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Macrophages are most important immune cell population in the heart. Cardiac macrophages have broad-spectrum and heterogeneity, with two extreme polarization phenotypes: M1 pro-inflammatory macrophages (CCR2-ly6Chi) and M2 anti-inflammatory macrophages (CCR2-ly6Clo). Cardiac macrophages can reshape their polarization states or phenotypes to adapt to their surrounding microenvironment by altering metabolic reprogramming. The phenotypes and polarization states of cardiac macrophages can be defined by specific signature markers on the cell surface, including tumor necrosis factor α, interleukin (IL)-1β, inducible nitric oxide synthase (iNOS), C-C chemokine receptor type (CCR)2, IL-4 and arginase (Arg)1, among them, CCR2+/- is one of most important markers which is used to distinguish between resident and non-resident cardiac macrophage as well as macrophage polarization states. Dedicated balance between M1 and M2 cardiac macrophages are crucial for maintaining heart development and cardiac functional and electric homeostasis, and imbalance between macrophage phenotypes may result in heart ventricular remodeling and various heart diseases. The therapy aiming at specific target on macrophage phenotype is a promising strategy for treatment of heart diseases. In this article, we comprehensively review cardiac macrophage phenotype, metabolic reprogramming, and their role in maintaining heart health and mediating ventricular remodeling and potential therapeutic strategy in heart diseases.

PurposeOvarian cancer (OC) is a common gynecological malignancy with poor prognosis and substantial tumor heterogeneity. Due to the complex tumor immune microenvironment (TIME) among ovarian cancer, only a few patients have an immune response to immunotherapy. To investigate the differences in immune function and identify potential biomarkers in OC, we established a prognostic risk scoring model (PRSM) with differential expression of immune-related genes (IRGs) to identify critical prognostic IRG signatures.MethodsSingle-sample gene set enrichment analysis (ssGSEA) was used to investigate the infiltration of various immune cells in 372 OC patients. Then, COX regression analysis and Lasso regression analysis were used to screen IRGs and construct PRSM. Next, the immunotherapy sensitivity of different risk groups regarding the immune checkpoint expression and tumor mutation burden was evaluated. Finally, a nomogram was created to guide the clinical evaluation of the patient prognosis.ResultsIn this study, 320 immune-related genes (IRGs) were identified, 13 of which were selectively incorporated into a Prognostic Risk Scoring Model (PRSM). This model revealed that the patients in the high-risk group were characterized as having poorer prognosis, lower expression of immune checkpoints, and decreased tumor mutation load levels compared with those in the low-risk group. The nomogram based on the risk score can distinguish the risk subtypes and individual prognosis of patients with OC. Additionally, M1 macrophages may be the critical target for immunotherapy in OC patients.ConclusionWith the in-depth analysis of the immune microenvironment of OC, the PRSM was constructed to predict the OC patient prognosis and identify the subgroup of the patients benefiting from immunotherapy.

Background: Thyroid cancer is a common malignant tumor of the endocrine system that has shown increased incidence in recent decades. We explored the relationship between tumor-infiltrating immune cell classification and the prognosis of thyroid carcinoma.Methods: RNA-seq, SNV, copy number variance (CNV), and methylation data for thyroid cancer were downloaded from the TCGA dataset. ssGSEA was used to calculate pathway scores. Clustering was conducted using ConsensusClusterPlus. Immune infiltration was assessed using ESTIMATE and CIBERSORT. CNV and methylation were determined using GISTIC2 and the KNN algorithm. Immunotherapy was predicted based on TIDE analysis. Results: Three molecular subtypes (Immune-enrich(E), Stromal-enrich(E), and Immune-deprived(D)) were identified based on 15 pathways and the corresponding genes. Samples in Immune-E showed higher immune infiltration, while those in Immune-D showed increased tumor mutation burden (TMB) and mutations in tumor driver genes. Finally, Immune-E showed higher CDH1 methylation, higher progression-free survival (PFS), higher suitability for immunotherapy, and higher sensitivity to small-molecule chemotherapeutic drugs. Additionally, an immune score (IMScore) based on four genes was constructed, in which the low group showed better survival outcome, which was validated in 30 cancers. Compared to the TIDE score, the IMScore showed better predictive ability.Conclusion: This study constructed a prognostic evaluation model and molecular subtype system of immune-related genes to predict the thyroid cancer prognosis of patients. Moreover, the interaction network between immune genes may play a role by affecting the biological function of immune cells in the tumor microenvironment.

Biliary tract cancer (BTC) is a highly aggressive malignant tumor. Serum microRNAs (ser-miRNAs) serve as noninvasive biomarkers to identify high risk individuals, thereby facilitating the design of precision therapies. The study is to prioritize key synergistic ser-miRNAs for the diagnosis of early BTC. Sampling technology, significant analysis of microarrays, Pearson Correlation Coefficients, t-test, decision tree, and entropy weight were integrated to develop a global optimization algorithm of decision forest. The source code is available at https://github.com/SuFei-lab/GOADF.git. Four key synergistic ser-miRNAs were prioritized and the synergistic classification performance was better than the single miRNA’ s. In the internal feature evaluation dataset, the area under the receiver operating characteristic curve (AUC) for each single miRNA was 0.8413 (hsa-let-7c-5p), 0.7143 (hsa-miR-16-5p), 0.8571 (hsa-miR-17-5p), and 0.9365 (hsa-miR-26a-5p), respectively, whereas the synergistic AUC value increased to 1.0000. In the internal test dataset, the single AUC was 0.6500, 0.5125, 0.6750, and 0.7500, whereas the synergistic AUC increased to 0.8375. In the independent test dataset, the single AUC was 0.7280, 0.8313, 0.8957, and 0.8303, and the synergistic AUC was 0.9110 for discriminating between BTC patients and healthy controls. The AUC for discriminating BTC from pancreatic cancer was 0.9000. Hsa-miR-26a-5p was a predictor of prognosis, patients with high expression had shorter survival than those with low expression. In conclusion, hsa-let-7c-5p, hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-26a-5p may act as key synergistic biomarkers and provide important molecular mechanisms that contribute to pathogenesis of BTC.

Yes-associated protein (YAP) and its associated coactivator of PDZ-binding motif (TAZ) are co-transcriptional regulators and down effectors of the Hippo signaling pathway. Recent studies have shown that the Hippo/YAP signaling pathway may play a role in mediating vascular homeostasis. This study investigated the role of YAP/TAZ in endothelial dysfunction and vascular inflammation in angiotensin (Ang)II hypertensive mice. The infusion of AngII (1.1 mg/kg/day by mini-pump) for 3 weeks induced the activation of YAP/TAZ, manifested by decreased cytosolic phosphor-YAP and phosphor-TAZ, and increased YAP/TAZ nuclear translocation, which were prevented by YAP/TAZ inhibitor verteporfin. AngII significantly increased systolic blood pressure (SBP), macrophage infiltration, and expressions of proinflammatory cytokines, and impaired endothelial function in the aorta of the mice. Treatment with verteporfin improved endothelial function and reduced vascular inflammation with a mild reduction in SBP. AngII also induced YAP/TAZ activation in human umbilical vein endothelial cells in vitro, which were prevented by LB-100, an inhibitor of protein phosphatase 2A (PP2A, a major dephosphorylase). Treatment with LB-100 reversed AngII-induced proinflammatory cytokine expression and impairment of phosphor-eNOS expression in vitro. Our results suggest that AngII induces YAP/TAZ activation via PP2A-dependent dephosphorylation, which may contribute to the impairment of endothelial function and the induction of vascular inflammation in hypertension. YAP/TAZ may be a new target for hypertensive vascular injury.

Background: Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of obesity, insulin resistance and cardiovascular diseases (CVDs). Impairment of insulin vascular action may represent a mechanism linking insulin resistance and CVDs. The present study tested the hypothesis that adipocyte-derived resistin inhibits insulin-stimulated endothelial NO production through the induction of ER stress.Methods and Results: Human umbilical vein endothelial cells (HUVC) were incubated with tunicamycin (an inducer of ER stress, 1–20 μg/mL) or resistin (10–100 ng/mL) for 1 h. Either tunicamycin or resistin increased GRP78 (an ER stress marker) expression associated with the impairment of insulin-stimulated Akt/eNOS phosphorylation, which were prevented by TUDCA (an ER stress suppressor). Resistin increased reactive oxygen species (ROS) production, antioxidant treatment inhibited resistin-induced GRP78 expression and impairment of insulin Akt/eNOS signaling, suggesting that ROS may involve resistin-induced ER stress. Resistin also increased JNK phosphorylation, which was prevented by TUDCA. JNK inhibitor SP600125 relieved the resistin inhibitory effects on endothelial insulin Akt/eNOS signaling. In ex vivo experiments, the incubation of aortic rings with resistin impaired insulin- but not acetylcholine-induced vasodilation, which was restored by TUDCA. LNAME (a NOS inhibitor) abolished insulin-induced vasorelaxation in the control or the resistin-treated aortic rings. In addition, resistin increased the mRNA expressions of proinflammatory cytokines tumor nuclear factor (TNF)α and interleukin (IL)-1β, which were also prevented by TUDCA.Conclusion: Our results support the ideal that ER stress may play an important role for resistin impairment of vascular insulin signaling and insulin action. The mitigation of ER stress may represent a new strategy for prevention and treatment of CVDs in obesity and insulin resistant-related diseases.