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Excess cholesterol accumulation induces the accumulation of foam cells, eventually accelerating atherosclerosis progress. Historically, the mechanisms of macrophage-derived foam cells have attracted attention because of their central role in plaque development, which was challenged by lineage tracing in union with single-cell sequencing (sc-seq). Accumulated studies have uncovered how vascular smooth muscle cells (VSMCs) proliferate and migrate to the vascular intima and accumulate, then transform into foam cells induced by surplus lipids, finally accounting for 30% to 70% of the total foam cells within the plaque of both mice and humans. Therefore, the mechanisms of VSMC-derived foam cells have received increasing attention. The review intends to summarize the transformation mechanism of VSMCs into foam cells induced by oxidized low-density lipoproteins (ox-LDL) in atherosclerosis. [ABSTRACT FROM AUTHOR]

Nowadays, cardiovascular diseases are the most common cause of death worldwide. Besides, atherosclerosis is a cardiovascular disease that occurs with persistent narrowing of arteries, especially medium and large-sized arteries. Atherosclerosis begins with a local elevation in the permeability of the arterial wall as a result of endothelial inflammation. Subsequently, excess LDL permeates into the arterial wall. Then, through several chemical responses and reactions, foam cells are produced. These foam cells serve as a crucial indicator for assessing the development of atherosclerosis within the arteries. In this study, the effect of endothelial layer modeling, heart rate (HR) and hypertension on the foam cell accumulation is numerically investigated in a patient-specific geometry of the human thoracic aorta. Navier–Stokes, Darcy, and mass transfer equations are used to obtain the velocity and concentration field within the domain. Regarding the dependence of endothelial cell properties on time-averaged wall shear stress, it is observed that foam cells are mainly concentrated in the outer curvature of the aortic arch, downstream of the left subclavian artery. However, considering oscillatory-shear-rate as the determinant of endothelial cell properties leads to the accumulation of foam cells in the inner curvature of the descending aorta. Regarding the HR, with the increase of HR, the volume average concentration of the foam cell decreases. However, there is no substantial difference between the cases of different HRs. Moreover, foam cell concentration significantly increases in the hypertension case. This result implies that a slight increase in the blood pressure may induce irreparable problems in the circulatory system. [ABSTRACT FROM AUTHOR]

Aim To investigate the impact of bakuchiol (BAK) on lipid accumulation in macrophage-derived foam cell and explore the underlying mechanisms. Methods MTT assay was used to determine the non-toxic concentration of BAK on foam cell. Oil red O staining, NBD cholesterol, and Dil-ox-LDL were used to assess lipid accumulation in foam cell. RT-qPCR and Western blot were utilized to measure mRNA and protein expression, respectively. Results BAK promoted cholesterol effux and reduced lipid accumulation in foam cell. BAK upregulated the mRNA and protein expression levels of ATP-binding cassette transporter A1 (ABCA1) and concurrently downregulated the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2). Treatment with the ERK1/2 activator Ro 67-7476 resulted in decreased ABCA1 protein expression compared with the BAK-treated group. Conclusion BAK reduced lipid accumulation in foam cell by inhibiting ERK1/2 phosphorylation, upregulating ABCA1 expression, and promoting cholesterol efflux, thereby suppressing foam cell formation. [ABSTRACT FROM AUTHOR]

Aim To investigate the effect of theaflavin on oxidized low density lipoprotein (ox-LDL)-induced foam cell formation and oxidative stress in THP-1 macrophages and its mechanism. Methods THP-1 derived macrophages were pretreated with 50 μmol/L theaflavin and (or) 10 μmol/L nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor ML385, then 100 mg/L ox-LDL was added to the cells for 24 h to establish the foam cell model. The effect of theaflavin on THP-1 macrophages viability was evaluated by CCK-8 assay and LDH release. The expression of inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. The release of inflammatory cytokines were detected by enzyme linked immunosorbent assay (ELISA). Intracellular lipid accumulation was detected by Oil red O staining, and lipid absorption was observed by DiL-labeled oxidized low density lipoprotein (DiL-ox-LDL) staining. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The expression of lipid uptake, cholesterol efflux and oxidative stress-related proteins were detected by Western blot and RT-qPCR. Results Treatment with 100 mg/L ox-LDL significantly decreased cell viability and cholesterol efflux-related protein expressions, increased lipid uptake, accumulation and lipid uptake-related protein expressions, and significantly promoted inflammation and ROS level, as well as the expressions of myeloperoxidase (MPO), NADPH oxidase 2 (NOX2) in THP-1 macrophages (all P<0. 05). After pretreatment with theaflavin, cell viability was increased, intracellular lipid uptake, accumulation and lipid uptake-related protein expressions were significantly reduced, cholesterol efflux-related protein expressions were significantly increased, the expression and release of IL-6, IL-1β and TNF-α were significantly decreased, ROS level was significantly decreased, and the expression of MPO and NOX2 were decreased (all P<0. 05). Pretreatment with theaflavin effectively alleviated intracellular oxidative stress by altering the expression of NRF2, heme oxygenase-1 (HO-1) and Kelch-like ECH-associated protein 1 (KEAP1) in NRF2 signaling pathway, and enhanced the translocation of NRF2 into the nucleus. After pretreatment with ML385, the expression levels of NRF2, HO-1, KEAP1 and CD36 were significantly decreased. Conclusion Theaflavin can significantly inhibit ox-LDL-induced foam cell formation, inflammation, and oxidative stress through NRF2/HO-1 signaling pathway in THP-1 macrophages. [ABSTRACT FROM AUTHOR]

Our previous studies have demonstrated that Mito-Tempol (also known as 4-hydroxy-Tempo), a mitochondrial reactive oxygen species scavenger, alleviates oxidized low-density lipoprotein (ox-LDL)-triggered foam cell formation. Given the effect of oxidative stress on activating the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, which promotes foam cell formation, we aimed to explore whether Mito-Tempo inhibits ox-LDL-triggered foam cell formation by regulating NLRP3 inflammasome. The results revealed that Mito-Tempo re-activated Nrf2 and alleviated macrophage foam cell formation induced by ox-LDL, whereas the effects were reversed by ML385 (a specific Nrf2 inhibitor). Mito-Tempo restored the expression and nuclear translocation of Nrf2 by decreasing ox-LDL-induced ubiquitination. Furthermore, Mito-Tempo suppressed ox-LDL-triggered NLRP3 inflammasome activation and subsequent pyroptosis, whereas the changes were blocked by ML385. Mito-Tempo decreased lipoprotein uptake by inhibiting CD36 expression and suppressed foam cell formation by regulating the NLRP3 inflammasome. Taken together, Mito-Tempo exhibits potent anti-atherosclerotic effects by regulating Nrf2/NLRP3 signaling. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen capable of adapting and surviving within macrophages, utilizing host nutrients for its growth and replication. Cholesterol is the main carbon source during the infection process of Mtb. Cholesterol metabolism in macrophages is tightly associated with cell functions such as phagocytosis of pathogens, antigen presentation, inflammatory responses, and tissue repair. Research has shown that Mtb infection increases the uptake of low-density lipoprotein (LDL) and cholesterol by macrophages, and enhances de novo cholesterol synthesis in macrophages. Excessive cholesterol is converted into cholesterol esters, while the degradation of cholesterol esters in macrophages is inhibited by Mtb. Furthermore, Mtb infection suppresses the expression of ATP-binding cassette (ABC) transporters in macrophages, impeding cholesterol efflux. These alterations result in the massive accumulation of cholesterol in macrophages, promoting the formation of lipid droplets and foam cells, which ultimately facilitates the persistent survival of Mtb and the progression of tuberculosis (TB), including granuloma formation, tissue cavitation, and systemic dissemination. Mtb infection may also promote the conversion of cholesterol into oxidized cholesterol within macrophages, with the oxidized cholesterol exhibiting anti-Mtb activity. Recent drug development has discovered that reducing cholesterol levels in macrophages can inhibit the invasion of Mtb into macrophages and increase the permeability of anti-tuberculosis drugs. The development of drugs targeting cholesterol metabolic pathways in macrophages, as well as the modification of existing drugs, holds promise for the development of more efficient anti-tuberculosis medications. [ABSTRACT FROM AUTHOR]

Aim To investigate how chili-derived exosome-like nanovesicle (CDELN) inhibited ox-LDL uptake and reduced ox-LDL-induced intracellular cholesterol accumulation. Methods CDELN were isolated and purified using tissue crushing, differential centrifugation, ultracentrifugation and sucrose density gradient centrifugation. Ox-LDL was used to stimulate THP-1-derived macrophages for 24 hours to establish a foam cell model in vitro, and the effect of CDELN on macrophage foam and its mechanism were further studied. Confocal laser microscopy was used to detect the uptake of CDELN and DiL-acetylated low density lipoprotein (DiL-ac-LDL) by THP-1 macrophages. Oil red O staining was used to detect intracellular cholesterol content and the positive area of oil red O staining in cells was analyzed to evaluate the effect of intracellular lipid accumulation. RT-qPCR and Western blot were used to detect mRNA and protein levels of scavenger receptor A (SRA) and cluster of differentiation 36 (CD36), lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), ATP-binding cassette transporter A1 / G1 (ABCA1 / G1). The expression of mitogen-activated protein kinase (MAPK) pathway proteins including p-ERK, p-p38 MAPK and p-c-Jun, were also analyzed. Results CDELN were exosome-like nanovesicles with uniform size and double membrane, rich in protein and nucleic acids, which can be taken up by macrophages. The results of DiL-ac-LDL uptake showed that CDELN could inhibit cholesterol uptake of macrophages. Oil red O staining showed that CDELN could reduce ox-LDL-induced intracellular cholesterol accumulation. RT-qPCR and Western blot showed that CDELN could significantly reduce mRNA levels of matrix metalloprotein-9 (MMP-9), SRA, CD36 and LOX-1 and protein levels of p-ERK, SRA, CD36 and LOX-1 in ox-LDL-induced THP-1-derived macrophages. Treatment with the p-ERK agonist Yoda1 diminished the protective effect of CDELN. Conclusion CDELN can significantly inhibit macrophage foam cell formation, and this effect may be associated with the inhibition of phosphorylation levels of ERK1 / 2 in the MAPK pathway. [KEY WORDS] atherosclerosis; chili-derived [ABSTRACT FROM AUTHOR]

Excess cholesterol accumulation induces the accumulation of foam cells, eventually accelerating atherosclerosis progress. Historically, the mechanisms of macrophage-derived foam cells have attracted attention because of their central role in plaque development, which was challenged by lineage tracing in union with single-cell sequencing (sc-seq). Accumulated studies have uncovered how vascular smooth muscle cells (VSMCs) proliferate and migrate to the vascular intima and accumulate, then transform into foam cells induced by surplus lipids, finally accounting for 30% to 70% of the total foam cells within the plaque of both mice and humans. Therefore, the mechanisms of VSMC-derived foam cells have received increasing attention. The review intends to summarize the transformation mechanism of VSMCs into foam cells induced by oxidized low-density lipoproteins (ox-LDL) in atherosclerosis.

The accumulation of foam cells in the subendothelial space of the vascular wall to form plaques is the real cause of atherosclerotic lesions. Conventional interventions, such as statins and anti-cytokine or anti-inflammatory therapies, suffer problems in terms of their short therapeutic outcomes and potential disruption of the immune system. The development of more efficient therapeutics to restrict the initial progression of plaques appears to be crucial for treating and preventing atherosclerosis. Decreasing foam cell formation by reversing the excessive phagocytosis of modified low-density lipoprotein (LDL) in macrophages is highly desirable. Here, we developed a strategy based on engineered monocytes to dynamically regulate lipid uptake by macrophages inspired by a CD47–SIRPα signaling-induced defect in the phagocytosis of lesional macrophages at the advanced stage of AS. Briefly, a complex called CD47p-GQDs-miR223, which is designed to interact with SIRPα, was synthesized to remodel monocytes by decreasing the uptake of oxidized LDL through the activation of CD47-SIRPα signaling. After injection, these monocytes compete for recruitment to atherosclerotic plaques, release gene drugs and mediate anti-inflammatory phenotypic remodeling of the aboriginal macrophages, effectively inhibiting the development of foam cells. Our strategy provides a new therapeutic for preventing the progression of atherosclerosis.

Aim To explore the effect of Pueraria Lobata Flowers Extract (PFE) on lipid accumulation in macrophage-derived foam cells. Methods The concentration of PFE in THP-1-derived foam cells was screened by MTT, intracellular lipid accumulation was detected by oil red O staining and cholesterol detection kit, intracellular cholesterol efflux levels were detected by cholesterol efflux assay kit, RT-qPCR and Western blot were used to analyze mRNA and protein expression. Results PFE significantly reduced lipid accumulation in THP-1-derived foam cells. PFE did not affect the mRNA expression of CD36, scavenger receptor-AⅠ (SR-AⅠ), sterol regulatory element-binding protein 2 (SREBP2), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), but it could upregulate the mRNA and protein expression levels of ATP-binding cassette transporter A1 (ABCA1) (P<0. 05), and promote the intracellular cholesterol efflux of macrophage-derived foam cells (P<0. 01). PFE could activate the activity of peroxisome proliferator-activated receptor γ (PPARγ) (P<0. 01) and upregulate the mRNA and protein expression levels of PPARγ (P<0. 05). Compared with the PFE control group, the expression of PPARγ and ABCA1 proteins decreased and cholesterol efflux decreased after GW9662 treatment (all P<0. 01). Conclusion PFE could significantly prevent the lipid accumulation in THP-1-derived foam cells and inhibit the formation of foam cells by upregulating ABCA1 expression and cholesterol efflux mediated by PPARγ. [ABSTRACT FROM AUTHOR]

Helicobacter is a genus of spiral-shaped Gram-negative enterohepatic bacteria whose members are capable of causing bacteremia in humans. One of the poorly studied members of this genus is the bacterium Helicobacter cinaedi. This microorganism was first isolated from human fecal samples in 1984. Although it was long considered to be associated with only immunocompromised patients, more evidence in recent years has implicated H. cinaedi in causing serious pathologies in immunocompetent populations. In addition, H. cinaedi is also reported to be associated with a few chronic or severe illnesses, such as atherosclerosis, which in turn can lead to the development of other cardiovascular pathologies: one of the leading causes of mortality worldwide. Helicobacter cinaedi often goes unnoticed in standard diagnostic methods due to its slow growth under microaerobic conditions. This often leads to significant underdetection and hence undermines the role of this bacterium in the pathogenesis of various diseases and the extent of its spread in humans. In this review, we have compiled information on pathologies associated with H. cinaedi, the occurrence of the bacterium in humans and animals, and the latest developments in diagnosing the bacterium and treating associated diseases. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results in a large amount of tissue cell debris in the lesion site, which interacts with various cytokines, including inflammatory factors, and the intrinsic glial environment of the central nervous system(CNS) to forman inhibitory microenvironment that impedes nerve regeneration. The efficient clearance of tissue debris is crucial for the resolution of the inhibitory microenvironment after SCI. Macrophages are themain cells responsible for tissue debris removal after SCI. However, the high lipid content in tissue debris and the dysregulation of lipid metabolism within macrophages lead to their transformation into foamy macrophages during the phagocytic process. This phenotypic shift is associated with a further pro-inflammatory polarization that may aggravate neurological deterioration and hamper nerve repair. In this review, we summarize the phenotype and metabolism of macrophages under inflammatory conditions, as well as the mechanisms and consequences of foam cell formation after SCI. Moreover, we discuss two strategies for foamcell modulation and several potential therapeutic targets that may enhance the treatment of SCI. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of bergamot (BGM) on the progression of atherosclerosis, and to unravel the mechanism of action. Methods: Oxidized low-density lipoprotein (Ox-LDL)-induced HUVECs were used as an in vitro model of atherosclerosis. CCK-8, flow cytometry (FCM), and enzyme-linked Immunosorbent assay (ELISA) assays were performed to confirm the effects of BGM on the viability and inflammation of ox-LDLinduced HUVECs. Oil-red staining and immunoblot tests were conducted to determine the effects of BGM on foam cell formation and macrophage polarization. Furthermore, The mechanism of action of BGM was examined by immunoblot studies. Results: BGM alleviated the ox-LDL-stimulated decline in HUVEC cell viability, and the ox-LDLstimulated HUVEC inflammation, but inhibited ox-LDL-stimulated foam cell formation and macrophage polarization in vitro (p < 0.05). In addition, BGM regulated SIRT1/NF-κB pathway, thereby alleviating atherosclerosis (p < 0.05). Conclusion: BGM regulates OX-LDL-induced inflammation and foam cell formation of HUVECs by mediating SIRT1/NF-κB pathway, and therefore can potentially serve as a drug for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Exserolides are isocoumarin derivatives containing lactone moiety. Recently, some isocoumarins have been demonstrated to ameliorate hyperlipidemia, a major factor for inducing cardiovascular diseases. However, the effects and mechanisms of action of exserolides on hyperlipidemia are not known. The aim of this study is to investigate whether the marine fungus Setosphaeria sp.-derived exserolides (compounds I, J, E, and F) exert lipid-lowering effects via improving reverse cholesterol transport (RCT) in vitro. RAW264.7 macrophages and HepG2 cells were used to establish lipid-laden models, and the levels of intracellular lipids and RCT-related proteins were determined by assay kits and Western blotting, respectively. We observed that exserolides (at a 5 μM concentration) significantly decreased intracellular cholesterol and triglyceride levels in oxidized low-density lipoprotein-laden RAW264.7 cells and markedly improved [3H]-cholesterol efflux. Among the four tested compounds, exserolide J increased the protein levels of ATP-binding cassette transporter A1, peroxisome proliferator-activated receptor α (PPARα), and liver X receptor α (LXRα). Furthermore, treatment with exserolides significantly decreased oleic acid-laden lipid accumulation in HepG2 hepatocytes. Mechanistically, exserolides enhance PPARα protein levels; furthermore, compound J increases cholesterol 7 alpha-hydroxylase A1 and LXRα protein levels. Molecular docking revealed that exserolides, particularly compound J, can interact with PPARα and LXRα proteins. These data suggest that the terminal carboxyl group of compound J plays a key role in lowering lipid levels by stimulating LXRα and PPARα proteins. In conclusion, compound J exhibits powerful lipid-lowering effects in vitro. However, its hypolipidemic effects in vivo should be investigated in the future.

Objective To explore the roles of iron overload in pro - atherogenic activation of foam cells. Methods RAW264.7 and MOVAS cells were stimulated by oxLDL, ferrimine citrate and deferoxamine respectively. Prussian Blue and Oil Red O staining were used to detect iron deposition and foam cell. CCK-8 test, DHE probe, ELISA, RT-qPCR were performed to detect the cell death rate, reactive oxygen species (ROS) generation, lipid peroxidation molecules [glutathione peroxidase (GSH), glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) content] and the mRNA level of ATP binding cassette transporter A1 (ABCA1), ATP binding cassette transporter G1 (ABCG1), inductible nitris oxide synthase (iNOS), arginase-1 (Arg-1), a-smooth muscle actin (a-SMA), smooth muscle 22 alpha (SM22a), osteopontin (OPN), Interleukin-ip (IL-ip), tumor necrosis factor-a (TNF-a). Results Iron overload could reduced reverse cholesterol transporters (ABCA1 and ABCG1), promote foam cells generation, increased cell death rate, induced the expression of lipid peroxidation molecules (GSH, GPX4, MDA), and promoted pro-inflammatory M1 marker of macrophage and synthetic marker expression of vascular smooth muscle cell (VSMC) and inflammatory cytokines (IL-ip, TNF-a). Conclusion Iron overload promotes the generation of foam cells derived from macrophages and smooth muscle cells and transform them into pro - atherosclerotic phenotype, aggravates cell lipid peroxidation and inflammatory reaction, which contributes to the progress of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background and Aims Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. Methods The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. Results The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cβ/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. Conclusions Macrophage P2Y6R regulates phospholipase Cβ/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies have shown that atorvastatin can up-regulate the expression of heme oxygenase-1 and enhance the anti-inflammation and antioxidative damage ability of cells. However, whether atorvastatin can regulate macrophage polarization, inhibit inflammation and reduce cholesterol accumulation by inducing heme oxygenase-1 expression remains unclear. OBJECTIVE: To investigate the effect of atorvastatin on polarization, inflammation and cholesterol content of oxidized low-density lipoprotein stimulated RAW264.7 macrophages by inducing heme oxygenase-1 expression and its related mechanism. METHODS: Firstly, RAW264.7 cells were randomly divided into six groups and incubated with different concentrations of atorvastatin for 24 hours. The expression of heme oxygenase-1 protein and cell activity were detected to explore the optimal dose of atorvastatin for subsequent studies. RAW264.7 cells were randomly divided into control group, atorvastatin group and heme oxygenase-1 inhibition group. Cells were preincubated with pure medium, atorvastatin 20 μmol/L and atorvastatin 20 μmol/L + zinc protoporphyrin IX 10 μmol /L for 24 hours, and then oxidized low-density lipoprotein 50 mg/L was added for 48 hours. The polarization of macrophages was detected by flow cytometry. The secretion of inflammatory factors such as transforming growth factor β, interleukin 10, interleukin 1β, and tumor necrosis factor α was detected by ELISA. The expression levels of heme oxygenase-1, LC3II, LC3I, P62, PPARγ and ABCA1 were detected by western blot assay. The intracellular cholesterol content was measured with the oxidose method and the accumulation degree of intracellular lipid droplets was evaluated by oil red O staining. RESULTS AND CONCLUSION: (1) Atorvastatin could induce the expression of heme oxygenase-1 protein in macrophages in a dose-dependent manner. (2) Oxidized low-density lipoprotein could induce macrophages to polarize towards M1, secrete proinflammatory factors, and increase the accumulation of intracellular cholesterol. (3) Compared with the control group, the heme oxygenase-1 protein expression of macrophages was increased after atorvastatin intervention, and the cells turned to M2-type polarization and mainly secreted anti-inflammatory factors such as transforming growth factor-β and interleukin-10. PPARγ, ABCA1, LC3II/I and other signal molecules reflecting cholesterol efflux and autophagy increased, and the contents of intracellular cholesterol and lipid droplets decreased significantly (P < 0.05). (4) The heme oxygenase-1 inhibition group treated with zinc protoporphyrin IX significantly reversed the above changes in the atorvastatin group. (5) The results have shown that atorvastatin may promote the polarization of macrophages stimulated by oxidized low-density lipoprotein to M2 type and inhibit inflammation by up-regulating the expression of heme oxygenase-1 and by up-regulating PPARγ/ABCA1 signaling pathway and enhancing autophagy. Atorvastatin can increase the outflow of intracellular cholesterol and reduce the accumulation of intracellular lipids. [ABSTRACT FROM AUTHOR]

The formation of foam cells, lipid-loaded macrophages, is the hallmark event of atherosclerosis. Since cigarette smoking is a risk factor for developing atherosclerosis, the current study investigated the effects of cigarette smoke extract (CSE) on different events like expressions of genes involved in lipid influx and efflux, lipophagy, etc., that play vital roles in foam cell formation. The accumulation of lipids after CSE treatment U937 macrophage cells was examined by staining lipids with specific dyes: Oil red O and BODIPY493/503. Results showed an accumulation of lipids in CSE-treated cells, confirming foam cell formation by CSE treatment. To decipher the mechanism, the levels of CD36, an ox-LDL receptor, and ABCA1, an exporter of lipids, were examined in CSE-treated and -untreated U937 cells by real-time PCR and immunofluorescence analysis. Consistent with lipid accumulation, an increased level of CD36 and a reduction in ABCA1 were observed in CSE-treated cells. Moreover, CSE treatment caused inhibition of lipophagy-mediated lipid degradation by blocking lipid droplets (LDs)-lysosome fusion and increasing the lysosomal pH. CSE also impaired mitochondrial lipid oxidation. Thus, the present study demonstrates that CSE treatment affects lipid homeostasis by altering its influx and efflux, lysosomal degradation, and mitochondrial utilization, leading to the formation of lipid-loaded foam cells. Moreover, the current study also showed that the leucine supplement caused a significant reduction of CSE-induced foam cell formation in vitro. Thus, the current study provides insight into CS-induced atherosclerosis and an agent to combat the disease. [ABSTRACT FROM AUTHOR]

Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation. [ABSTRACT FROM AUTHOR]

Helicobacter is a genus of spiral-shaped Gram-negative enterohepatic bacteria whose members are capable of causing bacteremia in humans. One of the poorly studied members of this genus is the bacterium Helicobacter cinaedi. This microorganism was first isolated from human fecal samples in 1984. Although it was long considered to be associated with only immunocompromised patients, more evidence in recent years has implicated H. cinaedi in causing serious pathologies in immunocompetent populations. In addition, H. cinaedi is also reported to be associated with a few chronic or severe illnesses, such as atherosclerosis, which in turn can lead to the development of other cardiovascular pathologies: one of the leading causes of mortality worldwide. Helicobacter cinaedi often goes unnoticed in standard diagnostic methods due to its slow growth under microaerobic conditions. This often leads to significant underdetection and hence undermines the role of this bacterium in the pathogenesis of various diseases and the extent of its spread in humans. In this review, we have compiled information on pathologies associated with H. cinaedi, the occurrence of the bacterium in humans and animals, and the latest developments in diagnosing the bacterium and treating associated diseases.

Foam cell formation is a crucial process in the progression of atherosclerosis, a chronic inflammatory disease characterized by the accumulation of plaques in the arteries. This study aimed to examine the physiochemical changes in Laminaria japonica during fermentation with Bacillus subtilis and assess the inhibitory effects of the fermented sample on the oxidation of low-density lipoprotein (LDL) and the formation of foam cells. Polysaccharide decompositions and increase of total phenols and reducing power of L. japonica were observed during fermentation. The Fourier-transform infrared spectroscopy analysis revealed the peaks of seaweed polysaccharides of the fermented L. japonica (F sample). The presence of F sample reduced the oxidative stress induced by Cu2+ on LDL and inhibited foam cell formation. Additionally, the levels of proteins involved in foam cell activation, such as CD36, scavenger receptor-A, TLR4, and TLR6, were significantly decreased. Further proteomic analysis revealed that out of 1439 proteins up-regulated by oxidized LDL (oxLDL) in macrophages, 953 were downregulated in the presence of the F sample. The Ingenuity Pathway Analysis identified the activation of canonical pathways associated with atherosclerosis by oxLDL, which were subsequently suppressed by the F sample treatment. Protein-protein interaction network analysis uncovered the role of MAPK3 in regulating multiple pathways. This study suggests that B. subtilis-fermented brown seaweed L. japonica can inhibit LDL oxidation and foaming cell production. Additionally, it offers mechanistic insights for future research in this area.

Macrophages play an important role in the pathogenesis of atherosclerosis (AS) by mediating oxidative stress, inflammation and lipid metabolism, which can lead to the formation of vascular plaque. The Rac family isoforms of small molecules GTPase are active by binding to GTPase, but are inactivated by binding to GDP, and play a role in the switch of cell information conduction. This experiment adopts shRNA interference THP-1 cells respectively each subtype expression and inhibiting Rac1, Rac2, Rac3 activity, each subtype of Rac family on lipid metabolism, inflammatory reaction and oxidative stress. THP-1 cells were stimulated with Ox-LDL to establish AS cell models including lipid loading, adhesion, migration and chemotaxis. Oil Red O staining, cell immunofluorescence, scratching test, transwell, Western blot and other experiments were performed. To observe the different effects of three subtypes of Rac family on multiple links in the foaming process of THP-1 cells. ApoE-/- mice on a high-fat diet were used as animal models to examine the effects of Rac subtypes in vivo. The results showed that the activation of immune cells induced by ox-LDL was inhibited when Rac1, Rac2 and Rac3 in THP-1 were decreased, respectively. Thus, Rac1 and Rac3 act in combination with ox-LDL and are associated with cellular oxidative stress and inflammation. This study provides new means and ideas for finding potential intervention targets that have important regulatory effects on atherosclerosis, and provides a new direction for the development of clinical drugs. • Rac1, Rac2 and Rac3 can promote ox-LDL induced foam cell deposition by activating inflammatory responses. • The effect of Rac2 was more significant than that of Rac1 and Rac3. • Inhibiting Rac2, but not Rac1 or Rac3, can decrease the atherosclerotic plaques in ApoE knockout mice on high-fat diet. [ABSTRACT FROM AUTHOR]

Macrophage‐derived foam cell formation is critical for the initiation and development of atherosclerosis, which contributes to atherosclerotic cardiovascular disease (ASCVD). Glutathione peroxidase 4 (GPX4), a crucial ferroptosis regulator, protects cells from excessive oxidative stress by neutralizing lipid peroxidation. However, the role of macrophage GPX4 in foam cell formation remains unknown. We reported that oxidized low‐density lipoprotein (oxLDL) upregulated GPX4 expression in macrophages. Using the Cre‐loxP system, we generated myeloid cell‐specific Gpx4 knockout (Gpx4myel‐KO) mice. Bone marrow‐derived macrophages (BMDMs) were isolated from WT and Gpx4myel‐KO mice and incubated with modified low‐density lipoprotein (LDL). We found that Gpx4 deficiency promoted foam cell formation and increased the internalization of modified LDL. Mechanistic studies unveiled that Gpx4 knockout upregulated scavenger receptor type A and LOX‐1 expression and downregulated ABCA1 and ABCG1 expression. Collectively, our study lends a novel insight into the role of GPX4 in suppressing macrophage‐derived foam cell formation and suggests GPX4 as a promising therapeutic target to interfere with atherosclerosis‐related diseases. [ABSTRACT FROM AUTHOR]

Abstract We explored the effect of thrombin on human aortic smooth muscle cells (HASMCs) and further analyzed its role in the pathogenesis of atherosclerosis (AS). Thrombin-induced differentially expressed genes (DEGs) in HASMCs were identified by analyzing expression profiles from the GEO. Subsequently, enrichment analysis, GSEA, PPI network, and gene-microRNAs networks were interrogated to identify hub genes and associated pathways. Enrichment analysis results indicated that thrombin causes HASMCs to secrete various pro-inflammatory cytokines and chemokines, exacerbating local inflammatory response in AS. Moreover, we identified 9 HUB genes in the PPI network, which are closely related to the inflammatory response and the promotion of the cell cycle. Additionally, we found that thrombin inhibits lipid metabolism and autophagy of HASMCs, potentially contributing to smooth muscle-derived foam cell formation. Our study deepens a mechanistic understanding of the effect of thrombin on HASMCs and provides new insight into treating AS.

Background Foam cells are markers of atherosclerosis and characterise advanced atherosclerotic plaque, stimulated by inflammation caused by high lipid levels in macrophages. The combination of decaffeinated coffee and green tea extract (DCGTE) has been suggested to have a role in foam cell inhibition. Objective We investigated the inhibiting role of DCGTE against foam cell formation, through modulation of the inflammation process and cholesterol metabolism in macrophage colony stimulating factor- (M-CSF) and oxidized low-density lipoprotein (oxLDL)-exposed macrophages. Methods Coffee and green tea were extracted by filtration and infusion respectively, and underwent decaffeination using active carbon and blanching methods, respectively. Cells were administered 160/160 and 320/320μg/ml of DCGTE. Foam cell formation was observed using a light microscope after staining with Oil Red O (ORO), and the accumulation of lipids in macrophages with ELISA. Observations of lipid influx and efflux were determined through semiquantitative cluster differentiation 36 (CD36) and ATP binding cassette transporter A1 (ABCA1) expression through immunofluorescence. The inflammation process was quantified using inflammatory/anti-inflammatory markers, e.g., tumor necrosis factor α (TNFα) and interleukin 10 (IL10) with ELISA. Peroxisome proliferator activated response γ (PPARγ) expression and activity were assessed with PCR and ELISA, respectively. The expression of microRNA 155 (miR-155) was examined using qPCR. Results DCGTE at the above concentrations tended to reduce foam cell numbers, significantly inhibited lipid accumulation (p=0.000), reduced CD36 expression (p=0.000) and TNFα secretion (p=0.000) in Raw264.7 exposed to M-CSF 50ng/ml and oxLDL 50μg/ml. PPARγ expression (p=0.00) and activity (p=0.001), miR-155 relative expression (p=0.000), and IL10 production (p=0.000) also increased. Conclusion DCGTE lowered foam cell numbers, possibly through attenuation of the inflammatory process and improvement of lipid/efflux mechanisms in M-CSF and oxLDL-stimulated Raw264.7 cells, via upregulation of PPARγ and miR-155. Our results suggest DCGTE may help prevent atherosclerosis-based diseases.

Foam cell vasculopathy is an obliterating type of vasculitis characterized by fibrinoid necrosis, sub-intimal foam cell deposition, vessel wall hyalinosis, and lymphocytic infiltrate. Isolated intra-tumoral foam cell vasculitis is rare and similar changes have been reported in a leiomyoma attributed to treatment with tranexamic acid and gonadotropin-releasing hormone (GnRH) analogs. A 68-year-old hypertensive and diabetic female (P2L2) presented with vaginal spotting and vague abdominal pain. An ultrasound abdomen showed an anterior wall fibroid measuring 5 × 4 cm. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Microscopic sections from the leiomyoma showed multiple foci of obliterating vasculitis, along with fibrinoid necrosis, sub-intimal foam cell deposition, and hyalinosis. There was no involvement of the endometrium, cervix, or ovaries. There were no pulmonary, skin, or renal lesions, or history of systemic vasculitis, and treatment by tranexamic acid or GnRH analogs. This prompted a diagnosis of idiopathic intra-tumoral foam cell vasculitis. This finding has been documented previously in three instances, namely, within a renal angiomyolipoma, cerebral Hodgkin’s lymphoma, and a gastrointestinal stromal tumor; the present case provides the first-ever documentation of isolated intra-tumoral acute atherosis-like/foam cell vasculopathy in leiomyoma.

Foam cell vasculopathy is an obliterating type of vasculitis characterized by fibrinoid necrosis, sub‑intimal foam cell deposition, vessel wall hyalinosis, and lymphocytic infiltrate. Isolated intra‑tumoral foam cell vasculitis is rare and similar changes have been reported in a leiomyoma attributed to treatment with tranexamic acid and gonadotropin‑releasing hormone (GnRH) analogs. A 68‑year‑old hypertensive and diabetic female (P2L2) presented with vaginal spotting and vague abdominal pain. An ultrasound abdomen showed an anterior wall fibroid measuring 5 × 4 cm. She underwent a total abdominal hysterectomy with bilateral salpingo‑oophorectomy. Microscopic sections from the leiomyoma showed multiple foci of obliterating vasculitis, along with fibrinoid necrosis, sub‑intimal foam cell deposition, and hyalinosis. There was no involvement of the endometrium, cervix, or ovaries. There were no pulmonary, skin, or renal lesions, or history of systemic vasculitis, and treatment by tranexamic acid or GnRH analogs. This prompted a diagnosis of idiopathic intra‑tumoral foam cell vasculitis. This finding has been documented previously in three instances, namely, within a renal angiomyolipoma, cerebral Hodgkin’s lymphoma, and a gastrointestinal stromal tumor; the present case provides the first‑ever documentation of isolated intra‑tumoral acute atherosis‑like/foam cell vasculopathy in leiomyoma. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic immune inflammatory disease. Aspirin eugenol ester (AEE) is a novel safe and non-toxic compound with many pharmacological effects such as anti-inflammatory, anti-hyperlipidemic and anti-thrombotic action. In order to investigate the effect of AEE on the inhibition of aortic lipid plaque formation and macrophage-derived foam cell formation induced by oxidized low density lipoprotein (ox-LDL), in vivo atherosclerosis model by feeding ApoE-/- mice with a high-fat diet and foam cells formation in vitro model by ox-LDL-induced RAW264.7 macrophages were established. It was found that AEE decreased the levels of TC and LDL-C in serum, and the plaque formation area and lipid accumulation in the aortic intima of ApoE-/- mice. In vitro studies showed that AEE could prevent the uptake of ox-LDL and reduce the contents of TC and FC in cells. AEE enhanced the cholesterol efflux by increasing the expression of ABCA1, ABCG1 and PPARγ, which effectively alleviated excess cholesterol accumulated in the cells. Meanwhile, AEE also reduced the secretion and expression of inflammatory factors in the cells. In addition, AEE could reverse the action of PPARγ inhibitor T0070907 and/or ox-LDL. Therefore, AEE may become an effective candidate drug for the prevention of atherosclerosis.

Giant arachnoid granulations (GAGs) are poorly investigated. Here, we document clinical findings associated with five new GAGs and illustrate the anatomical composition of these structures as well as diagnostic considerations in three symptomatic adults. The GAGs ranged from 1.1 to 3.6 cm (mean, 2.2 cm) in maximum dimension and manifested in middle-aged individuals who presented with long-standing brain mass and/or chronic headache. On imaging examinations, the tissues appeared as irregular parasagittal and/or perisinus structures that demonstrated heterogeneous internal elements. The GAGs abutted dura, extended through calvarial marrow spaces, and impinged on dural venous sinuses, causing their stenosis. The histologic workup of two GAG specimens resected from separate individuals revealed central collagen with pronounced internal vascular proliferation. One specimen additionally exhibited reactive changes within the lesion, including venous thrombosis, hemorrhage, and conspicuous inflammation. The salient immune component consisted of a foam cell-rich infiltrate that obstructed subcapsular and internal sinusoidal GAG spaces. Within this specimen, meningothelial hyperplasia was also appreciated. Notably, proliferated lymphatic vascular elements were additionally observed within the structure, extending into deep central collagen regions and engulfing many extravasated erythrocytes in the subcapsular space. In both surgically treated patients, symptoms resolved completely following resection. This report is the first to definitively depict reactive vascular and immunological changes within GAGs that were clinically associated with headache. The frequency of reactive changes within these meningeal structures is unclear in the literature, as GAGs are rarely sampled and investigated. Further systematic analyses are warranted to elucidate the causes and consequences of GAG genesis and their roles in physiology and disease states. [ABSTRACT FROM AUTHOR]

As the most common cardiovascular disease, atherosclerosis (AS), is a leading cause of high mortality in patients with chronic renal failure. Rab27a has been reported to regulate the progression of cardiovascular and renal diseases. Nevertheless, little studies investigated the role and mechanism of Rab27a in uremic-accelerated AS (UAAS). An animal model of UAAS was established in apolipoprotein E knockout (apoE−/−) mice using 5/6 nephrectomy (NX). We conducted in vitro and in vivo functional experiments to explore the role of Rab27a in UAAS, including the presence of oxidized low-density lipoprotein (ox-LDL). Rab27a expression was upregulated in the plaque tissues of NX apoE−/− mice. The knockout of Rab27a (Rab27a−/−) reduced AS-induced artery injury, as manifested by the reductions of plaque area, collagen deposition, inflammation and lipid droplet. Besides, cholesterol efflux was increased, while the expression of lipid metabolism-related proteins and the secretions of pro-inflammatory factors were decreased in ox-LDL-induced NX Rab27a−/−apoE−/− mice group. Further, Rab27a deletion inhibited the activation of nuclear factor κB (NF-κB) pathway. In conclusion, our study indicated that Rab27a deficiency attenuated foam cell formation and macrophage inflammation, depending on the NF-κB pathway activation, to inhibit AS progression in uremic apoE−/− mice. This finding may provide a new targeting strategy for UAAS therapy. [ABSTRACT FROM AUTHOR]

Background: Foam cells, the markers of early atherosclerosis and characterise the advanced atherosclerotic plaque, are stimulated by inflammation due to the excess of lipid in macrophages. The combination of decaffeinated coffee and green tea extract (DCGTE) has been suggested to have a role in foam cell inhibition. Objective: to investigate the role of DCGTE against foam cell formation, through modulation of the inflammation process and cholesterol metabolism in macrophage colony stimulating factor (M-CSF) and oxidized low-density lipoprotein (oxLDL)-exposed macrophages. Methods: Coffee and green tea were extracted by filtration and infusion respectively. Both of coffee and green tea underwent decaffeination using active carbon and blanching methods, respectively. Raw 264.7 Cells were administered with 160/160 and 320/320 μg/ml of DCGTE. Foam cell formation was observed using a light microscope after staining with Oil Red O (ORO), and quantified with ELISA. The expression of cluster differentiation 36 (CD36) ( lipid influx) and ATP binding cassette transporter A1 (ABCA1) ( cholesterol efflux) were determined through immunofluorescence. Tumor Necrosis Factor α (TNFα) and Interleukin10 (IL10) were quantified with ELISA. Peroxisome proliferator activated response γ (PPARγ) expression and activity were assessed with Polymerase Chain Reaction (PCR) and ELISA, respectively. The expression of microRNA 155 (miR-155) was examined using qPCR. Results: DCGTE at the above concentrations tended to reduce foam cell numbers, significantly inhibited lipid accumulation (p=0.000), reduced CD36 expression (p=0.000) and TNFα secretion (p=0.000) in Raw264.7 exposed to M-CSF 50 ng/ml and oxLDL 50 μg/ml. The PPARγ expression (p=0.000), PPARγ activity (p=0.001), ABCA1 (p=0.002), miR-155 relative expression (p=0.000), and IL10 production (p=0.000) also increased in DCGTE groups. Conclusion: DCGTE lowered foam cell possibly through attenuation of the inflammatory process and improvement of lipid/efflux mechanisms via upregulation of PPARγ and miR-155 in M-CSF and oxLDL-stimulated Raw264.7 cells. Our results suggest DCGTE might help to prevent atherosclerosis-based diseases.

Atherosclerosis is an inflammatory disease initiated by endothelial activation, in which lipoprotein, cholesterol, extracellular matrix, and various types of immune and non-immune cells are accumulated and formed into plaques on the arterial wall suffering from disturbed flow, characterized by low and oscillating shear stress. Foam cells are a major cellular component in atherosclerotic plaques, which play an indispensable role in the occurrence, development and rupture of atherosclerotic plaques. It was previously believed that foam cells were derived from macrophages or smooth muscle cells, but recent studies have suggested that there are other sources of foam cells. Many studies have found that the distribution of atherosclerotic plaques is not random but distributed at the bend and bifurcation of the arterial tree. The development and rupture of atherosclerotic plaque are affected by mechanical stress. In this review, we reviewed the advances in foam cell formation in atherosclerosis and the regulation of atherosclerotic plaque and lipid metabolism by mechanical forces. These findings provide new clues for investigating the mechanisms of atherosclerotic plaque formation and progression. [ABSTRACT FROM AUTHOR]

Disordered lipid accumulation in the arterial wall is a hallmark of atherosclerosis. Previous studies found that the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane receptor of the immunoglobulin family, is increased in mouse atherosclerotic aortic plaques. However, it remains unknown whether TREM2 plays a role in atherosclerosis. Here we investigated the role of TREM2 in atherosclerosis using ApoE knockout (ApoE−/−) mouse models, primary vascular smooth muscle cells (SMCs), and bone marrow-derived macrophages (BMDMs). In ApoE−/− mice, the density of TREM2-positive foam cells in aortic plaques increased in a time-dependent manner after the mice were fed a high-fat diet (HFD). Compared with ApoE−/− mice, the Trem2−/−/ApoE−/− double-knockout mice showed significantly reduced atherosclerotic lesion size, foam cell number, and lipid burden degree in plaques after HFD feeding. Overexpression of TREM2 in cultured vascular SMCs and macrophages exacerbates lipid influx and foam cell formation by upregulating the expression of the scavenger receptor CD36. Mechanistically, TREM2 inhibits the phosphorylation of p38 mitogen-activated protein kinase and peroxisome proliferator activated-receptor gamma (PPARγ), thereby increasing PPARγ nuclear transcriptional activity and subsequently promoting the transcription of CD36. Our results indicate that TREM2 exacerbates atherosclerosis development by promoting SMC- and macrophage-derived foam cell formation by regulating scavenger receptor CD36 expression. Thus, TREM2 may act as a novel therapeutic target for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Sulforaphane (SFN), an isothiocyanate, is one of the major dietary phytochemicals found in cruciferous vegetables. Many studies suggest that SFN can protect against cancer and cardiometabolic diseases. Despite the proposed systemic and local vascular protective mechanisms, SFN's potential to inhibit atherogenesis by targeting macrophages remains unknown. In this study, in high fat diet fed ApoE-deficient (ApoE−/−) mice, oral SFN treatment improved dyslipidemia and inhibited atherosclerotic plaque formation and the unstable phenotype, as demonstrated by reductions in the lesion areas in both the aortic sinus and whole aorta, percentages of necrotic cores, vascular macrophage infiltration and reactive oxygen species (ROS) generation. In THP-1-derived macrophages, preadministration SFN alleviated oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation, oxidative stress and mitochondrial injury. Moreover, a functional study revealed that peritoneal macrophages isolated from SFN-treated mice exhibited attenuated cholesterol influx and enhanced apolipoprotein A-I (apoA-I)- and high-density lipoprotein (HDL)-mediated cholesterol efflux. Mechanistic analysis revealed that SFN supplementation induced both intralesional and intraperitoneal macrophage phenotypic switching toward high expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and ATP-binding cassette subfamily A/G member 1 (ABCA1/G1) and low expression of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36), which was further validated by the aortic protein expression. These results suggest that the regulation of macrophages' cholesterol transport and accumulation may be mainly responsible for SFN's potential atheroprotective properties, and the regulatory mechanisms might involve upregulating ABCA1/G1 and downregulating CD36 via the modulation of PPARγ and Nrf2. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a process in which macrophages play a key role, is accelerated in diabetes. Elevated concentrations of serum-oxidized low-density lipoproteins (oxLDL) represent a common feature of both conditions. The main goal of this study was to determine the contribution of oxLDL to the inflammatory response of macrophages exposed to diabetic-mimicking conditions. THP1 cells and peripheral blood monocytes purified from non-diabetic healthy donors were cultured under normal (5 mM) or high glucose (HG) (15 mM) with oxLDL. Then, foam cell formation, expression of CD80, HLADR, CD23, CD206, and CD163, as well as toll-like receptor 4 (TLR4) and co-receptors CD36 and CD14 (both at the cell surface and soluble (sCD14)), and inflammatory mediators' production were measured by flow cytometry, RT-qPCR, or ELISA. Additionally, serum sCD14 was determined in subjects with subclinical atherosclerosis with and without diabetes by ELISA. Our results showed that oxLDL-mediated intracellular lipid accumulation via CD36 increased under HG and that HG + oxLDL enhanced TNF, IL1B, and IL8, and decreased IL10. Moreover, TLR4 was upregulated in macrophages under HG and monocytes of subjects with diabetes and atherosclerosis. Interestingly, HG-oxLDL upregulated CD14 gene expression, although its total cellular protein abundance remained unaltered. sCD14 shedding via PRAS40/Akt-dependent mechanisms, with pro-inflammatory activity, was significantly increased in cultured macrophages and plasma from subjects with diabetes and subclinical atherosclerosis or hypercholesterolemia. Our data support an enhanced synergistic pro-inflammatory effect induced by HG and oxLDL in cultured human macrophages, possibly explained by increased sCD14 shedding. [ABSTRACT FROM AUTHOR]

We explored the effect of thrombin on human aortic smooth muscle cells (HASMCs) and further analyzed its role in the pathogenesis of atherosclerosis (AS). Thrombin-induced differentially expressed genes (DEGs) in HASMCs were identified by analyzing expression profiles from the GEO. Subsequently, enrichment analysis, GSEA, PPI network, and gene-microRNAs networks were interrogated to identify hub genes and associated pathways. Enrichment analysis results indicated that thrombin causes HASMCs to secrete various pro-inflammatory cytokines and chemokines, exacerbating local inflammatory response in AS. Moreover, we identified 9 HUB genes in the PPI network, which are closely related to the inflammatory response and the promotion of the cell cycle. Additionally, we found that thrombin inhibits lipid metabolism and autophagy of HASMCs, potentially contributing to smooth muscle-derived foam cell formation. Our study deepens a mechanistic understanding of the effect of thrombin on HASMCs and provides new insight into treating AS. [ABSTRACT FROM AUTHOR]

Burdock fructooligosaccharide (BFO) is a type of linear inulin extracted from burdock root. In this study, we studied the effect of BFO in hypercholesterolemic mice model and found that BFO could decrease the total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and oxidized LDL (ox-LDL). BFO also reduce the hepatocyte damage, improve the antioxidant enzymes activity and regulate genes related to the cholesterol homeostasis in liver. Besides, we found that BFO protected the blood vessels by significantly balancing inflammatory cytokines and alleviating the up-regulation of TLR4/MyD88/NF-κB pathway in aorta. Furthermore, we established a foam cells model induced by ox-LDL in vitro and found that 500 and 1000 μg/mL BFO could effectively inhibit cell proliferation and reduce the production of intracellular lipids and inflammatory cytokines. Therefore, BFO can reduce the risk of hypercholesterolemia by maintaining cholesterol homeostasis, reducing vascular inflammation and alleviating macrophage foaming to prevent its further development into cardiovascular diseases.

Diabetes results in an increased risk of atherosclerotic cardiovascular disease. This minireview will discuss whether monocyte and macrophage lipid loading contribute to this increased risk, as monocytes and macrophages are critically involved in the progression of atherosclerosis. Both uptake and efflux pathways have been described as being altered by diabetes or conditions associated with diabetes, which may contribute to the increased accumulation of lipids seen in macrophages in diabetes. More recently, monocytes have also been described as lipid-laden in response to elevated lipids, including triglyceride-rich lipoproteins, the class of lipids often elevated in the setting of diabetes.

Apolipoprotein A-I (apoA-I) mediates reverse cholesterol transport (RCT) out of cells. In addition to its important role in the RTC, apoA-I also possesses anti-inflammatory and antioxidative functions including the ability to activate inflammasome and signal via toll-like receptors. Dysfunctional apoA-I or its low abundance may cause accumulation of cholesterol mass in alveolar macrophages, leading to the formation of foam cells. Increased numbers of foam cells have been noted in the lungs of mice after experimental exposure to cigarette smoke, silica, or bleomycin and in the lungs of patients suffering from different types of lung fibrosis, including idiopathic pulmonary fibrosis (IPF). This suggests that dysregulation of lipid metabolism may be a common event in the pathogenesis of interstitial lung diseases. Recognition of the emerging role of cholesterol in the regulation of lung inflammation and remodeling provides a challenging concept for understanding lung diseases and offers novel and exciting avenues for therapeutic development. Accordingly, a number of preclinical studies demonstrated decreased expression of inflammatory and profibrotic mediators and preserved lung tissue structure following the administration of the apoA-I or its mimetic peptides. This review highlights the role of apoA-I in lung fibrosis and provides evidence for its potential use in the treatment of this pathological condition. [ABSTRACT FROM AUTHOR]

Objective: In addition to diet and metabolism, the occurrence of foam cells and atherosclerosis are also related to environmental factors. Individual studies have shown that ultraviolet B (UVB) can regulate the progression of atherosclerosis, but with different results. Whether or not UVB has a dual effect on atherosclerosis and what mechanism is involved has not been reported. Methods: After THP-1-derived foam cells were treated with UVB in different ways, the effects of UVB on foam cells were investigated by western blotting, cholesterol efflux experiment, oil red O staining and other methods. Results: UVB plays a dual role on foam cell formation, and this effect is related to cholesterol efflux. UVB of 50 mJ/cm2 can promote cholesterol efflux in foam cells, while UVB of 200 mJ/cm2 can inhibit cholesterol efflux. UVB induces cholesterol efflux from foam cells in an autophagy-dependent manner, as the beneficial effect of UVB at 50 mJ/cm2 can be reversed by the autophagy inhibitor 3-Methyladenine (3-MA). In addition, silencing the expression of ultraviolet radiation resistance-associated gene (UVRAG) can inhibit autophagy and reduce cholesterol efflux, and overexpressing UVRAG yields the opposite result. Conclusion: In conclusion, our research proves that UVB exhibits a dual role in foam cell formation by regulating cholesterol efflux. Further more, we also reveal that UVRAG-mediated autophagy is the underlying mechanism of UVB-induced cholesterol efflux. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a well-known proprotein convertase that influences foam cell formation and modulates atherosclerosis. Inclisiran is a novel chemosynthetic small interfering RNA that inhibits PCSK9 synthesis. This study aimed to explore the effect of inclisiran on oxidized low-density lipoprotein (ox-LDL)-induced foam cell formation in Raw264.7 macrophages and to investigate the underlying mechanisms. Raw264.7 cells were treated with ox-LDL to induce the formation of macrophage-derived foam cells. Oil Red O staining and high-performance liquid chromatography were performed to detect lipid accumulation and cholesterol levels. Dil-ox-LDL uptake assay, CCK-8, RT-qPCR, and Western blotting analysis were performed to examine ox-LDL uptake, cell viability, and expression of scavenger receptor-related factors. Inclisiran reduced lipid accumulation in ox-LDL-treated macrophages in a dose-dependent manner. Inclisiran significantly inhibited the levels of total cholesterol, free cholesterol, and cholesterol ester in the supernatant of Raw264.7 cells. Inclisiran reduced ox-LDL uptake and increased Raw264.7 cell viability. Meanwhile, inclisiran downregulated the expression of SR-A, LOX-1, and CD36 and upregulated SR-BI, ApoE, and ABCA1. Furthermore, inclisiran increased PPARγ activity and decreased NF-κB activity. An inhibitor of PPARγ (T0070907) reversed the beneficial effects of inclisiran on ox-LDL uptake, NF-κB inactivation, and cytokine expression. In conclusion, these data suggested that inclisiran inhibited the formation of macrophage-derived foam cells by activating the PPARγ pathway.Highlights Inclisiran reduces lipid accumulation in Raw264.7 cells; Inclisiran reduces ox-LDL uptake and increases Raw264.7 cell viability; Inclisiran inhibits foam cell formation by activating the PPARγ pathway.

This study investigated the effects and mechanisms of 7-ketocholesterol in promoting macrophage foaming and inflammation. Single-cell RNA sequencing showed that dietary cholesterol oxidation products increased the inflammatory macrophage and Trem2high macrophage numbers in the atherosclerotic aorta of ApoE−/− mice. Enrichment analysis demonstrated activation of inflammation-related pathways (NF-κB pathway and NLRP3 inflammasome) in inflammatory macrophages and cholesterol metabolism-related pathways (LDLR and ABCG1) in Trem2high macrophages. An oxidized-LDL-treated macrophage model was employed to verify the effects and mechanisms of 7-KC on macrophage inflammation and foam cell formation. 7-KC promoted the inflammation and M1 polarization of macrophage in association with the activations of the NF-κB pathway and NLRP3 inflammasome. Furthermore, 7-KC-mediated excessive cholesterol accumulation was attributed to enhanced cholesterol uptake rather than inhibition of cholesterol efflux. Consequently, LDLR expression was up-regulated by 7-KC, while no significant effect on ABCG1 expression was observed. [Display omitted] • Dietary COPs increased aortic inflammatory/Trem2high macrophage in ApoE−/− mice. • Inflammation pathways were enriched in inflammatory macrophage. • Cholesterol metabolism-related pathways were enriched in Trem2high macrophage. • NF-κB and NLRP3 mediated the 7-KC-induced formation of inflammatory macrophages. • LDLR-mediated the 7-KC-induced macrophage cholesterol accumulation. [ABSTRACT FROM AUTHOR]

Allium Macrostemon Bge. (AMB) is a well-known homology of herbal medicine and food that has been extensively used for thousands of years to alleviate cardiovascular diseases. It contains a significant amount of polysaccharides, yet limited research exists on whether these polysaccharides are responsible for its cardiovascular protective effects. In this study, the anti-atherosclerosis effect of the crude polysaccharides of AMB (AMBP) was evaluated using ApoE−/− mice fed a high-fat diet, along with ox-LDL-induced Thp-1 foam cells. Subsequently, guided by the inhibitory activity of foam cells formation, a major homogeneous polysaccharide named AMBP80-1a was isolated and purified, yielding 11.1 % from AMB. The molecular weight of AMBP80-1a was determined to be 10.01 kDa. AMBP80-1a was firstly characterized as an agavin-type fructan with main chains consisting of →1)- β - d -Fru f -(2→ and →1,6)- β - d -Fru f -(2→ linked to an internal glucose moiety, with →6)- β - d -Fru f -(2→ and β - d -Fru f -(2→ serving as side chains. Furthermore, the bio-activity results indicated that AMBP80-1a reduced lipid accumulation and cholesterol contents in ox-LDL-induced Thp-1 foam cell. These findings supported the role of AMBP in alleviating atherosclerosis in vivo/vitro. AMBP80-1a, as the predominant homogeneous polysaccharide in AMB, was expected to be developed as a functional agent to prevent atherosclerosis. [Display omitted] [ABSTRACT FROM AUTHOR]

While the cardiovascular system is a primary target of organophosphorus flame retardants (OPFRs), particularly aryl-OPFRs, it is still exclusive whether the diisodecyl phenyl phosphate (DIDPP), widely used and broadly present in the environment at high concentrations, elicits atherosclerosis effects. Liver X receptors (LXRs) play a direct role in regulating the formation of atherosclerotic lesions. This study was the first to demonstrate that DIDPP acts as an LXRα ligand and functions as an LXRα antagonist with a half-maximal inhibitory concentration of 16.2 μM. We showed that treatment of an in vitro macrophage model with 1 to 10 μM of DIDPP resulted in the downregulation of direct targets of LXRα, namely ABCA1, ABCG1 and SR-B1, thereby leading to a 7.9–13.2 % reduction in cholesterol efflux. This caused dose-dependent, 24.1–43.1 % increases in the staining intensity of foam cells in the macrophage model. This atherosclerotic effect of DIDPP was proposed to be due to its antagonism of LXRα activity, as DIDPP treatment did not alter cholesterol influx. In conclusion, the findings of this study demonstrate that exposure to DIDPP may be a risk factor for atherosclerosis due to the LXRα-antagonistic activity of DIDPP and its ubiquity in the environment. [Display omitted] • DIDPP was identified as a LXRα antagonist in drinking water. • DIDPP markedly hinders cholesterol efflux from macrophages due to its LXRα transcriptional activity. • DIDPP significantly stimulates foam cell formation. [ABSTRACT FROM AUTHOR]

Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.

Abstract Background Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, most of which are caused by atherosclerosis. Discerning processes that participate in macrophage-to-foam cell formation are critical for understanding the basic mechanisms underlying atherosclerosis. To explore the molecular mechanisms of foam cell formation, differentially expressed proteins were identified. Methods Human peripheral blood mononuclear cells were stimulated with macrophage colony-stimulating factor, and obtained macrophages were transformed into foam cells by oxidized low-density lipoprotein. Tandem mass tag (TMT) labeling combined with mass spectrometry was performed to find associations between foam cell transformation and proteome profiles. Results Totally, 5146 quantifiable proteins were identified, among which 1515 and 182 differentially expressed proteins (DEPs) were found in macrophage/monocyte and foam cell/macrophage, respectively. Subcellular localization analysis revealed that downregulated DEPs of macrophages/monocytes were mostly located in the nucleus, whereas upregulated DEPs of foam cells/macrophages were mostly extracellular or located in the plasma membrane. Functional analysis of DEPs demonstrated that cholesterol metabolism-related proteins were upregulated in foam cells, whereas immune response-related proteins were downregulated in foam cells. The protein interaction network showed that the DEPs with the highest interaction scores between macrophages and foam cells were mainly concentrated in lysosomes and the endoplasmic reticulum. Conclusions Proteomics analysis suggested that cholesterol metabolism was upregulated, while the immune response was suppressed in foam cells. KEGG enrichment analysis and protein-protein interaction analysis indicated that DEPs located in the endoplasmic reticulum and lysosomes might be key drivers of foam cell formation. These data provide a basis for identifying the potential proteins associated with the molecular mechanism underlying macrophage transformation to foam cells.

Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicarpa rubella Lindl., a traditional Chinese medicine, have been reported to have anti-inflammatory activity. However, little is known about the effects of these diterpenoids on macrophage foam cell formation.Methods: A macrophage-derived foam cell formation model was established by treating RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) for 24 h. Oil red O staining were used to detect the intracellular lipids. The cholesterol efflux capacity was assayed by labeling cells with 22-NBD-cholesterol. Western blots and real-time PCRs were performed to quantify protein and mRNA expressions.Results: Two diterpenoid molecules, 14α-hydroxyisopimaric acid (C069002) and isopimaric acid (C069004), extracted from the flowers of Callicarpa rubella Lindl., significantly attenuated ox-LDL-induced foam cell formation in RAW264.7 macrophages. Further investigation showed that these two diterpenoids could promote cholesterol efflux from RAW264.7 macrophages to apolipoprotein A-I or high-density lipoproteins, which was associated with upregulated expression of ATP-binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα), and peroxisome proliferator-activated receptor-γ (PPARγ). Unexpectedly, the diterpenoids C069002 and C069004 failed to enhance the mRNA transcription of the ABCG1 gene in macrophage-derived foam cells induced by ox-LDL. To evaluate the effects of diterpenoids on macrophage foam cell formation and determine the underlying mechanism, two drugs (lovastatin and rosiglitazone) were used as positive controls. Although both drugs could reduce macrophage foam cell formation and promote cholesterol efflux, they each had distinctive abilities to modulate the expression of cholesterol efflux-related genes. In contrast to lovastatin, rosiglitazone showed a similar influence on the expression of cholesterol efflux-related genes (including ABCA1, LXRα, and PPARγ) as the diterpenoids regardless of the presence or absence of ox-LDL, implying a similar mechanism by which they may exert atheroprotective effects.Conclusion: Our research indicates that diterpenoids effectively inhibit ox-LDL-induced macrophage foam cell formation by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1 pathway. Further investigation of diterpenoids as potential drugs for the treatment of atherosclerosis is warranted.