXCR4 protein levels in ischemic zone. After 1～7 days of modeling, BrdU (50 mg/kg) was continuously injected intraperitoneally. After 14 days, immunofluorescence double staining was used to detect the number of BrdU＋Nestin＋and BrdU＋DCX＋ cells in the SVZ region. 5 days before modeling, retroviruses carrying GFP were injected into the SVZ region. After 14 days, immunofluorescence double staining was used to detect the number of GFP＋DCX＋, GFP＋MAP-2＋ and GFP＋GFAP＋ cells in infarction area. C17.2 cells were divided into control group, oxygen-glucose deprivation (OGD) group, oxiracetam (final concentration:200 mg/L) group, and oxiracetam (final concentration:200 mg/L)＋AMD3100 (final concentration:100 μmol/L) group. OGD was used to create cell CI model. After 12 hours, immunofluorescence double staining was used to detect the number of BrdU＋/Nestin＋ and BrdU＋/MAP-2＋ cells, Transwell experiment was used to detect cell migration, Western blot was used to detect SDF-1α and CXCR4 protein levels in cell culture supernatant. Results Animal experiment results showed:compared with control group, mNSS score in CI group was increased, cerebral infarction volume was increased, the number of surviving cells in infarcted area was decreased, SDF-1α and CXCR4 protein levels were increased, the number of GFP＋DCX＋, GFP＋MAP-2＋ and GFP＋GFAP＋ cells in SVZ region were increased (P＜0.05); compared with CI group, mNSS score in oxiracetam group was decreased, cerebral infarction volume was decreased, the number of surviving cells in infarcted area was increased, SDF-1α and CXCR4 protein levels were increased, the number of GFP＋DCX＋, GFP＋MAP-2＋ and GFP＋GFAP＋ cells in SVZ region were increased, the number of GFP＋DCX＋, GFP＋MAP-2＋ and GFP＋GFAP＋ cells in infarcted area were increased (P＜0.05); compared with oxiracetam group, mNSS score in oxiracetam＋AMD3100 group was increased, cerebral infarction volume was increased, the number of surviving cells in infarcted area was decreased, CXCR4 protein level was decreased, the number of GFP＋DCX＋, GFP＋MAP-2＋ and GFP＋GFAP＋ cells in the SVZ region were decreased (P＜0.05). Cell experiment results showed:compared with control group, the number of BrdU＋/Nestin＋ and BrdU＋/MAP-2＋cells in OGD group were increased, the number of cell migration, SDF-1α and CXCR4 protein levels in cell culture supernatant were increased (P＜0.05); compared with OGD group, the number of BrdU＋/Nestin＋ and BrdU＋/MAP-2＋cells in oxiracetam group were increased, the number of cell migration, SDF-1α and CXCR4 protein levels in cell culture supernatant were increased (P＜0.05); compared with oxiracetam group, the number of BrdU＋/Nestin＋ and BrdU＋/MAP-2＋cells in oxiracetam＋AMD3100 group were decreased, the number of cell migration, CXCR4 protein level in cell culture supernatant were decreased (P＜0.05). Conclusion Oxiracetam may promote the migration of neural stem cells from the SVZ region to the ischemic zone, promoting neurogenesis and functional recovery in rats with cerebral infarction by activating SDF-1α/CXCR4 pathway.

Abstract:Aim To investigate the effect of CDR132L (miR-132 antisense oligonucleotide) on vascular remodeling and function in mice with hypertension and hyperlipidemia, and explore its possible mechanism. Methods A total of 30 8-week-old male C57BL/6 mice were randomly divided into three groups:control group, model group and CDR132L group, with 10 mice in each group. The control group received with a standard diet while the model group and CDR132L group received N-nitro-L-arginine methyl ester (L-NAME) and high-fat diet to induce hypertension and hyperlipidemia. The CDR132L group was administered with intraperitoneal injection of CDR132L at a dose of 20 mg/kg once weekly for six consecutive weeks, whereas the control group and the model group were given intraperitoneal injection of an equivalent volume of normal saline. The tail-cuff method was utilized for blood pressure measurement, blood lipid and glucose levels were assayed by an automatic biochemical analyzer, the thoracic aorta structure was observed by HE staining, endothelium-dependent relaxation of the thoracic aorta was evaluated by the vascular ring test, the expression level of miR-132 in the thoracic aorta was measured by qPCR, the protein expression levels of Gab1 and endothelial nitric oxide synthase (eNOS) in the thoracic aorta were determined by Western blot. Results Compared with the control group, the model group demonstrated notable rises in systolic and diastolic blood pressure, serum triglyceride, total cholesterol levels, and body weight. Moreover, the intima of thoracic aorta and the thickness of vascular wall was uneven, the smooth muscle cells of the tunica media were arranged irregularly, with a large amount of fat deposition in the vascular wall, and the endothelium-dependent relaxation response of thoracic aorta was decreased (P＜0.05). The expression level of miR-132 in the thoracic aorta was significantly increased (P＜0.05), while the expression level of Gab1 and eNOS protein was markedly decreased (P＜0.05). Compared with the model group, the CDR132L group showed no significant differences in systolic and diastolic blood pressure, serum triglyceride and total cholesterol levels, as well as body weight (P＞0.05).However, the CDR132L group exhibited a complete and smooth intima of the thoracic aorta with minimal intravascular lipid deposition, the thickness of the vascular wall was uniform, the smooth muscle cells of the tunica media were arranged orderly, accompanied by enhanced endothelium-dependent relaxation response of the thoracic aorta (P＜0.05). The expression level of miR-132 in the thoracic aorta was significantly decreased (P＜0.05), while the expression levels of Gab1 and eNOS protein were significantly increased (P＜0.05). Conclusion CDR132L can improve vascular remodeling and endothelium-dependent relaxation in hypertensive and hyperlipidemia mice, which may be related to the decrease of miR-132 expression level and the up-regulation of Gab1 and eNOS protein expression levels in the thoracic aorta.

Abstract:Aim To reveal the mechanism of cross-species ischemic heart failure from the perspective of spatial and gene co-expression networks. Methods GSE210374 and GSE57338 high-throughput sequencing datas were retrieved from the national center for biotechnology information gene expression database (NCBI-GEO), and R language software packages was used to analyze and screen differentially expressed genes (DEG) in different myocardial regions of myocardial infarction rats, as well as DEG of myocardial samples from patients with ischemic heart failure and healthy controls, and the regional expression of common genes was analyzed. Weighted gene co-expression network analysis (WGCNA) was used to screen the genes related to myocardial infarction and to carry out enrichment analysis, protein-protein interaction network (PPI) was constructed to screen core genes (HG). Results A total of 4 835 differentially expressed genes were screened out in myocardial infarction rats and normal controls, and 51 differentially expressed genes were screened out in ischemic heart failure patients and normal control samples, which revealed representative gene sets in the left ventricular myocardial infarction area (I area), border area (BZ area), and remote area (R area) after myocardial infarction. Spatial expression analysis revealed that there were 20 co-expressed genes in each myocardial region, 16 of which were expressed in all three regions, the number of genes specifically expressed in I, BZ and R regions were 2,0 and 2, respectively. Enrichment analysis showed that the functions of co-expressed genes were different in different region. The I and BZ regions were related to collagen fiber assembly, stress-induced cardiomyocyte hypertrophy, down-regulation of c-Jun amino terminal kinase (JNK signal) and cell proliferation, and complement signaling pathways; The I and R regions were enriched in the binding of Wnt and collagen; As a non-ischemic distal R region, the co-expressed genes were significantly enriched in the extracellular matrix for functions such as compressive resistance, cytolysis and inhibition of T cell proliferation. Furthermore, it was worth noting that the products of co-expressed genes in the three regions were mostly located in the extracellular space and extracellular matrix, suggesting that there may be active cellular secretion and interaction regulation. Further PPI analysis suggested that asporin (ASPN) , osteoglycin (OGN) and collagentype ⅩⅣ alpha chain (COL14A1) gene might be the core genes of the mechanism mentioned above. Conclusions The common mechanism of ischemic heart failure in rats and human involves multiple signaling pathways such as complement and coagulation cascade signaling and Wnt; which may be closely related to cell apoptosis mediated by extracellular matrix and exosomes; ASPN, OGN, and COL14A1 may be the core genes. This work is expected to provide spatial and pathway reference for the selection of intervention targets and pathway in the transformation research related to ischemic heart failure.

Abstract:Aim To analyze the influencing factors of adverse cardiovascular events in elderly patients with acute ST-segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI), and to establish a nomogram prediction model. Methods A total of 216 elderly patients with acute STEMI who underwent PCI in Jinqiu Hospital of Liaoning Province from February 2021 to January 2023 were selected and divided into occurrence group (n＝33) and non-occurrence group (n＝183) according to the occurrence of postoperative adverse cardiovascular events. General data, laboratory indicators, imaging information, and postoperative medication data of all patients were collected.Univariate and multivariate Logistic regression analysis were used to explore independent risk factors for adverse cardiovascular events. A nomogram prediction model was constructed according to independent risk factors of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), C-reactive protein/albumin ratio (CAR), C-reactive protein to high density lipoprotein cholesterol ratio (CHR), calibration curve was drawn to verify the nomogram model, and receiver operating characteristic (ROC) curve was drawn to analyze the predictive efficacy of the predictive model for column line diagrams. Results The levels of NLR, PLR, CAR, CHR, Gensini score, and platelet aggregation ratio (PAR) were significantly higher in occurrence group than those in non-occurrence group, left ventricular ejection fraction(LVEF) was significantly lower in occurrence group (P＜0.05). Logistic regression analysis showed that Gensini score, LVEF, PAR, NLR, PLR, CAR and CHR were independent risk factors for adverse cardiovascular events after PCI in elderly acute STEMI patients (P＜0.05). The column-line diagram model for predicting the risk of adverse cardiac events after PCI in elderly acute STEMI patients was constructed based on independent risk factors, and the calibration curve of the model was close to the ideal model, and the ROC curve showed that the area under the ROC curve for the prediction of the risk of adverse cardiovascular events in the elderly acute STEMI patients was 0.914. Conclusion NLR, PLR, CAR and CHR are independent risk factors for adverse cardiovascular events in elderly acute STEMI patients after PCI, and the nomogram model constructed based on these factors can effectively predict the risk of adverse cardiovascular events in elderly acute STEMI patients after PCI.

Abstract:Aim To investigate whether elevated monocyte to lymphocyte ratio (MLR) is associated with the in-hospital mortality risk in elderly patients with acute myocardial infarction (AMI). Methods The medical history of 1 550 elderly patients with AMI hospitalized in the Department of Cardiology of the Second Affiliated Hospital of Dalian Medical University from December 2015 to December 2021 was retrospectively collected, including 132 patients who died during hospitalization. It mainly includes gender, age, height, body weight, blood routine, lipid related indicators, fasting blood glucose (FBG), myocardial enzyme, type of myocardial infarction, estimated glomerular filtration rate (eGFR), in-hospital outcomes, prevalence of heart failure, diabetes, hypertension, and use of statins and antiplatelets during hospitalization. According to ROC curve analysis, patients with MLR＞0.342 were defined as high MLR group (n＝699), whereas patients with MLR≤0.342 were defined as low MLR group (n＝851). Results The age, white blood cell count, monocyte count, MLR, cardiac troponin I (cTnI), FBG, eGFR＜60 mL/(min·1.73 m²), male patients, heart failure, and proportion of all-cause deaths occurred during hospitalisation were higher in the high MLR group than those in the low MLR group (P＜0.05), body mass index (BMI), lymphocyte count, low density lipoprotein cholesterol (LDLC), eGFR＞60 mL/(min·1.73 m²), hypertension, and use of antiplatelet agents were lower in the high MLR group compared to the low MLR group (P＜0.05). Multivariate Logistic regression results showed that high MLR was independently associated with the in-hospital mortality risk in elderly AMI patients (OR＝1.812,95%CI:1.106～2.969,P＝0.018). The results of ROC curve analysis showed that the predictive ability of MLR combined with cTnI or FBG would be significantly improved, and the area under ROC curve was 0.789 and 0.739, respectively. Restrictive cubic spline (RCS) analysis results indicated a linear dose-response relationship between MLR and in-hospital outcomes in elderly AMI patients. Conclusion Elevated MLR is independently associated with the in-hospital mortality risk in elderly AMI patients, and clinicians can consider using MLR indicators in daily diagnosis for risk stratification and related treatment of such patients to improve their short-term prognosis.

Abstract:Aim To explore the application value of a predictive model constructed based on superb microvascular imaging (SMI) blood flow grading indicators and serological indicators in evaluating the risk of carotid plaque shedding. Methods A total of 122 patients diagnosed with carotid plaque in Lishui Central Hospital from February 2019 to February 2021 were selected. SMI was used to observe the blood flow grading and plaque characteristics in carotid plaque, and baseline clinical data of the patients were recorded. All patients were followed up for a period of 2 years, with the occurrence of transient ischemic attack (TIA) or acute ischemic stroke (AIS) as the endpoint event, and were divided into plaque shedding group and non-shedding group. Clinical data of the two groups were compared and analyzed, and multiple regression analysis was conducted to identify the relevant factors affecting carotid plaque shedding. According to the SMI ultrasound characteristics and serological indicators,Rü software was adopted to establish the nomogram model and evaluate effectiveness of the model. Results During the 2-year follow-up period, 21 TIA cases and 14 AIS cases were found in the remaining 112 patients excluding 10 lost to follow up. The SMI blood flow grading, neutrophil to lymphocyte ratio (NLR), matrix metalloproteinase-9 (MMP-9), and low density lipoprotein cholesterol (LDLC) levels in the plaque shedding group were higher than those in the non-shedding group, and the differences were statistically significant (P＜0.05). Multivariate Logistic regression analysis showed that SMI blood flow grade 3 (OR＝38.095), LDLC (OR＝19.730), NLR (OR＝34.525) and MMP-9 (OR＝1.225) were independent risk factors for carotid plaque shedding (P＜0.05). The R software established a column chart model and applied it to the ROC curve analysis. The AUC of the column chart model in early prediction of plaque shedding was 0.917, with a sensitivity of 82.86% and a specificity of 90.91%. Conclusion The predictive model constructed by combining blood flow grading within carotid artery plaques and serological indicators through SMI can provide early warning of plaque shedding and guide clinical early intervention to reduce the risk of TIA and AIS.

Abstract:Aim To study whether genetically predicted serum testosterone level is causally associated with systemic multisite atherosclerosis. Methods Based on two pooled databases of genome-wide association studies on testosterone and atherosclerosis in European populations from two separate foreign countries, the causal effect between testosterone and atherosclerosis was assessed using two-sample Mendelian randomization analysis with data on testosterone-associated genetic variants as instrumental variables (IV), and by using the inverse-variance weighted (IVW) method, MR-Egger regression, and weighted median estimation. Results IVW results showed that genetically predicted circulating testosterone levels were negatively associated with the risk of peripheral atherosclerosis (OR=0.3,5%CI:0.86~1.00, P＝0.01), and that elevated testosterone level may reduce the risk of developing peripheral atherosclerosis, while no evidence of a potential causal association was found with cerebral atherosclerosis, coronary atherosclerosis and other atherosclerosis type (P＞0.05). Conclusion The final analysis showed a causal relationship between genetically predicted testosterone level and the risk of developing peripheral atherosclerosis, and the role of testosterone therapy in the prevention and treatment of atherosclerosis deserves attention and further study.

Abstract:Non-alcoholic fatty liver disease (NAFLD), a metabolic stress-induced liver injury, is characterized by excessive accumulation of fat in the liver, which is closely related to insulin resistance and genetic susceptibility. It is estimated that 25% of the world's population are currently diagnosed with NAFLD, which has a huge impact on socioeconomic development and people's health. The prevalence of NAFLD in different countries/regions is different based on the living customs and population genetic differences in different regions, and there are also certain differences in the diagnostic criteria and treatment plans of NAFLD in the recommendations given by the national/regional diagnosis and treatment guidelines. This article aims to compare the latest domestic and international guidelines on the diagnosis and treatment of NAFLD, as well as summarise the latest research advances in the treatment of NAFLD, in order to provide recommendations for the clinical management of NAFLD.

Abstract:Endoplasmic reticulum (ER) is the predominant membrane structure in eukaryotic cells and is a key organelle for the occurrence of important intracellular physiological processes. Under the action of various internal and external factors, the homeostasis of ER is disrupted to block protein processing and transport, and the accumulation of unfolded or misfolded proteins in the ER lumen, forms endoplasmic reticulum stress (ERS) and triggers the unfolded protein response (UPR). Moderate ERS reduces protein synthesis, promotes protein degradation, and increases molecular chaperones that assist protein folding through the UPR signaling pathway, ultimately relieving ER stress. However, if the ERS is too strong or prolonged and exceeds the cell's ability to regulate itself, the UPR can initiate apoptosis and lead to diseases.Numerous studies have shown that ERS is closely associated with the development of several cardiovascular diseases (CVD). This review focuses on the research progress of UPR in several common types of CVD and targets UPR as a potential therapeutic approach for CVD.

Abstract:Obstructive sleep apnea (OSA) is an independent risk factor for several cardiovascular diseases, and its characteristic intermittent hypoxic environment induces dysregulation of miRNA in cells and circulation, which promotes cellular dysfunction and metabolic disorders, and participates in the formation of atherosclerosis (As). This article reviews the potential role of miRNA in the occurrence and progression of OSA-related As, which helps to understand the molecular pathways underlying the pathogenesis of OSA-related As and provides new insights for the development of miRNA based therapies for OSA-related cardiovascular diseases.