Myocardium ischemia reperfusion (MI/R) is easy to induce myocardial injury and cardiomyocyte apoptosis. Deleted in Breast Cancer-1 (DBC-1), also known as CCAR2, playing an important role in p53-mediated apoptosis, can promote the production of TNF-α and up-regulates the signal of TNF-α, which further aggravates the occurrence of apoptosis. However, whether DBC-1 can promote cardiomyocyte apoptosis and whether DBC1 play a role through TNF-α after MI/R have not been studied. Thus, we aimed to explore that whether DBC-1 mediates cardiomyocyte apoptosis after MI/R via increasing TNF-α-induced activation of p38/casepase-8 pathway. To identify the cardiac dysfunction induced by MI/R injury, the murine MI/R model was established. After MI/R, the deterioration of cardiac function and progression of cardiomyocyte apoptosis were found. In the injured heart, the level of DBC-1 and TNF-α increased greatly compared with the sham group. Furthermore, MI/R activates the P38-caspase signal in myocardial cells. In vitro, knock down DBC-1 protected the H9C2 cells from H2O2 induced apoptosis, enhanced cell viability and decreased the mRNA and protein level of p38MAPK and caspase-8. Meanwhile, the level of TNF-α and TNFR1 were deceased after DBC1-siRNA transfection. Further study found that exogenous TNF-α treatment decreased the cell viability and up-regulated the levels of p38 and caspase-8 in H9C2 cells compared to control group. Once knock down TNF-α, H2O2 induced apoptosis of H9C2 cells was alleviated, and caspase-8, p38 mRNA level decreased dramaticly. Taken together, DBC-1 was increased in the injured heart after MI/R, which contribute to the cardiomyocyte apoptosis by up-regulating TNF-α-induced activation of p38-caspase8 pathways. It provides new insights into the endogenous regulatory and injury mechanistic basic for myocardial apoptosis after MI/R.

Effective interventions to improve the outcome of patients subjected to myocardial ischemia reperfusion (MI/R) are urgent in clinical settings. Tanshinone IIA (TSA) is reported to attenuate myocardial injury and improve ventricular remodeling post MI/R. Here, we evaluated the efficacy of AFC1 compound that is similar to TSA structure in murine MI/R models. We found that AFC1 had a comparable effect of improving murine cardiac function after MI/R while it was superior to TSA in safety profile. Administration of AFC1 reduced reactive oxygen species (ROS) production, inflammatory cells infiltration, and the expression of platelet derived growth factor receptors (PDGFR) in infarcted myocardium. Treatment with AFC1 also attenuated MI/R-induced cardiac remodeling and contributed to the recovery of cardiac function. Additionally, AFC1 reversed the elevation of PDGFR expression induced by PDGF-AB in both neonatal rat cardiomyocytes (NCMs) and neonatal rat cardiac fibroblasts (NCFs) and suppressed PDGF-AB induced NCM hypertrophy via STAT3 pathway and NCF collagen synthesis through p38-MAPK signaling in vitro. Similarly, AFC1 may contribute to the recovery of cardiac function in mice post MI/R via suppressing STAT signaling. Our results confirmed that AFC1 exerts anti-hypertrophic and anti-fibrotic effects against MI/R-induced cardiac remodeling, and suggest that AFC1 may have a promising potential in improving the outcome of patients who suffered from MI/R.

CD4+ T-cells play crucial roles in the injured heart. However, the way in which different CD4+ T subtypes function in the myocardial infarction/reperfusion (MI/R) heart is still poorly understood. We aimed to detect the dynamic profile of distinct CD4+ subpopulation-associated cytokines/chemokines by relying on a closed-chest acute murine MI/R model. The protein levels of 26 CD4+ T-cell-associated cytokines/chemokines were detected in the heart tissues and serum of mice at day 7 and day 14 post-MI/R or sham surgery. The mRNA levels of IL-4, IL-6, IL-13, IL-27, MIP-1β, MCP-3, and GRO-α were measured in blood mononuclear cells. The protein levels of IL-4, IL-6, IL-13, IL-27, MIP-1β, MCP-3, and GRO-α increased in both injured heart tissues and serum, while IFN-γ, IL-12P70, IL-2, IL-1β, IL-18, TNF-α, IL-5, IL-9, IL-17A, IL-23, IL-10, eotaxin, MIP-1α, RANTES, MCP-1, and MIP-2 increased only in MI/R heart tissues in the day 7 and day 14 groups compared to the sham group. In serum, the IFN-γ, IL-23, and IL-10 levels were downregulated in the MI/R model at both day 7 and day 14 compared to the sham. Compared with the protein expressions in injured heart tissues at day 7, IFN-γ, IL-12P70, IL-2, IL-18, TNF-α, IL-6, IL-4, IL-5, IL-9, IL-17A, IL-23, IL-27, IL-10, eotaxin, IP-10, RANTES, MCP-1, MCP-3, and GRO-α were reduced, while IL-1β and MIP-2 were elevated at day 14. IL-13 and MIP-1β showed higher levels in the MI/R serum at day 14 than at day 7. mRNA levels of IL-4, IL-6, IL-13, and IL-27 were increased in the day 7 group compared to the sham, while MIP-1β, MCP-3, and GRO-α mRNA levels showed no significant difference between the MI/R and sham groups in blood mononuclear cells. Multiple CD4+ T-cell-associated cytokines/chemokines were upregulated in the MI/R hearts at the chronic stage. These results provided important evidence necessary for developing future immunomodulatory therapies after MI/R.

Deleted in breast cancer 1 (DBC1) gene was first found to be heterozygous for deletion in breast cancer.Recent studies have demonstrated that DBC1 plays different roles in gene expression,cell cycle,apoptosis and tumor occurrence.Therefore,it may be a therapeutic target for cancer,inflammation and metabolic diseases.This review summarized the roles of DBC1 in tumor progression,lymphocytes function and some metabolic diseases.

Acute allograft rejection is a principal conundrum in lung obliterative bronchiolitis (OB). Monocytes/macrophages infiltration has been proved to be the main reason for acute rejection. IL-17 contributes to the recruitment and function of macrophages. However, the mechanism of IL-17 underlying OB progression remains elusive. In the present study, we showed that the deficiency of IL-17 attenuated the pathology of murine heterotopic trachea allografts. Compared to WT recipients, IL-17−/− mice displayed higher frequency of CD206+ cells and lower ratio of CD86+ cells among F4/80+ macrophages in allografts and spleens on day 7 post heterotopic trachea transplantation. Moreover, mRNA levels of pro-inflammatory cytokines including IL-6, TNF-α, and IL-1β decreased in allografts of IL-17−/− recipients, but these of MRC1 and Arg-1 increased in comparison with WT. IL-17 deficiency can inhibit LPS induced M1 while promote IL-4 induced M2 polarization of bone marrow-derived macrophages. Further data demonstrated that the deficiency of IL-17 suppressed the lipopolysaccharide-induced M1 polarization and function through prevention of phosphorylation of both STAT3 and STAT5. Therefore, IL-17 contributes to OB pathogenesis through regulating macrophages function, thereby it may unravel part of the complexity of IL-17 in OB and enhance future therapeutic development.

目的 研究CD4 +T细胞在糖尿病性心肌病(diabetes cardiomyopathy,DCM)中的作用.方法 SPF级C57BL/6小鼠,雄性,4周龄,饲喂高脂饲料(high fat diet,HFD)6周,腹腔注射链脲菌素(sueptozotocin,STZ),普通饲料喂养的C57BL/6小鼠作为对照,饲喂6周后腹腔注射柠檬酸缓冲液.注射1周后两组小鼠做心脏超声检测,后处死小鼠,心肌组织进行H-E染色,观察心肌病理改变情况,Q-PCR检测两组小鼠心肌组织中相关炎症因子的表达水平.流式细胞检测小鼠体内CD4 +T细胞的表型.结果 与普通饮食喂养小鼠相比,2型糖尿病模型小鼠出现了明显的心功能损害和心肌病理学改变.糖尿病模型小鼠心肌组织中Th1细胞转录因子T-bet及炎症因子TNF-α和IFN-γmRNA均较对照组明显升高.糖尿病模型小鼠纵隔淋巴结中CD4 +CD44 +T细胞比例较对照组明显升高.结论 2型糖尿病模型小鼠出现了明显的心功能损害,纵隔淋巴结CD4+ CD44+T细胞比例明显增加,心肌组织中Th1细胞转录因子T-bet升高,提示激活的CD4+ Th1细胞可能在DCM中扮演着重要角色,TNF-α可能也参与了这一过程.