Epigenetic modifications in abdominal aortic aneurysms: from basic to clinical.

Abdominal Aortic Aneurysm (AAA) is a disease characterized by localized dilation of the abdominal aorta, involving multiple factors in its occurrence and development, ultimately leading to vessel rupture and severe bleeding. AAA has a high mortality rate, and there is a lack of targeted therapeutic drugs. Epigenetic regulation plays a crucial role in AAA, and the treatment of AAA in the epigenetic field may involve a series of related genes and pathways. Abnormal expression of these genes may be a key factor in the occurrence of the disease and could potentially serve as promising therapeutic targets. Understanding the epigenetic regulation of AAA is of significant importance in revealing the mechanisms underlying the disease and identifying new therapeutic targets. This knowledge can contribute to offering AAA patients better clinical treatment options beyond surgery. This review systematically explores various aspects of epigenetic regulation in AAA, including DNA methylation, histone modification, non-coding RNA, and RNA modification. The analysis of the roles of these regulatory mechanisms, along with the identification of relevant genes and pathways associated with AAA, is discussed comprehensively. Additionally, a comprehensive discussion is provided on existing treatment strategies and prospects for epigenetics-based treatments, offering insights for future clinical interventions.

Improving cancer immunotherapy by preventing cancer stem cell and immune cell linking in the tumor microenvironment.

Cancer stem cells are the key link between malignant tumor progression and drug resistance. This cell population has special properties that are different from those of conventional tumor cells, and the role of cancer stem cell-related exosomes in progression of tumor malignancy is becoming increasingly clear. Cancer stem cell-derived exosomes carry a variety of functional molecules involved in regulation of the microenvironment, especially with regard to immune cells, but how these exosomes exert their functions and the specific mechanisms need to be further clarified. Here, we summarize the role of cancer stem cell exosomes in regulating immune cells in detail, aiming to provide new insights for subsequent targeted drug development and clinical strategy formulation.

Mitochondrial quality control in abdominal aortic aneurysm: From molecular mechanisms to therapeutic strategies.

Mitochondria are the energy supply sites of cells and are crucial for eukaryotic life. Mitochondrial dysfunction is involved in the pathogenesis of abdominal aortic aneurysm (AAA). Multiple mitochondrial quality control (MQC) mechanisms, including mitochondrial DNA repair, biogenesis, antioxidant defense, dynamics, and autophagy, play vital roles in maintaining mitochondrial homeostasis under physiological and pathological conditions. Abnormalities in these mechanisms may induce mitochondrial damage and dysfunction leading to cell death and tissue remodeling. Recently, many clues suggest that dysregulation of MQC is closely related to the pathogenesis of AAA. Therefore, specific interventions targeting MQC mechanisms to maintain and restore mitochondrial function have become promising therapeutic methods for the prevention and treatment of AAA.

Through network pharmacology and molecular docking to explore the underlying mechanism of Artemisia annua L. treating in abdominal aortic aneurysm.

Background: Abdominal aortic aneurysm (AAA) is a degenerative disease that causes health problems in humans. However, there are no effective drugs for the treatment of AAA. Artemisia annua L. (A. annua) is a traditional herbal that has been widely used in cardiovascular disease. Based on network pharmacology and molecular docking technology, this study predicted the practical components and potential mechanisms of A. annua inhibiting the occurrence and development of AAA. Methods: The main active ingredients and targets of A. annua were screened through the TCMSP database; the GeneCards, OMIM, PharmGkb, and TTD databases were used to search for the targeted genes of AAA and map them to the targets of the active ingredients to obtain the active ingredient therapy of A. annua. The targets of AAA were to construct a protein interaction network through the STRING platform. R software was used to carry out the enrichment analysis of GO and KEGG for relevant targets, and Cytoscape was used to construct the active ingredient-target network prediction model of A. annua. Finally, AutoDock Vina was used to verify the results of the active ingredients and critical targets. Results: The main active ingredients obtained from A. annua for the treatment of AAA include quercetin, luteolin, kaempferol, isorhamnetin, and artemetin, as well as 117 effective targets, including RELA, MAPK14, CCND1, MAPK1, AKT1, MYC, MAPK8, TP53, ESR1, FOS, and JUN. The 11 targeted genes might play a key role in disease treatment. Enriched in 2115 GO biological processes, 159 molecular functions, 56 cellular components, and 156 KEGG pathways, inferred that its mechanism of action might be related to PI3K-Akt signaling pathway, fluid shear stress, atherosclerosis, and AGE-RAGE signaling pathway. Molecular docking results showed that the top five active components of A. annua had a good affinity for core disease targets and played a central role in treating AAA. The low binding energy molecular docking results provided valuable information for the development of drugs to treat AAA. Conclusion: Therefore, A. annua may have multiple components, multiple targets, and multiple signaling pathways to play a role in treating AAA. A. annua may have the potential to treat AAA.

User Interface (UI) Design and User Experience Questionnaire (UEQ) Evaluation of a To-Do List Mobile Application to Support Day-To-Day Life of Older Adults.

Because of the spread of smartphones, older adults enjoy the assistance of smartphones. However, fewer mobile applications are designed for older adults. Smartphone user interface (UI) serves as an external brain to capture information, and older adults may have memory complaints that affect self-confidence and lead to memory decline. Non-declarative memory requires more effort. Therefore, this study aims to design and evaluate a to-do list application to help older adults encode, store, and retrieve non-declarative memory, such as tasks they plan to do. We recruited 15 participants (5 men and 10 women) aged 60 to 75 years old (SD = 5.32). They were asked to complete nine usability tasks, and to answer a user experience questionnaire (UEQ) and a few interview questions. Sixty percent of users completed with only one or two attempts (median = 2.80, SD = 1.63). We found three usability issues and proposed an iteration plan. The application has attractiveness, efficiency, dependability, stimulation, novelty, and good perspicuity for older adults. The product was rated excellent except for perspicuity, which met the users' expectations. This indicates that the user is satisfied with the application prototype. The results of this measurement can be utilized as a benchmark for the next model for developing mobile to-do list applications on user experience.

Identification of key monocytes/macrophages related gene set of the early-stage abdominal aortic aneurysm by integrated bioinformatics analysis and experimental validation.

Objective: Abdominal aortic aneurysm (AAA) is a lethal peripheral vascular disease. Inflammatory immune cell infiltration is a central part of the pathogenesis of AAA. It's critical to investigate the molecular mechanisms underlying immune infiltration in early-stage AAA and look for a viable AAA marker. Methods: In this study, we download several mRNA expression datasets and scRNA-seq datasets of the early-stage AAA models from the NCBI-GEO database. mMCP-counter and CIBERSORT were used to assess immune infiltration in early-stage experimental AAA. The scRNA-seq datasets were then utilized to analyze AAA-related gene modules of monocytes/macrophages infiltrated into the early-stage AAA by Weighted Correlation Network analysis (WGCNA). After that, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis for the module genes was performed by ClusterProfiler. The STRING database was used to create the protein-protein interaction (PPI) network. The Differentially Expressed Genes (DEGs) of the monocytes/macrophages were explored by Limma-Voom and the key gene set were identified. Then We further examined the expression of key genes in the human AAA dataset and built a logistic diagnostic model for distinguishing AAA patients and healthy people. Finally, real-time quantitative polymerase chain reaction (RT-qPCR) and Enzyme Linked Immunosorbent Assay (ELISA) were performed to validate the gene expression and serum protein level between the AAA and healthy donor samples in our cohort. Results: Monocytes/macrophages were identified as the major immune cells infiltrating the early-stage experimental AAA. After pseudocell construction of monocytes/macrophages from scRNA-seq datasets and WGCNA analysis, four gene modules from two datasets were identified positively related to AAA, mainly enriched in Myeloid Leukocyte Migration, Collagen-Containing Extracellular matrix, and PI3K-Akt signaling pathway by functional enrichment analysis. Thbs1, Clec4e, and Il1b were identified as key genes among the hub genes in the modules, and the high expression of Clec4e, Il1b, and Thbs1 was confirmed in the other datasets. Then, in human AAA transcriptome datasets, the high expression of CLEC4E, IL1B was confirmed and a logistic regression model based on the two gene expressions was built, with an AUC of 0.9 in the train set and 0.79 in the validated set. Additionally, in our cohort, we confirmed the increased serum protein levels of IL-1ß and CLEC4E in AAA patients as well as the increased expression of these two genes in AAA aorta samples. Conclusion: This study identified monocytes/macrophages as the main immune cells infiltrated into the early-stage AAA and constructed a logistic regression model based on monocytes/macrophages related gene set. This study could aid in the early diagnostic of AAA.

Cellular senescence and abdominal aortic aneurysm: From pathogenesis to therapeutics.

As China's population enters the aging stage, the threat of abdominal aortic aneurysm (AAA) mainly in elderly patients is becoming more and more serious. It is of great clinical significance to study the pathogenesis of AAA and explore potential therapeutic targets. The purpose of this paper is to analyze the pathogenesis of AAA from the perspective of cellular senescence: on the basis of clear evidence of cellular senescence in aneurysm wall, we actively elucidate specific molecular and regulatory pathways, and to explore the targeted drugs related to senescence and senescent cells eliminate measures, eventually improve the health of patients with AAA and prolong the life of human beings.

Influences of remote ischemic preconditioning on postoperative delirium and cognitive dysfunction in adults after cardiac surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: Remote ischemic preconditioning (RIPC) has been suggested to confer neuroprotective effect. However, influences of RIPC on postoperative delirium (POD) and cognitive dysfunction (POCD) in adults after cardiac surgery are less known. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of RIPC on POD and POCD. METHODS: Relevant studies were obtained by search of PubMed, Embase, and Cochrane's Library databases. A random-effect model was used to pool the results. RESULTS: Ten RCTs including 2303 adults who received cardiac surgery were included. Pooled results showed that RIPC did not significantly affect the incidence of POD (six RCTs, odds ratio [OR] 1.07, 95% confidence interval [CI] 0.81 to 1.40, P = 0.65) with no significant heterogeneity (I2 = 0%). In addition, combined results showed that RIPC did not significantly reduce the incidence of POCD either (six RCTs, OR 0.64, 95% CI 0.37 to 1.11, P = 0.11) with moderate heterogeneity (I2 = 44%). Sensitivity analysis by excluding one RCT at a time showed consistent results (P values all > 0.05). CONCLUSIONS: Current evidence from RCTs did not support that RIPC could prevent the incidence of POD or POCD in adults after cardiac surgery. Although these findings may be validated in large-scale RCTs, particularly for the results of POCD, based on these findings, RIPC should not be routinely used as a preventative measure for POD and POCD in adult patients after cardiac surgery.

The protective effect of HOXA5 on carotid atherosclerosis occurs by modulating the vascular smooth muscle cell phenotype.

The phenotypic change of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic form is a key player in atherogenic processes. Homeobox A5 (HOXA5), a transcription factor of the homeobox gene family, has been shown to regulate cell differentiation and morphogenesis. The present study was designed to clarify the involvement of HOXA5 in VSMC phenotypic transition in carotid atherosclerosis (CAS). Activated VSMCs in vitro and ApoE-/- mice in vivo were employed to determine HOXA5's function. Results showed that both the mRNA and protein expression levels of HOXA5 were decreased in platelet-derived growth factor-BB (PDGF-BB)-induced VSMCs. Overexpression of HOXA5 suppressed VSMC conversion from a contractile to a synthetic type in the presence of PDGF-BB, as evidenced by increased contractile markers (calponin, α-SMA and SM22α) along with decreased synthetic markers (vimentin, PCNA and thrombospondin). PDGF-BB-induced proliferation and migration of VSMCs were recovered by HOXA5. Knockdown of HOXA5 had the opposite effect on VSMCs. In vivo, a CAS model was established using ApoE-/- mice fed with a Western-type diet and placing a perivascular carotid collar. We observed a significant reduction in HOXA5 in the carotid arteries of CAS mice. Similar to the in vitro results, HOXA5 overexpression reduced neointimal hyperplasia and plaque formation and inhibited VSMC dedifferentiation and migration. Furthermore, PPARγ was also downregulated in vitro and in vivo, and its antagonist GW9662 reversed HOXA5-mediated inhibition of VSMC dedifferentiation and migration. In summary, we suggest that HOXA5 protects against CAS progression by inhibiting VSMC dedifferentiation through activation of PPARγ.

HOXA5 induces M2 macrophage polarization to attenuate carotid atherosclerosis by activating MED1.

Macrophage polarization is of great importance in the formation of atherosclerotic plaque. Homeobox A5 (HOXA5), one of the homeobox transcription factors, has been revealed to be closely associated with macrophage phenotype switching. This study aims to investigate the role of HOXA5 in carotid atherosclerosis (CAS). Herein, the role of HOXA5 was explored in polarized RAW264.7 macrophages in vitro and ApoE-/- mice in vivo. Interestingly, compared with that in M0 macrophages, both the mRNA and protein expression levels of HOXA5 were decreased in lipopolysaccharide (LPS)/interferon (IFN)-γ-induced M1 macrophages, while increased in IL-4-induced M2 macrophages. In addition, in the presence of IL-4, HOXA5-overexpressing RAW264.7 cells preferred to polarizing toward M2 phenotypes. Furthermore, we found that HOXA5 bound to the promoter region and activated the expression of mediator subunit 1 (MED1), a gene known to regulate macrophage differentiation. Knocking MED1 down inhibited HOXA5-enhanced M2 macrophage polarization. In vivo, the CAS model was induced in ApoE-/- mouse fed with a Western-type diet and placed a perivascular carotid collar. Decreased mRNA and protein expressions of HOXA5 were observed in carotid arteries of CAS mice. Forced overexpression of HOXA5 reduced intimal hyperplasia and lipid accumulation in carotid vessels, and it also promoted the polarization of macrophages to M2 subtypes. The expression of MED1 was decreased in atherosclerotic carotid vessels, while HOXA5 overexpression restored its change. Collectively, HOXA5 in carotid arteries is involved in the macrophage M1/M2 switching in atherosclerotic plaque, which may be associated with its transcriptional regulation of MED1.

A Brush-Spin-Coating Method for Fabricating In Vitro Patient-Specific Vascular Models by Coupling 3D-Printing.

PURPOSE: In vitro patient-specific flexible vascular models are helpful for understanding the haemodynamic changes before and after endovascular treatment and for effective training of neuroendovascular interventionalists. However, it is difficult to fabricate models of overall unified or controllable thickness using existing manufacturing methods. In this study, we developed an improved and easily implemented method by combining 3D printing and brush-spin-coating processes to produce a transparent silicone model of uniform or varied thickness. METHODS: First, a water-soluble inner-skeleton model, based on clinical data, was printed on a 3D printer. The skeleton model was subsequently fixed in a single-axis-rotation machine to enable continuous coating of silicone, the thickness of which was manually controlled by adsorption and removal of excess silicone in a brush-spinning operation. After the silicone layer was solidified, the inner skeleton was further dissolved in a hot water bath, affording a transparent vascular model with real geometry. To verify the controllability of the coating thickness by using this method, a straight tube, an idealised aneurysm model, a patient-specific aortic arch model, and an abdominal aortic aneurysm model were manufactured. RESULTS: The different thicknesses of the manufactured tubes could be well controlled, with the relative standard deviations being 5.6 and 8.1% for the straight and aneurysm tubes, respectively. Despite of the diameter changing from 33 to 20 mm in the patient-specific aorta, the thickness of the fabricated aortic model remains almost the same along the longitudinal direction with a lower standard deviation of 3.1%. In the more complex patient-specific abdominal aneurysm model, varied thicknesses were realized to mimic the measured data from the CT images, where the middle of the aneurysm was with 2 mm and abdominal aorta as well as the iliac arteries had the normal thickness of 2.3 mm. CONCLUSION: Through the brush-spin-coating method, models of different sizes and complexity with prescribed thickness can be manufactured, which will be helpful for developing surgical treatment strategies or training neuroendovascular interventionalists.

Melatonin Plays a Critical Protective Role in Nicotine-Related Abdominal Aortic Aneurysm.

Aim: Smoking is a major risk factor for abdominal aortic aneurysm (AAA). Among the components of smoke, nicotine is known to exert pro-atherosclerotic, prothrombotic, and proangiogenic effects on vascular smooth muscle cells (VSMCs). The current study was designed to investigate the mechanisms through which nicotine induces vascular wall dysfunction and to examine whether melatonin protects against nicotine-related AAA. Methods: In this study, an enzyme-linked immunosorbent assay (ELISA) was used to measure melatonin and TNF-α levels, as well as total antioxidant status (TAS), in patients with AAA. We established a nicotine-related AAA model and explored the mechanisms underlying the therapeutic effects of melatonin. Tissue histopathology was used to assess vascular function, while western blotting (WB) and immunofluorescence staining were performed to detect protein expression. Results: We observed melatonin insufficiency in the serum from patients with AAA, particularly smokers. Moreover, melatonin level was positively correlated with antioxidant capacity. In the in vivo model, nicotine accelerated AAA expansion and destroyed vascular structure. Furthermore, OPN, LC3II, p62, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), NF-κB p65, TNF-α, phosphorylated AKT, and phosphorylated mTOR levels were increased, in vivo, following nicotine treatment, while SM22α and α-SMA levels were reduced. Additionally, melatonin attenuated the effects of nicotine on AAA and reversed changes in protein expression. Moreover, melatonin lost its protective effects following bafilomycin A1-mediated inhibition of autophagy. Conclusion: Based on our data, melatonin exerts a beneficial effect on rats with nicotine-related AAA by downregulating the AKT-mTOR signaling pathway, improving autophagy dysfunction, and restoring the VSMC phenotype.

Saphenous vein graft aneurysm formation in a patient with idiopathic multiple aneurysms.

True aneurysmal vein graft dilation is rare, and its etiology remains speculative. However, systemic dilation diathesis is regarded as a risk factor. We herein report a case of a rapidly expanding aneurysm in a great saphenous vein graft, resulting in distal malperfusion in a patient who had previously undergone open repair of multiple popliteal artery aneurysms. After an unsuccessful endovascular intervention, the dilated section was eventually replaced by a reversed segment of the contralateral great saphenous vein. Subsequent whole-exome sequencing identified no relevant mutations. This case provides further evidence that aneurysmal disease may be associated with systemic dilation diathesis.