This study aimed to explore the key efferocytosis-related genes in diabetic retinopathy (DR) and their regulatory mechanisms. Public DR-related gene expression datasets, GSE160306 (training) and GSE60436 (validation), were downloaded. Differentially expressed efferocytosis-related genes (DEERGs) were analyzed using differential expression analysis and weighted gene co-expression network analysis. Functional enrichment analysis was conducted. Moreover, efferocytosis-related signature genes were identified using machine learning analysis, and their expression levels and diagnostic value were analyzed. Furthermore, nomograms were constructed; immune cell infiltration was analyzed; and gene set enrichment analysis, transcriptional regulation analysis, and small-molecule drug (SMD) prediction of efferocytosis-related signature genes were performed. In total, 36 DEERGs were identified in DR, and were markedly enriched in multiple functions, such as visual system development. Through further machine learning analysis, two efferocytosis-related signature genes, Ferritin Light Chain (FTL) and Fc Gamma Binding Protein (FCGBP), were identified, and were found to be upregulated in DR samples and showed high diagnostic performance for DR. A nomogram constructed using FTL and FCGBP accurately predicted the risk of DR. Moreover, the level of infiltration of immature B cells was positively correlated with FTL and FCGBP expression levels. Multiple transcription factors (TFs), such as CCCTC-Binding Factor (CTCF) and KLF Transcription Factor 9 (KLF9), were found to interact with both FTL and FCGBP. In addition, FTL can be targeted by miRNAs, such as miR-22-3p, and FCGBP can be targeted by miR-7973. In addition, both FTL and FCGBP can be targeted by SMDs, such as bisphenol A. Key efferocytosis-related genes, such as FTL and FCGBP, may promote DR development. Detecting or targeting FTL and FCGBP may aid in the prevention, diagnosis, and treatment of DR.

This study aimed to assess the predictive capacity of specialized pro-resolving mediators (SPMs) regarding the complexity and prognosis of coronary heart disease (CHD). Total of 602 CHD patients were included in this study and categorized into low-risk, medium-risk, and high-risk groups based on the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score. Follow-up was conducted for two years, during which patients were dichotomized into poor and good prognosis groups. Additionally, twenty healthy controls were incorporated. Plasma concentrations of lipoxin A4 (LXA4), resolvin D1 (RvD1), protectin D1 (PD1), C-reactive protein (CRP), interleukin-6 (IL-6), and IL-10 were quantified. Plasma LXA4, RvD1, PD1, and the ratios LXA4/IL-6, RvD1/IL-6, PD1/IL-6 exhibited a gradual decrease across control, low-risk, medium-risk, and high-risk groups and exhibited a negative correlation with the SYNTAX score. Spearman's correlation analysis revealed negative correlations between plasma LXA4, RvD1, PD1, and both CRP and IL-6, and positive correlations with IL-10. Multiple linear regression models demonstrated negative associations between plasma LXA4, RvD1, PD1, and SYNTAX score. Moreover, both univariate and multivariate binary logistic regression analyses identified plasma LXA4, RvD1, and PD1 as protective factors against medium/high-risk SYNTAX score categorization. In the poor prognosis group, plasma PD1 was reduced at short-term follow-up, and the ratios LXA4/IL-6, RvD1/IL-6, PD1/IL-6 were reduced at long-term follow-up. Plasma LXA4, RvD1, and PD1 demonstrated negative correlations with CHD complexity and potentially served as protective factors against CHD. Plasma PD1 provided predictive value for short-term prognosis, while the ratios LXA4/IL-6, RvD1/IL-6, PD1/IL-6 were indicative for long-term prognosis.

Atherosclerosis (AS) is a major pathological factor contributing to the mortality associated with ischemic heart disease and is driven primarily by macrophage-mediated lipid accumulation and inflammatory processes. Conventional cardiovascular pharmacotherapies address these pathological mechanisms but often show limited efficacy, highlighting the need for innovative agents capable of effectively reducing lipid accumulation and inflammation with minimal toxicity. In this study, decursin, a monomer derived from traditional Chinese medicine, is shown to inhibit both lipid accumulation and inflammatory responses in macrophages through direct interaction with protein kinase Cδ (PKCδ), resulting in low cytotoxicity in vitro and negligible toxicity in vivo. To address the short half-life of decursin, a targeted cascade drug delivery system (ALD@EM), which is specifically designed to target AS pathophysiology, is developed. This system employs ICAM-1 and VCAM-1 antibodies for plaque localization and incorporates low-density lipoproteins (LDLs) to facilitate chemotaxis to lesion sites, with an inner layer of apoptotic endothelial cell membranes to increase macrophage internalization and drug release. As a result, ALD@EM nanovesicles significantly increased the accumulation and therapeutic efficacy of decursin within plaques, substantially reducing lipid deposition and plaque inflammation, thereby offering a novel strategy for targeted AS treatment.

Inflammatory and autoimmune disorders, characterized by dysregulated immune responses leading to tissue damage and chronic inflammation, present significant health challenges. This review uniquely focuses on efferocytosis-the phagocyte-mediated clearance of apoptotic cells-and its pivotal role in these disorders. We delve into the intricate mechanisms of efferocytosis' four stages and their implications in disease pathogenesis, distinguishing our study from previous literature. Our findings highlight impaired efferocytosis in conditions like atherosclerosis and asthma, proposing its targeting as a novel therapeutic strategy. We discuss the therapeutic potential of efferocytosis in modulating immune responses and resolving inflammation, offering a new perspective in treating inflammatory disorders.

Recent studies have shown that chronic inflammation in atherosclerotic (ATH) lesions is due to an inability to resolve the inflammatory response. We evaluated the therapeutic potential of specialized pro-resolving mediators (SPMs) incorporated into biomimetic lipid nanoemulsions covered with macrophage membranes (Bio-LN/SPMs) to enhance their stability, targeting, and bioactivity in resolving atherosclerotic plaque inflammation. We utilized both in vitro and in vivo experimental models to test this hypothesis. In vitro, we found that Bio-LN/SPMs significantly reduced the inflammatory markers VCAM-1, MCP-1 in TNF-α-activated endothelial and smooth muscle cells, and iNOS, and NLRP3 in LPS-activated macrophages. In contrast, free SPMs exhibited a more modest effect. In vivo, the i.v. administration of Bio-LN/SPMs in ApoE-deficient mice with progressive atherosclerotic lesions developed after administration for 4 and 8 weeks of a high-fat diet, reduced plasma triglycerides, improved renal function, and decreased plasma proteins associated with complement activation and inflammation (i.e. C4d, C5b-9, IL-6, and MCP-1) to a greater extent than other treatment groups. Bio-LN/SPMs also affected circulated monocyte subpopulations by increasing the percentage of anti-inflammatory Ly6Clow monocytes and reducing that of pro-inflammatory Ly6Chigh monocytes. Additionally, they promoted the transition of macrophages in atherosclerotic plaques to a reparative M2 phenotype. They decreased the production of TNF-α, IL-1β, and IL-6 cytokines, along with lipid deposits in the aorta of ApoE-deficient mice. These findings demonstrate the improved therapeutic efficacy of Bio-LN/SPMs compared to unincorporated SPMs and standard nanoemulsions (LN/SPMs), emphasizing their potential as a novel approach for treating atherosclerosis and other inflammatory diseases.

Atherosclerosis (AS) remains a leading cause of cardiovascular disease and mortality globally. This chronic condition is characterized by inflammation, lipid accumulation, and the deposition of cellular components within arterial walls. Emerging evidence has highlighted the multifaceted therapeutic potential of short-chain fatty acids (SCFAs) in mitigating AS progression. SCFAs have demonstrated anti-inflammatory properties and the ability to regulate immune responses, metabolic pathways, vascular integrity, and intestinal barrier function in animal models of AS. Consequently, SCFAs have garnered significant attention as a promising approach for the prevention and treatment of AS. However, further clinical trials and studies are necessary to fully elucidate the underlying mechanisms and effects of SCFAs. Additionally, different types of SCFAs may exert distinct impacts, necessitating more in-depth investigation into their specific roles and mechanisms. This review provides an overview of the diverse cellular mechanisms contributing to AS formation, as well as a discussion of the significance of SCFAs in AS pathogenesis and their multifaceted therapeutic potential. Nonetheless, additional research is warranted to comprehensively understand and harness the potential of various SCFAs in the context of AS.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, offering life-saving benefits to tumor patients. However, the utilize of ICI agents is often accompanied by immune-related adverse events (irAEs), among which cardiovascular toxicities have attracted more and more attention. ICI induced cardiovascular toxicities predominantly present as acute myocarditis and chronic atherosclerosis, both of which are driven by excessive immune activation. Reprogramming of T cells and macrophages has been demonstrated as a pivotal factor in the pathogenesis of these complications. Therapeutic strategies targeting glycolysis, fatty acid oxidation, reactive oxygen species (ROS) production and some other key signaling have shown promise in mitigating immune hyperactivation and inflammation. In this review, we explored the intricate mechanisms underlying ICI-induced cardiovascular toxicities and highlighted the protective potential of immune reprogramming. We emphasize the roles of T cell and macrophage reprogramming in the heart and vasculature, showcasing their contributions to both short-term and long-term regulation of cardiovascular health. Ultimately, a deeper understanding of these processes will not only enhance the safety of ICIs but also pave the way for innovative strategies to manage immune-related toxicities in cancers therapy.

Deep vein thrombosis is an acute medical condition, and the molecular basis of this etiology will be crucial in the discovery of more advanced therapies. This review has focused at the Notch signaling pathway, which plays a significant role in different physiological activities such as homeostasis, development, and disease. Also, reveal macrophage function in inflammation and thrombosis in depth, with a focus on their polarization and interaction with the endothelium during thrombosis. In this context, some essential cellular and molecular mechanisms relevant to thrombus pathogenesis, DVT aetiology and risk factors, as well as elements and composition of the Notch pathway, are covered in the end, with a focus on elements that distinguish canonical from non-canonical signaling pathways and their biological relevance to macrophages. Notch signaling has been shown to influence macrophage activation and polarization, influencing their function in thrombosis breakdown and resolution. This interplay between Notch signaling and macrophages may reveal possible treatment targets for DVT. Discuss the physiological role of Notch signaling in vascular biology, as well as how it contributes to thrombosis. The difficulties in implementing these discoveries in clinical practice are discussed, along with the status of ongoing clinical trials and experimental investigations focussing on macrophage-directed treatments and Notch inhibitors. These molecular insights synthesis provides a basis for the creation of novel strategies for the efficient management of DVT.

Cell death plays a central role in atheroma plaque progression and aggravation. This study investigates the role of caspase-8 in regulating macrophage cell death modalities, specifically apoptosis and necroptosis, within atheroma plaques.

Bone marrow from caspase-8-deficient (Casp8komac ) and cohoused wildtype littermates were transplanted in atherosclerosis-prone Ldlr-/- recipient mice fed with a proatherogenic diet. Aortic plaque development, necrotic core formation, and cell death were analyzed through histological and biochemical assays. In vitro investigation of macrophages exposed to atherogenic stimuli assessed the effects of caspase-8 inhibition on apoptotic and necroptotic pathways.

Despite lower plasma cholesterol levels and reduced number of inflammatory monocytes, caspase-8-deficient mice exhibited more pronounced atherosclerotic lesions with enlarged necrotic cores and an increased number of dead cells. In vitro, in macrophages exposed to oxidized LDL or oxysterols, the inhibition of caspase-8 revealed a shift from apoptosis to necroptosis as confirmed by increased phosphorylation of MLKL along with decreased cleavage of caspase-3 and -7.

The study highlights the role of caspase-8 in atherosclerosis in tuning the balance between apoptosis and necroptosis. Caspase-8 inhibition leads to a switch towards necroptosis and accumulation of dead cell corpses that contributes to enhanced plaque severity. These findings suggest that reducing caspase-8-regulated necroptosis and necrosis in macrophages could represent a therapeutic strategy to stabilize plaques and reduce cardiovascular risk.

Atherosclerosis is a lipid disorder where modified lipids (especially oxidized LDL) induce macrophage foam cell formation in the aorta. Its pathogenesis involves a continuum of persistent inflammation accompanied by dysregulated anti-inflammatory responses. Changes in the immune cell status due to differences in the lesional microenvironment are crucial in terms of plaque development, its progression, and plaque rupture. Ly6Chi monocytes generated through both medullary and extramedullary cascades act as one of the major sources of plaque macrophages and thereby foam cells. Both monocytes and monocyte-derived macrophages also participate in pathological events in atherosclerosis-associated multiple organ systems through inter-organ communications. For years, macrophage phenotypes M1 and M2 have been shown to perpetuate inflammatory and resolution responses; nevertheless, such a dualistic classification is too simplistic and contains severe drawbacks. As the lesion microenvironment is enriched with multiple mediators that possess the ability to activate macrophages to diverse phenotypes, it is obvious that such cells should demonstrate substantial heterogeneity. Considerable research in this regard has indicated the presence of additional macrophage phenotypes that are exclusive to atherosclerotic plaques, namely Mox, M4, Mhem, and M(Hb) type. Furthermore, although the concept of macrophage clusters has come to the fore in recent years with the evolution of high-dimensional techniques, classifications based on such 'OMICS' approaches require extensive functional validation as well as metabolic phenotyping. Bearing this in mind, the current review provides an overview of the status of different macrophage populations and their role during atherosclerosis and also outlines possible therapeutic implications.

The quantification of coronary artery calcifications (CAC) is a mainstay in radiological assessment of coronary atherosclerosis and cardiovascular risk, but reflect advanced, possibly late-stage changes in the arteries. Increased volume and changes in attenuation of the epicardial adipose tissue (EAT) on computed tomography (CT) have been linked to adverse cardiovascular events, and these changes in the EAT might reflect earlier stages of the processes leading to clinically manifest atherosclerosis. The relationship between EAT and CAC is subject to a knowledge gap, especially in individuals with no previously known coronary artery disease.

Fully automated EAT analysis with an artificial intelligence-based model was performed in a population sample enriched for pre-diabetics, comprising a total of 1,945 individuals aged 50-64 years, where non-contrast CT images, anthropometric and laboratory data was available on established cardiovascular risk factors. Uni- and multivariable linear regression, gradient-boosting and correlation analyses were performed to determine the explanatory value of EAT volume and attenuation data with regards to CAC data.

Neither EAT volume nor EAT attenuation was associated with the presence or severity of CAC, when adjusting for established cardiovascular risk factors, and had only weak explanatory value in gradient-boosting and correlation analyses. Age was the strongest predictor of CAC in both sexes.

No independent association was found between CAC and total EAT volume or attenuation. Importantly, these findings do not rule out early stage or local effects on coronary atherosclerosis from the EAT immediately surrounding the coronary arteries.

Efferocytosis is considered the key to eliminate apoptotic cells (ACs) under physiological and pathological conditions in vivo, mainly through different types of macrophages to achieve this process. Especially, tissue-resident macrophages (TRMs) are very significant for inflammation regression and maintenance of homeostasis in vivo. Abnormal efferocytosis will lead to the accumulation of ACs and the release of a variety of pro-inflammatory factors, which mediates the occurrence of many inflammatory diseases, including atherosclerosis (AS). AS is a chronic inflammatory vascular disease with the participation of the immune system. Defective efferocytosis will accelerate the progress of AS to a certain extent. Therefore, it is of great significance to understand the mechanism of efferocytosis and realize the prevention and treatment of AS through efferocytosis. In this review, we will briefly describe the specific process of efferocytosis, deeply discuss the possible molecular mechanism of impaired efferocytosis promoting the development of AS, and summarize the ways to prevent and treat AS through efferocytosis intervention therapy.

Lysosomes in mammalian cells are recognized as key digestive organelles, containing a variety of hydrolytic enzymes that enable the processing of both endogenous and exogenous substrates. These organelles digest various macromolecules and recycle them through the autophagy-lysosomal system. Recent research has expanded our understanding of lysosomes, identifying them not only as centers of degradation but also as crucial regulators of nutrient sensing, immunity, secretion, and other vital cellular functions. The lysosomal pathway plays a significant role in vascular regulation and is implicated in diseases such as atherosclerosis. During atherosclerotic plaque formation, macrophages initially engulf large quantities of lipoproteins, triggering pathogenic responses that include lysosomal dysfunction, foam cell formation, and subsequent atherosclerosis development. Lysosomal dysfunction, along with the inefficient degradation of apoptotic cells and the accumulation of modified low-density lipoproteins, negatively impacts atherosclerotic lesion progression. Recent studies have highlighted that lysosomal dysfunction contributes critically to atherosclerosis in a cell- and stage-specific manner. In this review, we discuss the mechanisms of lysosomal biogenesis and its regulatory role in atherosclerotic lesions. Based on these lysosomal functions, we propose that targeting lysosomes could offer a novel therapeutic approach for atherosclerosis, shedding light on the connection between lysosomal dysfunction and disease progression while offering new insights into potential anti-atherosclerotic strategies.

Plaque rupture in atherosclerosis (AS) is a major cause of acute cardiovascular events. Macrophage-induced inflammatory responses and accumulation of excess reactive oxygen species (ROS) primarily induce unstable plaques. Therefore, targeting ROS clearance and functional modulation of macrophages are clinically crucial for improving plaque stability and inhibiting AS progression. Here, we constructed a bionic nano-delivery platform, PBP@siR@PM, using platelet membranes (PM) coated with black phosphorus nanosheets (BPNSs) to target macrophages in atherosclerotic plaques. Meanwhile, PM-coated BPNSs (PBP@siR@PM) were used to deliver small interfering RNA silencing Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) into macrophages. Furthermore, macrophage efferocytosis was restored by inhibiting CaMKIIγ and increasing the expression of MerTK, a cytosolic receptor, thus promoting the clearance of apoptotic cells from plaques. This study demonstrated that intraplaque macrophage-targeted therapy using the bionic nano-delivery platform PBP@siR@PM effectively removed excess ROS from macrophages, promoted efferocytosis, cleared apoptotic cells in plaques, improved plaque stability, and largely inhibited AS progression in ApoE-/- mice after high fat diet. In summary, this study proposes a therapeutic strategy for AS and highlights the outstanding therapeutic potential of biomimetic nanomaterials in this type of chronic inflammatory disease. STATEMENT OF SIGNIFICANCE: Rupture of atherosclerotic unstable plaques is a major cause of acute cardiovascular events. Macrophage-induced chronic inflammation and oxidative stress due to overloaded ROS are major contributors to plaque rupture. In this study, we focused on the improvement of macrophage efferocytosis within the plaque for the effective treatment of atherosclerosis. A bionic nano-delivery platform was constructed using platelet membranes (PM) coated black phosphorus nanosheets (BPNSs) to target macrophages in atherosclerotic plaques. In conclusion, intraplaque macrophage-targeted therapy based on the bionic nano-delivery platform PBP@siR@PM effectively scavenges overloaded ROS in macrophages, promotes efferocytosis, removes apoptotic cells from plaques, and improves plaque stability, which significantly inhibits the progression of atherosclerosis in ApoE-/- mice after a high-fat diet.

Vulnerable plaques, which are high-risk features of atherosclerosis, constitute critical elements in the disease's progression due to their formation and rupture. Macrophages and macrophage-derived foam cells are pivotal in inducing vulnerability within atherosclerotic plaques. Thus, understanding macrophage contributions to vulnerable plaques is essential for advancing the comprehension of atherosclerosis and devising novel therapeutic and diagnostic strategies. This review provides an overview of the pathological characteristics of vulnerable plaques, emphasizes macrophages' critical role, and discusses advanced strategies for their diagnosis and treatment. It aims to present a comprehensive macrophage-centered perspective for addressing vulnerable plaques in atherosclerosis.

Atherosclerosis (AS), an inflammatory cardiovascular disease driven by lipid deposition, presents global prevalence with high mortality. Effective anti-inflammatory or lipid removal is a promising strategy. However, current conventional drug delivery methods may face challenges in targeting disease sites and are deficient in the treatment of AS because of the nonspecific tissue distribution and uncontrollable release of the drug. In contrast, stimulus-responsive nanodrug delivery systems (NDDSs) can respond to stimulation and achieve controlled drug release rates at specific disease sites owing to the abnormal pathological microenvironment in plaques with low pH, excessive reactive oxygen species (ROS) and enzymes, and high shear stress. As a consequence, the efficacy of treatment is improved, and adverse reactions are reduced. On the other hand, NDDSs can combine exogenous stimulus responses (photothermal, ultrasound, etc.) to precisely control their function in time and space. This review for the first time focuses on the application of stimulus-responsive NDDSs in the treatment and diagnosis of AS in the last five years. In addition, its pivotal challenges and prospects are emphasized, aiming to facilitate its application for AS.

Atherosclerosis, a slowly progressing inflammatory disease, is characterized by the presence of monocyte-derived macrophages. Interventions targeting the inflammatory characteristics of atherosclerosis hold promising potential. Although interleukin (IL)-10 is widely acknowledged for its anti-inflammatory effects, systemic administration of IL-10 has limitations due to its short half-life and significant systemic side effects. In this study, we aimed to investigate the effectiveness of an approach designed to overexpress IL-10 in macrophages and subsequently introduce these genetically modified cells into ApoE-/- mice to promote atherosclerosis regression. We engineered RAW264.7 cells to overexpress IL-10 (referred to as IL-10M) using lentivirus vectors. The IL-10M exhibited robust IL-10 secretion, maintained phagocytic function, improved mitochondrial membrane potentials, reduced superoxide production and showed a tendency toward the M2 phenotype when exposed to inflammatory stimuli. IL-10M can selectively target plaques in ApoE-/- mice and has the potential to reduce plaque area and necrotic core at both early and late stages of plaque progression. Moreover, there was a significant reduction in MMP9, a biomarker associated with plaque rupture, in IL-10M-treated plaques from both the early and late intervention groups. Additionally, the administration of IL-10M showed no obvious side effects. This study serves as proof that cell therapy based on anti-inflammatory macrophages might be a promising strategy for the intervention of atherosclerosis.

Efferocytosis, the clearance of apoptotic cells, is a critical process that maintains tissue homeostasis and immune regulation. Defective efferocytosis is linked to the development of chronic inflammatory conditions, including atherosclerosis, neurological disorders, and autoimmune diseases. Moreover, the interplay between autophagy and efferocytosis is crucial for inflammation control, as autophagy enhances the ability of phagocytic cells. Efficient efferocytosis, in turn, regulates autophagic pathways, fostering a balanced cellular environment. Dysregulation of this balance can contribute to the pathogenesis of various disorders. Phytochemicals, bioactive compounds found in plants, have emerged as promising therapeutic agents owing to their diverse pharmacological properties, including antioxidant, anti-inflammatory, and immunomodulatory effects. This review aims to highlight the pivotal role of phytochemicals in enhancing efferocytosis and autophagy and explore their potential in the prevention and treatment of related disorders. This study examines how phytochemicals influence key aspects of efferocytosis, including phagocytic cell activation, macrophage polarization, and autophagy induction. The therapeutic potential of phytochemicals in atherosclerosis and neurological diseases is highlighted, emphasizing their ability to enhance efferocytosis and autophagy and reduce inflammation. This review also discusses innovative approaches, such as nanoformulations and combination therapies to improve the targeting and bioavailability of phytochemicals. Ultimately, this study inspires further research and clinical applications in phytochemical-mediated efferocytosis enhancement for managing chronic inflammatory and autoimmune conditions.

Atherosclerosis (AS) is one of the major catalysts of ischemic cerebrovascular disease, and the death and disease burden from AS and its cerebrovascular complications are increasing. Z-ligustilide (Z-LIG) is a key active ingredient in Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort. In this paper, we first introduced LIG's physicochemical properties and pharmacokinetics. Then, we reviewed Z-LIG's intervention and therapeutic mechanisms on AS and its cerebrovascular complications. The mechanisms of Z-LIG intervention in AS include improving lipid metabolism, antioxidant and anti-inflammatory effects, protecting vascular endothelium, and inhibiting vascular endothelial fibrosis, pathological thickening, and plaque calcification. In ischemic cerebrovascular diseases complicated by AS, Z-LIG exerts practical neuroprotective effects in ischemic stroke (IS), transient ischemic attack (TIA), and vascular dementia (VaD) through anti-neuroinflammatory, anti-oxidation, anti-neuronal apoptosis, protection of the blood-brain barrier, promotion of mitochondrial division and angiogenesis, improvement of cholinergic activity, inhibition of astrocyte proliferation, and endoplasmic reticulum stress. This paper aims to provide a basis for subsequent studies of Z-LIG in the prevention and treatment of AS and its cerebrovascular complications and, thus, to promote the development of interventional drugs for AS.

Vascular smooth muscle cells, endothelial cells and macrophages undergo phenotypic conversions throughout atherosclerosis progression, both as a consequence of chronic inflammation and as subsequent drivers of it. The inflammatory hypothesis of atherosclerosis has been catapulted to the forefront of cardiovascular research as clinical trials have shown that anti-inflammatory therapy reduces adverse cardiovascular events. However, no current therapies have been specifically designed to target the phenotype of plaque cells. Fate mapping has revealed that plaque cells convert to detrimental and beneficial cell phenotypes during atherosclerosis, with cumulative evidence highlighting that vascular cell plasticity is intimately linked with plaque inflammation, ultimately impacting lesion stability. Here we review vascular cell plasticity during atherosclerosis in the context of the chronic inflammatory plaque microenvironment. We highlight the need to better understand how plaque cells behave during therapeutic intervention. We then propose modulating plaque cell phenotype as an unexplored therapeutic paradigm in the clinical setting.

Lithospermum erythrorhizon (LE), a medicinal plant from the Boraginaceae family, is traditionally used in East Asia for its therapeutic effects on skin conditions, including infections, inflammation, and wounds. Recently, the role of extracellular vesicles (EVs) as mediators of intercellular communication that regulate inflammation and promote tissue regeneration has garnered increasing attention in the field of regenerative medicine. This study investigates exosome-like vesicles derived from LE callus (LELVs) and their potential in enhancing wound healing. In vitro studies using normal human dermal fibroblasts (NHDFs) demonstrated that LELVs significantly improved cell viability, proliferation, and wound closure, while also enhancing collagen type I synthesis, indicating anti-inflammatory and regenerative properties. For in vivo analysis, LELVs were applied to lipopolysaccharide (LPS)-induced wounds in mice, where wound healing progression was monitored over 14 days. LELV-treated wounds exhibited accelerated re-epithelialization, reduced inflammation, and improved tissue remodeling, with histological analysis revealing enhanced collagen deposition and reduced inflammatory cell infiltration. These results highlight the ability of LELVs to modulate the inflammatory response and promote wound healing. With their natural origin, low immunogenicity, and ease of production, LELVs represent a promising alternative to synthetic treatments for inflammation-associated skin injuries and hold significant potential for clinical applications in wound care.

Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD. Here, we report that the tricarboxylic acid cycle intermediate itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. ITA is produced by immunoresponsive gene 1 (IRG1), which we observe is highly elevated in myeloid cells of vulnerable plaques and absent from early or stable plaques in mice and humans. We additionally report development of an ITA-conjugated lipid nanoparticle that accumulates in plaque and bone marrow myeloid cells, epigenetically reduces inflammation via H3K27ac deacetylation, and reproduces the therapeutic effects of LCLFD-induced plaque resolution in multiple atherosclerosis models.

The impact of triglyceride levels is important to understand the changes in metabolism and structure. With an increase in obesity and hyperlipidemia due to diet; cardiovascular and neuronal structural changes have been shown to be more distinct.

This review aims to discuss the pathophysiology and mechanisms involved in increased levels of triglycerides leading to vascular impairment, metabolic syndrome and cognitive decline.

The literature search was performed using the PubMed, Google scholar and Scopus databases, among which 180 articles were shortlisted based on key words, abstract, materials and methods and results. Among these 74 articles have been cited for the review.

The review discusses the impact of hypertriglyceridemia on metabolism, triglyceride storage, and neurovascular integrity, highlighting mechanisms contributing to vascular dysfunction, metabolic syndrome, and cognitive deterioration.

Elevated triglyceride levels are a key factor in altering metabolic pathways and structural integrity in cardiovascular and neuronal systems. This review provides insights into the mechanisms underlying metabolic disorders caused by elevated triglyceride levels, It highlights the need for further studies to provide more supportive evidence and address existing limitations in understanding these changes.

Timely resolution of the acute inflammatory response (or inflammation resolution) is an active, highly coordinated process that is essential to optimal health. Inflammation resolution is regulated by specific endogenous signalling molecules that function as 'stop signals' to terminate the inflammatory response when it is no longer needed; to actively promote healing, regeneration and tissue repair; and to limit pain. Specialized pro-resolving mediators are a superfamily of signalling molecules that initiate anti-inflammatory and pro-resolving actions. Without an effective and timely resolution response, inflammation can become chronic, a pathological state that is associated with many widely occurring human diseases, including atherosclerotic cardiovascular disease. Uncovering the mechanisms of inflammation resolution failure in cardiovascular diseases and identifying useful biomarkers for non-resolving inflammation are unmet needs. In this Review, we discuss the accumulating evidence that supports the role of non-resolving inflammation in atherosclerosis and the use of specialized pro-resolving mediators as therapeutic tools for the treatment of atherosclerotic cardiovascular disease. We highlight open questions about therapeutic strategies and mechanisms of disease to provide a framework for future studies on the prevention and treatment of atherosclerosis.

Recently, cellular senescence-induced unstable carotid plaques have gained increasing attention. In this study, we utilized bioinformatics and machine learning methods to investigate the correlation between cellular senescence and the pathological mechanisms of unstable carotid plaques. Our aim was to elucidate the causes of unstable carotid plaque progression and identify new therapeutic strategies. First, differential expression analysis was performed on the test set GSE43292 to identify differentially expressed genes (DEGs) between the unstable plaque group and the control group. These DEGs were intersected with cellular senescence-associated genes to obtain 40 cellular senescence-associated DEGs. Subsequently, key genes were then identified through weighted gene co-expression network analysis, random forest, Recursive Feature Elimination for Support Vector Machines algorithm and cytoHubba plugin. The intersection yielded 3 CSA-signature genes, which were validated in the external validation set GSE163154. Additionally, we assessed the relationship between these CSA-signature genes and the immune landscape of the unstable plaque group. This study suggests that cellular senescence may play an important role in the progression mechanism of unstable plaques and is closely related to the influence of the immune microenvironment. Our research lays the foundation for studying the progression mechanism of unstable carotid plaques and provides some reference for targeted therapy.

This study utilized artificial intelligence (AI) to quantify coronary computed tomography angiography (CCTA) images, aiming to compare plaque characteristics and CT-derived fractional flow reserve (FFR-CT) in type 2 diabetes mellitus (T2DM) patients with or without hypertension (HTN).

A retrospective analysis was conducted on 1,151 patients with suspected coronary artery disease who underwent CCTA at a single center. Patients were grouped into T2DM (n = 133), HTN (n = 442), T2DM (HTN+) (n = 256), and control (n = 320). AI assessed various CCTA parameters, including plaque components, high-risk plaques (HRPs), FFR-CT, severity of coronary stenosis using Coronary Artery Disease Reporting and Data System 2.0 (CAD-RADS 2.0), segment involvement score (SIS), and segment stenosis score (SSS). Statistical analysis compared these parameters among groups.

The T2DM (HTN+) group had the highest plaque volume and length, SIS, SSS, and CAD-RADS 2.0 classification. In the T2DM group, 54.0% of the plaque volume was noncalcified and 46.0% was calcified, while in the HTN group, these values were 24.0 and 76.0%, respectively. The T2DM (HTN+) group had more calcified plaques (35.7% noncalcified, 64.3% calcified) than the T2DM group. The average necrotic core volume was 4.25 mm3 in the T2DM group and 5.23 mm3 in the T2DM (HTN+) group, with no significant difference (p > 0.05). HRPs were more prevalent in both T2DM and T2DM (HTN+) compared to HTN and control groups (p < 0.05). The T2DM (HTN+) group had a higher likelihood (26.1%) of FFR-CT ≤0.75 compared to the T2DM group (13.8%). FFR-CT ≤0.75 correlated with CAD-RADS 2.0 (OR = 7.986, 95% CI = 5.466-11.667, cutoff = 3, p < 0.001) and noncalcified plaque volume (OR = 1.006, 95% CI = 1.003-1.009, cutoff = 29.65 mm3, p < 0.001). HRPs were associated with HbA1c levels (OR = 1.631, 95% CI = 1.387-1.918).

AI analysis of CCTA identifies patterns in quantitative plaque characteristics and FFR-CT values. Comorbid HTN exacerbates partially calcified plaques, leading to more severe coronary artery stenosis in patients with T2DM. T2DM is associated with partially noncalcified plaques, whereas HTN is linked to partially calcified plaques.

Latexin (LXN) is abundant in macrophages and plays critical roles in inflammation. Much is known about macrophages in atherosclerosis, the role of macrophage LXN in atherosclerosis has remained elusive. Here, the expression of LXN in human and mouse atherosclerotic lesions was examined by immunofluorescence and immunohistochemistry. LXN knockout and LXN/ApoE double-knockout mice were generated to evaluate the functions of LXN in atherosclerosis. Bone marrow transplantation (BMT) experimentation was carried out to determine whether macrophage LXN regulates atherosclerosis. We found that LXN is enriched in human and murine atherosclerotic lesions, mainly localized to macrophages. LXN deletion ameliorated atherosclerosis in ApoE-/- mice. BMT demonstrate that deletion of LXN in bone marrow protects ApoE-/- mice against atherosclerosis. Mechanistically, we found that LXN targets and inhibits JAK1 in macrophages. LXN deficiency stimulates the JAK1/STAT3/ABC transporter pathway, thereby enhancing the anti-inflammatory and anti-oxidant phenotype, cholesterol efflux, subsequently minimizing foam cell formation and atherosclerosis. Gene therapy by treatment of atherosclerotic mice with adeno-associated virus harbouring LXN-depleting shRNA attenuated the disease phenotype. In summary, our study provides new clues for the role of LXN in the pathological regulation of atherosclerosis, and determines that LXN is a target for preventing atherosclerosis, which may be a potential new anti-atherosclerosis therapeutic target.

The buildup of plaques in atherosclerosis leads to cardiovascular events, with chronic unresolved inflammation and overproduction of reactive oxygen species (ROS) being major drivers of plaque progression. Nanotherapeutics that can resolve inflammation and scavenge ROS have the potential to treat atherosclerosis. Here we demonstrate the potential of black phosphorus nanosheets (BPNSs) as a therapeutic agent for the treatment of atherosclerosis. BPNSs can effectively scavenge a broad spectrum of ROS and suppress atherosclerosis-associated pro-inflammatory cytokine production in lesional macrophages. We also demonstrate ROS-responsive, targeted-peptide-modified BPNS-based carriers for the delivery of resolvin D1 (an inflammation-resolving lipid mediator) to lesional macrophages, which further boosts the anti-atherosclerotic efficacy. The targeted nanotherapeutics not only reduce plaque areas but also substantially improve plaque stability in high-fat-diet-fed apolipoprotein E-deficient mice. This study presents a therapeutic strategy against atherosclerosis, and highlights the potential of BPNS-based therapeutics to treat other inflammatory diseases.

Ferroptosis is a novel form of cell demise characterized primarily by the reduction of trivalent iron to divalent iron, leading to the release of reactive oxygen species (ROS) and consequent induction of intense oxidative stress. In atherosclerosis (AS), highly accumulated lipids are modified by ROS to promote the formation of lipid peroxides, further amplifying cellular oxidative stress damage to influence all stages of atherosclerotic development. Macrophages are regarded as pivotal executors in the progression of AS and the handling of iron, thus targeting macrophage iron metabolism holds significant guiding implications for exploring potential therapeutic strategies against AS. In this comprehensive review, we elucidate the potential interplay among iron overload, inflammation, and lipid dysregulation, summarizing the potential mechanisms underlying the suppression of AS by alleviating iron overload. Furthermore, the application of Traditional Chinese Medicine (TCM) is increasingly widespread. Based on extant research and the pharmacological foundations of active compounds of TCM, we propose alternative therapeutic agents for AS in the context of iron overload, aiming to diversify the therapeutic avenues.

The research progress of endoplasmic reticulum (ER) stress in atherosclerosis (AS) is of great concern. The ER, a critical cellular organelle, plays a role in important biological processes including protein synthesis, folding, and modification. Various pathological factors may cause ER stress, and sustained or excessive ER stress triggers the unfolded protein response, ultimately resulting in apoptosis and disease. Recently, researchers have discovered the importance of ER stress in the onset and advancement of AS. ER stress contributes to the occurrence of AS through different pathways such as apoptosis, inflammatory response, oxidative stress, and autophagy. Therefore, this review focuses on the mechanisms of ER stress in the development of AS and related therapeutic targets, which will contribute to a deeper understanding of the disease's pathogenesis and provide novel strategies for preventing and treating AS.

Atherosclerotic plaques are fatty deposits that form in the walls of major arteries and are one of the major causes of heart attacks and strokes. Macrophages are the main immune cells in plaques and macrophage dynamics influence whether plaques grow or regress. Macrophage proliferation is a key process in atherosclerosis, particularly in the development of mid-stage plaques, but very few mathematical models include proliferation. In this paper we reframe the lipid-structured model of Ford et al. (J Theor Biol 479:48-63, 2019. https://doi.org/10.1016/j.jtbi.2019.07.003 ) to account for macrophage proliferation. Proliferation is modelled as a non-local decrease in the lipid structural variable. Steady state analysis indicates that proliferation assists in reducing eventual necrotic core lipid content and spreads the lipid load of the macrophage population amongst the cells. The contribution of plaque macrophages from proliferation relative to recruitment from the bloodstream is also examined. The model suggests that a more proliferative plaque differs from an equivalent (defined as having the same lipid content and cell numbers) recruitment-dominant plaque in the way lipid is distributed amongst the macrophages. The macrophage lipid distribution of an equivalent proliferation-dominant plaque is less skewed and exhibits a local maximum near the endogenous lipid content.

Trem2 (triggering receptor on myeloid cells 2), a surface lipid receptor, is expressed on foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, and anti-inflammatory responses. Studies examining the role of Trem2 in atherosclerosis have shown that deletion of Trem2 leads to impaired foamy macrophage lipid uptake, proliferation, survival, and cholesterol efflux. Thus, we tested the hypothesis that administration of a Trem2 agonist antibody (AL002a) to atherogenic mice would enhance macrophage survival and decrease necrotic core formation to improve plaque stability.

To model a therapeutic intervention approach, atherosclerosis-prone mice (Ldlr [low-density lipoprotein receptor]-/-) were fed a high-fat diet for 8 weeks, then transitioned to treatment with AL002a or isotype control for an additional 8 weeks while continuing on a high-fat diet.

AL002a-treated mice had increased lesion size in both the aortic root and whole mount aorta, which correlated with an expansion of plaque macrophage area. This expansion was due to increased macrophage survival and proliferation in plaques. Importantly, plaques from AL002a-treated mice showed improved features of plaque stability, including smaller necrotic cores, increased fibrous caps, and greater collagen deposition. Single-cell RNA sequencing of whole aorta suspensions from isotype- and AL002a-treated atherosclerotic mice revealed that Trem2 agonism dramatically altered foamy macrophage transcriptome. This included upregulation of oxidative phosphorylation and increased expression of collagen genes. In vitro studies validated that Trem2 agonism with AL002a promoted foamy macrophage oxidized low-density lipoprotein uptake, survival, and cholesterol efflux.

Trem2 agonism expands atherosclerotic plaque macrophages by promoting cell survival and proliferation but improves features of plaque stability by rewiring foamy macrophage function to enhance cholesterol efflux and collagen deposition.

Atherosclerosis has traditionally been considered as a disorder characterized by the accumulation of cholesterol and thrombotic materials within the arterial wall. However, it is now understood to be a complex inflammatory disease involving multiple factors. Central to the pathogenesis of atherosclerosis are the interactions among monocytes, macrophages, and neutrophils, which play pivotal roles in the initiation, progression, and destabilization of atherosclerotic lesions. Recent advances in our understanding of atherosclerosis pathogenesis, coupled with results obtained from experimental interventions, lead us to propose the hypothesis that atherosclerosis may be reversible. This paper outlines the evolution of this hypothesis and presents corroborating evidence that supports the potential for atherosclerosis regression through the restoration of vascular copper homeostasis. We posit that these insights may pave the way for innovative therapeutic approaches aimed at the reversal of atherosclerosis.

The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients' quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.

Recent studies have suggested exosomes (EXO) as potential therapeutic tools for cardiovascular diseases, including atherosclerosis (AS). This study investigates the function of bone marrow stem cell (BMSC)-derived exosomes (EXO) on macrophage pyroptosis in AS and explores the associated mechanism. BMSC-EXO were isolated from healthy mice and identified. RAW264.7 cells (mouse macrophages) were exposed to oxLDL to simulate an AS condition. BMSC-EXO treatment enhanced viability and reduced lactate dehydrogenase release of macrophages. An animal model of AS was established using ApoE-/- mice. BMSC-EXO treatment suppressed plaque formation as well as macrophage and lipid infiltration in mouse aortic tissues. Moreover, BMSC-EXO decreased concentrations of pyroptosis-related markers interleukin (IL)-1β, IL-18, cleaved-caspase-1 and gasdermin D in vitro and in vivo. Long non-coding RNA AU020206 was carried by the BMSC-EXO, and it bound to CCAAT enhancer binding protein beta (CEBPB) to block CEBPB-mediated transcriptional activation of NLR family pyrin domain containing 3 (NLRP3). Functional assays revealed that silencing of AU020206 aggravated macrophage pyroptosis and exacerbated AS symptoms in mice. These exacerbations were blocked upon CEBPB silencing but then restored after NLRP3 overexpression. In conclusion, this study demonstrates that AU020206 delivered by BMSC-EXO alleviates macrophage pyroptosis in AS by blocking CEBPB-mediated transcriptional activation of NLRP3.

Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a DHA-derived specialized pro-resolving mediator, on metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanisms are not well understood. Our study aims to determine the mechanism by which RvD1 protects against MASH progression.

RvD1 was administered to mice with experimental MASH, followed by bulk and single-cell RNA sequencing analysis. Primary cells including bone marrow-derived macrophages (BMDMs), Kupffer cells, T cells, and primary hepatocytes were isolated to elucidate the effect of RvD1 on inflammation, cell death, and fibrosis regression genes.

Hepatic tissue levels of RvD1 were decreased in murine and human MASH, likely due to an expansion of pro-inflammatory M1-like macrophages with diminished ability to produce RvD1. Administering RvD1 reduced inflammation, cell death, and liver fibrosis. Mechanistically, RvD1 reduced inflammation by suppressing the Stat1-Cxcl10 signaling pathway in macrophages and prevented hepatocyte death by alleviating ER stress-mediated apoptosis. Moreover, RvD1 induced Mmp2 and decreased Acta2 expression in hepatic stellate cells (HSCs), and promoted Mmp9 and Mmp12 expression in macrophages, leading to fibrosis regression in MASH.

RvD1 reduces Stat1-mediated inflammation, mitigates ER stress-induced apoptosis, and promotes MMP-mediated fibrosis regression in MASH. This study highlights the therapeutic potential of RvD1 to treat MASH.

Accumulating evidence over the past decades has revealed an intricate relationship between dysregulation of cellular metabolism and the progression of atherosclerotic cardiovascular disease. However, an integrated understanding of dysregulated cellular metabolism in atherosclerotic cardiovascular disease and its potential value as a therapeutic target is missing. In this Review, we (1) summarize recent advances concerning the role of metabolic dysregulation during atherosclerosis progression in lesional cells, including endothelial cells, vascular smooth muscle cells, macrophages and T cells; (2) explore the complexity of metabolic cross-talk between these lesional cells; (3) highlight emerging technologies that promise to illuminate unknown aspects of metabolism in atherosclerosis; and (4) suggest strategies for targeting these underexplored metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas with a potential new generation of cardiovascular therapeutics.

Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β-glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin-induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β-Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β-glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β-glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury-mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury-mediated disorders.