Single-cell sequencing analysis and multiple machine-learning models revealed the cellular crosstalk of dendritic cells and identified FABP5 and KLRB1 as novel biomarkers for psoriasis.

Background: Psoriasis is an immune-mediated disorder influenced by environmental factors on a genetic basis. Despite advancements, challenges persist, including the diminishing efficacy of biologics and small-molecule targeted agents, alongside managing recurrence and psoriasis-related comorbidities. Unraveling the underlying pathogenesis and identifying valuable biomarkers remain pivotal for diagnosing and treating psoriasis. Methods: We employed a series of bioinformatics (including single-cell sequencing data analysis and machine learning techniques) and statistical methods to integrate and analyze multi-level data. We observed the cellular changes in psoriatic skin tissues, screened the key genes Fatty acid binding protein 5 (FABP5) and The killer cell lectin-like receptor B1 (KLRB1), evaluated the efficacy of six widely prescribed drugs on psoriasis treatment in modulating the dendritic cell-associated pathway, and assessed their overall efficacy. Finally, RT-qPCR, immunohistochemistry, and immunofluorescence assays were used to validate. Results: The regulatory influence of dendritic cells (DCs) on T cells through the CD70/CD27 signaling pathway may emerge as a significant facet of the inflammatory response in psoriasis. Notably, FABP5 and KLRB1 exhibited up-regulation and co-localization in psoriatic skin tissues and M5-induced HaCaT cells, serving as potential biomarkers influencing psoriasis development. Conclusion: Our study analyzed the impact of DC-T cell crosstalk in psoriasis, elucidated the characterization of two biomarkers, FABP5 and KLRB1, in psoriasis, and highlighted the promise and value of tofacitinib in psoriasis therapy targeting DCs.

SPRR1B is Related to the Immune Microenvironment and Can Be Used as a Biomarker for the Diagnosis of Psoriasis.

Background: Psoriasis, a chronic inflammatory disorder with an unknown cause, significantly impacts the physical and psychological well-being of patients. However, current biomarkers related to psoriasis lack clinical specificity, sensitivity, and predictive ability. Methods: In this study, we collected skin lesion tissues from 20 psoriasis patients and 20 normal skin samples. Additionally, we obtained four datasets from the GEO database, which included human psoriasis and healthy specimens. We utilized SVM-RFE analysis and the LASSO regression model to identify potential biomarkers. Furthermore, we examined the composition of immune cell types in psoriasis and their correlation with specific genes. Results: Our investigation revealed 57 differentially expressed genes (DEGs), and we identified significantly enriched pathways through KEGG pathway analysis. The results of machine learning and WGCNA suggested that LCE3D and SPRR1B could potentially be used as marker genes for diagnosing psoriasis. RT-PCR and immunohistochemical detection confirmed the abnormally high expression of the SPRR1B gene in psoriasis. Analysis of immune cell infiltration revealed a strong positive correlation between SPRR1B and Macrophages M0 and T cells follicular helper, while showing the strongest negative correlation with resting Mast cells. In addition, we found that silencing SPRR1B in IFN-γ-treated HaCat cells could significantly reduce the increase in IL-17, IL-22, KRT6, and KRT16 caused by IFN-γ. Conclusion: These findings suggest that SPRR1B may have a significant role in the pathogenesis of psoriasis and could be employed as a novel immunomarker for its development.

Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages.

BACKGROUND: Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of rapamycin complex 1)-autophagy defects in macrophages, accelerating atherosclerotic plaque progression. In addition, autophagy-lysosomal dysfunction contributes to plaque necrotic core enlargement and lipid accumulation. Therefore, it is essential to investigate the novel mechanism and molecules to reverse amino acid-mTORC1-autophagy signaling dysfunction in macrophages of patients with advanced atherosclerosis. METHODS: We observed that Gpr137b-ps (G-protein-coupled receptor 137B, pseudogene) was upregulated in advanced atherosclerotic plaques. The effect of Gpr137b-ps on the progression of atherosclerosis was studied by generating advanced plaques in ApoE-/- mice with cardiac-specific knockout of Gpr137b-ps. Bone marrow-derived macrophages and mouse mononuclear macrophage cell line RAW264.7 cells were subjected to starvation or amino acid stimulation to study amino acid-mTORC1-autophagy signaling. Using both gain- and loss-of-function approaches, we explored the mechanism of Gpr137b-ps-regulated autophagy. RESULTS: Our results demonstrated that Gpr137b-ps deficiency led to enhanced autophagy in macrophages and reduced atherosclerotic lesions, characterized by fewer necrotic cores and less lipid accumulation. Knockdown of Gpr137b-ps increased autophagy and prevented amino acid-induced mTORC1 signaling activation. As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. Furthermore, Gpr137b-ps interfered with the HSC70 binding to G3BP (Ras GTPase-activating protein-binding protein), which tethers the TSC (tuberous sclerosis complex) complex to lysosomes and suppresses mTORC1 signaling. In addition to verifying that the NTF2 (nuclear transport factor 2) domain of G3BP binds to HSC70 by in vitro protein synthesis, we further demonstrated that HSC70 binds to the NTF2 domain of G3BP through its W90-F92 motif by using computational modeling. CONCLUSIONS: These findings reveal that Gpr137b-ps plays an essential role in the regulation of macrophage autophagy, which is crucial for the progression of advanced atherosclerosis. Gpr137b-ps impairs the interaction of HSC70 with G3BP to regulate amino acid-mTORC1-autophagy signaling, and these results provide a new potential therapeutic direction for the treatment of advanced atherosclerosis.

IRGM/Irgm1 deficiency inhibits neutrophil-platelet interactions and thrombosis in experimental atherosclerosis and arterial injury.

BACKGROUND: Neutrophil extracellular traps (NETs) closely link inflammation and thrombosis. The immune-related GTPase family M protein (IRGM) and its ortholog of mouse IRGM1 are positively correlated with plaque rupture during atherosclerosis process. However, whether and how IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis remains unknown, which will further promote the development of antithrombotic treatment tools. METHODS: The thrombi images, platelet activation makers and NETs makers were detected in the serum of STEMI patients and controls. To futher investigate IRGM/IRGM1 affects NETs formation and atherothrombosis in vivo, ApoE-/-Irgm1+/- and ApoE-/- mice received diets rich in fat and 2.5% FeCl3 was then used to induce experimental arterial thrombosis in an atherosclerosis background. In vitro, PMA and thrombin were used to stimulate neutrophils and platelets, respectively, and the expression of IRGM/IRGM1 were modified. To reveal the molecular mechanisms, MAPK-cPLA2 signals inhibitors were used. RESULTS: Serum IRGM was positively correlated with PF4 and neutrophil elastase. Subsequently, Irgm1 deficient mice have a longer occlusion time and lower growth rate. In vitro, as expected, IRGM/Irgm1 deficiency inhibits platelet activation and platelet-neutrophil interaction. More importantly, IRGM promoted NETs production through activating MAPK-cPLA2 signals in PMA stimulated neuropils, whereas inhibiting the production of NETs eliminated the difference in platelet activation and thrombosis caused by IRGM/Irgm1 modification in vivo and vitro. Similarly, inhibition of platelet activation also eliminated the influence of IRGM/Irgm1 modification on NETs production. CONCLUSIONS: Overall, our data indicate that IRGM/Irgm1 deficiency in neuropils inhibits the intense interaction between neutrophils and platelets, and ultimately inhibits thrombosis.

ANRIL polymorphisms in psoriasis vulgaris patients in northern China

Background: Psoriasis is a systemic inflammatory disease. The autoimmune response plays a role in the pathogenesis of psoriasis. The long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) can regulate the immune response and participate in the pathogenesis of immune-related diseases, however, the role of ANRIL in the pathogenesis of psoriasis requires further clarification. Objectives: To study the association between ANRIL polymorphisms and psoriasis in the northern Chinese population. Materials & Methods: We genotyped six SNPs in ANRIL in 270 psoriasis vulgaris patients and 271 healthy controls in the northern Chinese population using an improved multiplexed ligation detection reaction method, in order to identify the role of ANRIL in psoriasis. Results: The C allele of rs3217992 and the T allele of rs2518723 were more prevalent in the case group than in the control group. The haplotypes, CTATAA, CCCCGG, and CTCCGG, were associated with risk of psoriasis, while the TCCCGG, TCATAA and CCATAA haplotypes were protective against psoriasis. Based on subgroup analysis, patients with the CT genotype at the rs3217992 and rs2518723 loci had a higher probability of a family history of psoriasis, and patients with the AA genotype had a higher mean age in the rs1333048 and rs10757278 groups, while those with the TT genotype had a higher mean age in the rs1333045 group. Conclusion: Our study identifies an association between ANRIL genetic variants and risk of psoriasis in northern China.

IRGM/Irgm1 facilitates macrophage apoptosis through ROS generation and MAPK signal transduction: Irgm1+/- mice display increases atherosclerotic plaque stability.

Rationale: Atherosclerosis plaque rupture (PR) is the pathological basis and chief culprit of most acute cardiovascular events and death. Given the complex and important role of macrophage apoptosis and autophagy in affecting plaque stability, an important unanswered question include is whether, and how, immunity-related GTPase family M protein (IRGM) and its mouse orthologue IRGM1 affect macrophage survival and atherosclerotic plaque stability. Methods: To investigate whether serum IRGM of ST-segment elevation myocardial infarction (STEMI) patients is related to plaque morphology, we divided 85 STEMI patients into those with and without plaque rupture (PR and non-PR, respectively) based on OCT image analysis, and quantified the patients' serum IRGM levels. Next, we engineered Irgm1 deficient mice (Irgm1+/-) and chimera mice with Irgm1 deficiency in the bone marrow on an ApoE-/- background, which were then fed a high-fat diet for 16 weeks. Pathological staining was used to detect necrotic plaque cores, ratios of neutral lipids and cholesterol crystal, as well as collagen fiber contents in these mice to characterize plaque stability. In addition, immunofluorescence, immunohistochemical staining and western blot were used to detect the apoptosis of macrophages in the plaques. In vitro, THP-1 and RAW264.7 cells were stimulated with ox-LDL to mimic the in vivo environment, and IRGM/IRGM1 expression were modified by specific siRNA (knockdown) or IRGM plasmid (knocked-in). The effect of IRGM/Irgm1 on autophagy and apoptosis of macrophages induced by ox-LDL was then evaluated. In addition, we introduced inhibitors of the JNK/p38/ERK signaling pathway to verify the specific mechanism by which Irgm1 regulates RAW264.7 cell apoptosis. Results: The serum IRGM levels of PR patients is significantly higher than that of non-PR patients and healthy volunteers, which may be an effective predictor of PR. On a high-fat diet, Irgm1-deficient mice exhibit reduced necrotic plaque cores, as well as neutral lipid and cholesterol crystal ratios, with increased collagen fiber content. Additionally, macrophage apoptosis is inhibited in the plaques of Irgm1-deficient mice. In vitro, IRGM/Irgm1 deficiency rapidly inhibits ox-LDL-induced macrophage autophagy while inhibiting ox-LDL-induced macrophage apoptosis in late stages. Additionally, IRGM/Irgm1 deficiency suppresses reactive oxygen species (ROS) production in macrophages, while removal of ROS effectively inhibits macrophage apoptosis induced by IRGM overexpression. We further show that Irgm1 can affect macrophage apoptosis by regulating JNK/p38/ERK phosphorylation in the MAPK signaling pathway. Conclusions: Serum IRGM may be related to the process of PR in STEMI patients, and IRGM/Irgm1 deficiency increases plaque stability. In addition, IRGM/Irgm1 deficiency suppresses macrophage apoptosis by inhibiting ROS generation and MAPK signaling transduction. Cumulatively, these results suggest that targeting IRGM may represent a new treatment strategy for the prevention and treatment of acute cardiovascular deaths caused by PR.

Luteolin prevents THP-1 macrophage pyroptosis by suppressing ROS production via Nrf2 activation.

Pyroptosis plays an important role in the pathogenesis of numerous infectious, autoimmune, and inflammatory diseases, which makes it a promising target for intervention. In this study, the effect of luteolin on pyroptosis and the underlying mechanism were investigated using the canonical NLRP3 inflammasome in THP-1 macrophages induced by LPS/ATP. The results showed that luteolin exhibited a potent preventive effect on THP-1 macrophage pyroptosis, as evidenced by the increase in cell viability and the decrease in LDH release. Moreover, luteolin was found to significantly reduce the expression of NLRP3, pro-CASP-1 and CASP-1, which are the key components of NLRP3 inflammasome, as well as the expression of N-GSDMD and IL-1ß, and we proved that the inhibition of luteolin on NLRP3 inflammasome activation is ROS-dependent. Furthermore, it was demonstrated that luteolin promoted Nrf2 nuclear translocation, thereby increasing the expression of HO-1 that reduces ROS production, while the anti-pyroptotic effect of luteolin was reversed by a specific Nrf2 inhibitor. Additionally, luteolin inhibited NF-κB p65 phosphorylation and nuclear translocation. In summary, we conclude that luteolin prevents THP-1 macrophage pyroptosis by suppressing ROS production via Nrf2 activation as well as NF-κB inactivation. These results support luteolin as a potential bioactive chemical against pyroptosis-related inflammatory diseases.

Differential RNA expression profiles and competing endogenous RNA-associated regulatory networks during the progression of atherosclerosis.

Aim: To identify differential mRNA and ncRNA expression profiles and competing endogenous RNA-associated regulatory networks during the progression of atherosclerosis (AS). Materials & methods: We systematically analyzed whole-transcriptome sequencing of samples from different stages of AS to evaluate their long noncoding RNA (lncRNA), circular RNA (circRNA), miRNA and mRNA profiles. Results: We constructed three AS-related competing endogenous RNA regulatory networks of differentially expressed circRNAs, lncRNAs, miRNAs and mRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that the circRNAs in the network were enriched in lipid metabolic processes and participated in the PPAR signaling pathway. Furthermore, lncRNAs were related to receptor activity, myofibrils and cardiovascular system development. Conclusion: The current findings further clarified the regulatory mechanisms at different stages of AS and may provide new ideas and targets for AS.

Promising Therapy for Heart Failure in Patients with Severe COVID-19: Calming the Cytokine Storm.

The coronavirus disease 19 (COVID-19) pandemic poses a serious global threat to human health and the economy. Based on accumulating evidence, its continuous progression involves not only pulmonary injury but also damage to the cardiovascular system due to intertwined pathophysiological risks. As a point of convergence in the pathophysiologic process between COVID-19 and heart failure (HF), cytokine storm induces the progression of COVID-19 in patients presenting pre-existing or new onset myocardial damage and even HF. Cytokine storm, as a trigger of the progression of HF in patients with COVID-19, has become a novel focus to explore therapies for target populations. In this review, we briefly introduce the basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and illuminate the mechanism and links among COVID-19, cytokine storm, and HF. Furthermore, we discuss drugs and therapeutic targets for patients with COVID-19 and HF.

Plasma irisin level associated with hemodynamic parameters and predict clinical outcome in patients with acute pulmonary embolism.

BACKGROUND: The purpose of the present study is to investigate the correlation of plasma irisin level and hemodynamic parameters in patients with acute pulmonary embolism (APE) and to estimate clinical outcome prediction value of plasma irisin level. METHODS: We prospectively recruited 86 adult patients with APE in the present study. All recruited patients conduct measurement of plasma irisin levels using ELISA kits. Baseline clinical characteristics, hemodynamic parameters and prognostic conditions were evaluated according to different plasma irisin levels. RESULTS: According to median values of irisin levels, APE patients were divided into high irisin group (irisin≥6.9 µg/ml) and low irisin group (irisin<6.9 µg/ml). Plasma NT-proBNP (P = 0.044), mean pulmonary artery pressure (mPAP, P = 0.013), systolic pulmonary artery pressure (sPAP, P = 0.001), mean right ventricular pressure (mRVP, P = 0.021) and systolic right ventricular pressure (sPVP, P = 0.003) were higher in low irisin group compared with high irisin group. Hemodynamic parameters of mPAP, sPAP, mRVP and sRVP were negatively correlated with plasma irisin levels. Kaplan- Meier survival analysis showed that APE patients with lower plasma irisin levels had significantly higher clinical worsening event rate (P = 0.026) and could be the independent predictor of prognosis in multivariate analysis (P = 0.035). CONCLUSION: Plasma irisin level was negatively correlated with hemodynamic parameters in patients with APE. Low irisin group patients had significantly higher clinical worsening event rate and could be the independent predictor of clinical outcome in multivariate analysis.

Differential Expression and Bioinformatics Analysis of CircRNA in PDGF-BB-Induced Vascular Smooth Muscle Cells.

Atherosclerosis is mediated by various factors and plays an important pathological foundation for cardiovascular and cerebrovascular diseases. Abnormal vascular smooth muscle cells (VSMCs) proliferation and migration have an essential role in atherosclerotic lesion formation. Circular RNAs (circRNA) have been widely detected in different species and are closely related to various diseases. However, the expression profiles and molecular regulatory mechanisms of circRNAs in VSMCs are still unknown. We used high-throughput RNA-seq as well as bioinformatics tools to systematically analyze circRNA expression profiles in samples from different VSMC phenotypes. Polymerase chain reaction (PCR), Sanger sequencing, and qRT-PCR were performed for circRNA validation. A total of 22191 circRNAs corresponding to 6273 genes (host genes) in the platelet-derived growth factor (PDGF-BB) treated group, the blank control group or both groups, were detected, and 112 differentially expressed circRNAs were identified between the PDGF-BB treated and control groups, of which 59 were upregulated, and 53 were downregulated. We selected 9 circRNAs for evaluation of specific head-to-tail splicing, and 10 differentially expressed circRNAs between the two groups for qRT-PCR validation. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses enrichment analyses revealed that the parental genes of the circRNAs mainly participated in cardiac myofibril assembly and positive regulation of DNA-templated transcription, indicating that they might be involved in cardiovascular diseases. Finally, we constructed a circRNA-miRNA network based on the dysregulated circRNAs and VSMC-related microRNAs. Our study is the first to show the differential expression of circRNAs in PDGF-BB-induced VSMCs and may provide new ideas and targets for the prevention and therapy of vascular diseases.

Macrophage-Enriched lncRNA RAPIA: A Novel Therapeutic Target for Atherosclerosis.

OBJECTIVE: Despite the current antiatherosclerotic and antithrombotic therapies, the incidence of advanced atherosclerosis-associated clinical events remains high. Whether long noncoding RNAs (lncRNAs) affect the progression of atherosclerosis and whether they are potential targets for the treatment of advanced atherosclerosis are poorly understood. Approach and Results: The progression of atherosclerotic lesions was accompanied by dynamic alterations in lncRNA expression, as revealed by RNA sequencing and quantitative polymerase chain reaction. Among the dynamically changing lncRNAs, we identified a novel lncRNA, lncRNA Associated with the Progression and Intervention of Atherosclerosis (RAPIA), that was highly expressed in advanced atherosclerotic lesions and in macrophages. Inhibition of RAPIA in vivo not only repressed the progression of atherosclerosis but also exerted atheroprotective effects similar to those of atorvastatin on advanced atherosclerotic plaques that had already formed. In vitro assays demonstrated that RAPIA promoted proliferation and reduced apoptosis of macrophages. A molecular sponge interaction between RAPIA and microRNA-183-5p was demonstrated by dual-luciferase reporter and RNA immunoprecipitation assays. Rescue assays indicated that RAPIA functioned at least in part by targeting the microRNA-183-5p/ITGB1 (integrin ß1) pathway in macrophages. In addition, the transcription factor FoxO1 (forkhead box O1) could bind to the RAPIA promoter region and facilitate the expression of RAPIA. CONCLUSIONS: The progression of atherosclerotic lesions was accompanied by dynamic changes in the expression of lncRNAs. Inhibition of the pivotal lncRNA RAPIA may be a novel preventive and therapeutic strategy for advanced atherosclerosis, especially in patients resistant or intolerant to statins.

Omentin-1 protects against high glucose-induced endothelial dysfunction via the AMPK/PPARδ signaling pathway.

High glucose-induced endothelial dysfunction is a critical initiating factor in the development of diabetic vascular complications. Omentin-1 has been regarded as a novel biomarker of endothelial function in subjects with type-2 diabetes (T2D); however, it is unclear whether omentin-1 has any direct effect in ameliorating high glucose-induced endothelial dysfunction. In the present study, we analyzed the effect of omentin-1 on high glucose-induced endothelial dysfunction in isolated mouse aortas and mouse aortic endothelial cells (MAECs). Vascular reactivity in aortas was measured using wire myography. The expression levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor δ (PPARδ), Akt, endothelial nitric-oxide synthase (eNOS), and endoplasmic reticulum (ER)-stress markers in MAECs were determined by Western blotting. The production of reactive oxygen species (ROS) and nitric oxide (NO) was assessed by diluted fluoroprobe, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA), respectively. We found that ex vivo treatment with omentin-1 reversed impaired endothelial-dependent relaxations (EDR) in mouse aortas after high-glucose insult. Elevated ER-stress markers, oxidative stress, and reduction of NO production induced by high glucose in MAECs were reversed by omentin-1 treatment. Omentin-1 also effectively reversed tunicamycin-induced ER stress responses in MAECs, as well as ameliorated impairment of endothelial-dependent relaxation in mouse aortas. Moreover, omentin-1 increased AMPK phosphorylation with a subsequent increase in PPARδ expression, while also restoring the decreased phosphorylation of Akt and eNOS. The effects of omentin-1 were abolished by cotreatment of compound C (AMPK inhibitor) and GSK0660 (PPARδ antagonist). These data indicate that omentin-1 protects against high glucose-induced vascular-endothelial dysfunction through inhibiting ER stress and oxidative stress and increasing NO production via activation of AMPK/PPARδ pathway.

Comprehensive circRNA expression profile and construction of circRNA-related ceRNA network in cardiac fibrosis.

Cardiac fibrosis is a common pathological condition that contributes to the progression of many cardiac diseases. Circular RNAs (circRNAs) are emerging as new regulators of cardiac fibrosis. However, the expression and function of circRNAs in cardiac fibrosis remain largely unknown. The present study aims to investigate the circRNA expression profile and identify the roles of circRNAs in cardiac fibrosis. Transforming growth factor-ß1 (TGF-ß1) was used to establish an in vitro model of cardiac fibrosis in cardiac fibroblasts. CircRNA sequencing revealed that a total of 283 circRNAs were aberrantly expressed in fibrotic cardiac fibroblasts, with 79 upregulated and 204 downregulated. The expression changes of randomly selected circRNAs were validated by real-time PCR. A circRNA-based competing endogenous RNA network 1755 nodes and 30394 edges was established, and module analysis was conducted using the plug-in MCODE. KEGG pathway enrichment analysis was performed for mRNAs involved in the top three enriched modules. The results showed that these mRNAs were enriched in cardiac fibrosis-related signalling pathways, including the 'TGF-beta signaling pathway', 'MAPK signaling pathway', 'AMPK signaling pathway', and 'PI3K-Akt signaling pathway'. The predicted ceRNAs and bioinformatics analysis revealed the potential role of circRNAs in cardiac fibrosis, which would provide useful information for understanding the mechanism and finding effective prevention and treatment targets for cardiac fibrosis.

MicroRNA 182 promotes T helper 1 cell by repressing hypoxia induced factor 1 alpha in experimental autoimmune encephalomyelitis.

MicroRNA 182 is important for the clonal expansion of CD4+ T cells (Th) following IL-2 stimulation and is a potential therapeutic target for autoimmune diseases. In the present study, we investigated the role of microRNA 182 in the differentiation of pro-inflammatory CD4+ T helper cell by overexpressing or silencing microRNA 182 expression both in in vivo and in vitro settings. We report that in the studied Chinese cohort, microRNA 182 is upregulated in patients with relapse and remitting multiple sclerosis (RRMS) and this upregulation is associated with increased IFN-γ producing CD4+ Th1 cells in the circulation. In the murine experimental autoimmune encephalomyelitis (EAE) model, global microRNA 182 overexpression exacerbates clinical symptoms and results in augmented CD4+ IFN-γ+ Th1 and CD4+ IL-17+ Th17 differentiation in vivo. Addition of microRNA 182 mimics in vitro represses both the protein expression and transcriptional activity of hypoxia induced factor 1α (HIF-1α) but increases the level of IFN-γ transcripts in sorted murine CD4+ T cells. Together, our results provide evidence that microRNA 182 may be one of the transitional hubs contribution to regulate Th cells expansion in response to self-antigens and differentiation of antigen specific Th cells during the progression of autoimmune inflammations.

Shrinkage as a potential mechanism of recurrent clinical events in patients with a large vulnerable plaque.

AIMS: This study aimed to investigate the progression and vascular shrinkage of vulnerable plaque lesions with a plaque burden at least 70% among patients with coronary artery disease by optical coherence tomography (OCT) and intravascular ultrasound (IVUS). METHODS: Fifty-six OCT-identified vulnerable plaques from 47 patients were included among coronary angiography-identified nonculprit/nontarget lesions. Serial IVUS images were used to assess plaque progression and vascular shrinkage. RESULTS: Thirty-five small vulnerable plaques (plaque burden <70%, group A) and 21 large vulnerable plaques (plaque burden ≥70%, group B) were identified. The IVUS results at baseline show that mean plaque areas (P < 0.001) and the percentage atheroma volume (PAV) (P < 0.0001) were greater and the minimal lumen area (P < 0.0001) was smaller in group B. The absolute and relative changes in the PAV and mean plaque area from baseline to follow-up were not significantly different. However, the lesions exhibited vessel shrinkage [the mean external elastic membrane (EEM) area (P = 0.02) and mean lumen area (P = 0.03) were significantly smaller in group B] from baseline to follow-up. Patients in group B also exhibited clinical events (recurrent angina symptoms) during the follow-up period. Positive correlations were found between changes in the mean plaque area and the mean EEM area in large vulnerable plaques (r = 0.61, P < 0.0001) and between changes in the mean EEM area and the mean lumen area in large vulnerable plaques (r = 0.61, P < 0.0001). CONCLUSION: Vulnerable plaque progression was not different between small and large vulnerable plaques. However, large vulnerable plaque lesions tended to exhibit vascular shrinkage, which is possible a cause of coronary artery lumen loss in patients with large vulnerable plaques.

Gender differences in plaque characteristics of nonculprit lesions in patients with coronary artery disease.

BACKGROUND: Although numerous reports suggest sex-related differences in atherosclerosis, limited data describing gender-associated differences in plaque morphology and composition are currently available. The aim of the present study was to compare coronary nonculprit plaque characteristics in women and men with coronary artery disease (CAD) by optical coherence tomography (OCT). METHODS: This was a retrospective study. A total of 187 nonculprit plaques were identified in 103 patients with CAD who underwent OCT imaging of all 3 coronary arteries. These patients included 77 (74.8%) men and 26 (25.2%) women. RESULTS: Female patients were significantly older than males (mean age, 70.8 ± 7.3 vs 60.8 ± 9.8 years; P < 0.001) and less likely to be current smokers (P = 0.007). OCT analysis included the presence of lipid-rich plaque, maximum lipid arc, lipid-core length, lipid index (LI), fibrous cap thickness, and the incidence of thin-cap fibroatheroma (TCFA). Nonculprit plaques in men exhibited greater lipid-core length and LI compared with those of women (9.4 ± 4.5 vs. 7.3 ± 4.3 mm, P = 0.024; 1615.1 ± 893.8 vs. 1237.8 ± 859.8, P = 0.035, respectively). In the univariate linear regression model, sex and current smoker were all associated with a larger LI, whereas only use of statin was independent risk factor for a larger LI in multivariate analysis. CONCLUSIONS: Coronary nonculprit plaques in male patients with CAD contain larger lipid cores than those of female patients.

Adipose-Derived Exosomes Exert Proatherogenic Effects by Regulating Macrophage Foam Cell Formation and Polarization.

BACKGROUND: Obesity is causally associated with atherosclerosis, and adipose tissue (AT)-derived exosomes may be implicated in the metabolic complications of obesity. However, the precise role of AT-exosomes in atherogenesis remains unclear. We herein aimed to assess the effect of AT-exosomes on macrophage foam cell formation and polarization and subsequent atherosclerosis development. METHODS AND RESULTS: Four types of exosomes isolated from the supernatants of ex vivo subcutaneous AT and visceral AT (VAT) explants that were derived from wild-type mice and high-fat diet (HFD)-induced obese mice were effectively taken up by RAW264.7 macrophages. Both treatment with wild-type VAT exosomes and HFD-VAT exosomes, but not subcutaneous AT exosomes, markedly facilitated macrophage foam cell generation through the downregulation of ATP-binding cassette transporter (ABCA1 and ABCG1)-mediated cholesterol efflux. Decreased expression of liver X receptor-α was also observed. Among the 4 types of exosomes, only HFD-VAT exosomes significantly induced M1 phenotype transition and proinflammatory cytokine (tumor necrosis factor α and interleukin 6) secretion in RAW264.7 macrophages, which was accompanied by increased phosphorylation of NF-κB-p65 but not the cellular expression of NF-κB-p65 or IκB-α. Furthermore, systematic intravenous injection of HFD-VAT exosomes profoundly exacerbated atherosclerosis in hyperlipidemic apolipoprotein E-deficient mice, as indicated by the M1 marker (CD16/32 and inducible nitric oxide synthase)-positive areas and the Oil Red O/Sudan IV-stained area, without affecting the plasma lipid profile and body weight. CONCLUSIONS: This study demonstrated a proatherosclerotic role for HFD-VAT exosomes, which is exerted by regulating macrophage foam cell formation and polarization, indicating a novel link between AT and atherosclerosis in the context of obesity.

Identification of Subpathway Signatures For Ovarian Cancer Prognosis by Integrated Analyses of High-Throughput miRNA and mRNA Expression.

BACKGROUND/AIMS: Ovarian cancer (OC) causes more death and serious conditions than any other female reproductive cancers, and many expression signatures have been identified for OC prognoses. However, no significant overlap is found among signatures from different studies, indicating the necessity of signature identifications at the functional level. METHODS: We performed an integrated analyses of miRNA and gene expressions to identify OC prognostic subpathways (pathway regions). Using The Cancer Genome Atlas data set, we identified core prognostic subpathways, and calculated subpathway risk scores using both miRNA and gene components. Finally, we performed global risk impact analyses to optimize core subpathways using the random walk algorithm. RESULTS: Subpathway-level analyses displayed more robust results than the gene- and miRNA-level analyses. Moreover, we verified the advantage of core subpathways over the entire pathway-based results and their prognostic performance in two independent validation data sets. Based on the global impact score, 13 subpathway signatures were selected and a combined subpathway-based risk score was further calculated for OC patient prognoses. CONCLUSIONS: Overall, it was possible to systematically perform integrated analyses of the expression levels of miRNAs and genes to identify prognostic subpathways and infer subpathway risk scores for use in OC clinical applications.