冰片"引经" 丹参对脑缺血/再灌注损伤的保护作用研究

目的:探讨丹参单用与丹参冰片合用对大鼠脑缺血/再灌注(Cerebral ischemia/reperfusion,CI/R)损伤的影响。方法:结扎颈总动脉缺血2 h再灌注48 h复制CI/R模型,将实验大鼠随机分为假手术组、模型组、丹参组以及丹参-冰片组,每组8只。采用2,3,5-氯化三苯基四氮唑蓝(TTC)染法测定脑梗死面积,苏木精-伊红(HE)染色法观察心肌病理学形态变化,并检测超氧化物歧化酶(SOD)、丙二醛(MDA)水平以及细胞核Nrf2蛋白表达水平。结果:与模型组比较,丹参单用与丹参-冰片组神经功能学评分均明显降低,脑梗死面积缩小,脑组织的病理损伤改善,MDA的含量显著降低,SOD的含量以及细胞核Nrf2蛋白表达水平增加(P0.05),且丹参-冰片组效果优于丹参组(P0.05)。结论:丹参单用与丹参冰片合用均能发挥脑保护作用,且丹参冰片配伍发挥脑保护作用明显优于丹参单用,其机制可能与抗氧化作用相关。     

The role of dendritic cells regulated by HMGB1/TLR4 signalling pathway in myocardial ischaemia reperfusion injury

Inflammatory response plays an important role in ischaemia reperfusion injury (IRI) through a variety of inflammatory cells. Apart from neutrophils, macrophages and lymphocytes, the role of dendritic cells (DCs) in IRI has been noticed. The study was aimed at investigating whether the high‐mobility group protein box‐1/toll like receptor 4 (HMGB1/TLR4) signalling pathway regulate the migration, adhesion and aggregation of DCs to the myocardium, induce DCs activation and maturation, stimulate the expression of surface costimulatory molecules and participate in myocardial IRI. In vivo, migration, adhesion, and aggregation of DCs was enhanced; the expression of peripheral blood DCs CD80 and CD86, myocardial adhesion molecules were increased; and the infarct size was increased during myocardial ischaemia reperfusion injury myocardial ischemic/reperfusion injury (MI/RI). These responses induced by MI/RI were significantly inhibited by HMGB1 specific neutralizing antibody treatment. Cellular experiments confirmed that HMGB1 promoted the release of inflammatory cytokines through TLR4/MyD88/NF‐κB, upregulated CD80 and CD86 expression, mediated the damage of cardiomyocytes and accelerated the apoptosis. Our results indicate that DCs activation and maturation, stimulate the expression of surface costimulatory molecules by promoting the release of inflammatory factors through NF‐κB pathway and participate in myocardial IRI.     

β‐arrestin 2 negatively regulates NOD2 signalling pathway through association with TRAF6 in microglia after cerebral ischaemia/reperfusion injury

We previously reported that nucleotide‐binding oligomerization domain‐containing protein (NOD) 2 was involved in the inflammatory responses to cerebral ischaemia/reperfusion (I/R) insult. However, the mechanism by which NOD2 participates in brain ischaemic injury and the regulation of NOD2 in the process are still obscure. Increased β‐arrestin 2 (ARRB2) expression was observed in microglia following cerebral I/R in wild‐type mice besides the up‐regulation of NOD2 and TRAF6. Stimulation of NOD2 by muramyl dipeptide (MDP) in BV2 cells induced the activation of NF‐κB by the phosphorylation of p65 subunit and the degradation of IκBα. Meanwhile, the protein level of Cyclooxygenase‐2 (COX‐2), the protein expression and activity of MMP‐9 were significantly increased in BV2 cells after administration of MDP. Furthermore, overexpression of ARRB2 significantly suppressed the inflammation induced by MDP, silence of ARRB2 significantly enhanced the inflammation induced by MDP in BV2 cells. In addition, we observed endogenous interaction of TRAF6 and ARRB2 after stimulation of MDP or cerebral I/R insult, indicating ARRB2 negatively regulates NOD2‐triggered inflammatory signalling pathway by associating with TRAF6 in microglia after cerebral I/R injury. Finally, the in vivo study clearly confirmed that ARRB2 negatively regulated NOD2‐induced inflammatory response, as ARRB2 deficiency exacerbated stroke outcomes and aggravated the NF‐κB signalling pathway induced by NOD2 stimulation after cerebral I/R injury. These findings revealed ARRB2 negatively regulated NOD2 signalling pathway through the association with TRAF6 in cerebral I/R injury.     

舒芬太尼预处理对大鼠脊髓缺血再灌注损伤中炎性因子MPO，IL-6，IL-15的影响

目的:探讨舒芬太尼预处理对大鼠脊髓缺血再灌注损伤模型中炎性因子MPO,IL-6,IL-15的影响。方法:健康SD雄性大鼠30只,随机分为假手术组(Sham组,n=10);缺血再灌注组(IR组n=10);舒芬太尼预处理5μg/kg组(Suf5组,n=10)。采用动脉夹夹闭胸主动脉方法制备脊髓缺血再灌注模型。Tarlov法测大鼠运动评分,HE染色观察大鼠脊髓组织细胞形态,Western Blot法测脊髓组织中MPO的表达,ELISA法检测脊髓组织中IL-6,IL-15含量。结果:IR组Tarlov评分高于sham组,Suf5组Tarlov评分低于IR组。HE染色显微镜下见IR组脊髓组织内出现广泛的变性神经元,胞核固缩偏位碎裂,并有有空泡形成;Suf5组脊髓组织神经元损伤坏死数量减少,细胞核形态基本正常。Suf5组中MPO,IL-6,IL-15,含量均低于IR组,IR组中MPO,IL-6,IL-15含量均高于sham组,差异均有统计学意义(P0.05)。结论:舒芬太尼能降低大鼠脊髓缺血再灌注损伤组织中MPO,IL-15,1L-6表达,减轻炎症损害,进而减轻脊髓缺血再灌注损伤。     

Ischemia-reperfusion and immediate T cell responses

The pathogenesis of ischemia-reperfusion injury (IRI) is complex and not well understood. Inflammation plays an important role in IRI, with involvement of leukocytes, adhesion molecules, chemokines and cytokines. Emerging data suggest a role of T cells as mediators of IRI both in renal and extra-renal organs. Divergent roles of T cell subsets have also been elucidated, suggesting a more complicated role of T cells in the different phases of IRI. This review presents recent evidence from various animal models that advances our understanding of the role T cells play in IRI. These findings entertain the possibility of using immunotherapeutic agents for the prevention and treatment of IRI.     

Downregulation of tripartite motif protein 11 attenuates cardiomyocyte apoptosis after ischemia/reperfusion injury via DUSP1-JNK1/2

Currently, the prevention of ischemic diseases such as myocardial infarction associated with ischemia/reperfusion (I/R) injury remains to be a challenge. Thus, this study was designed to explore the effects of tripartite motif protein 11 (TRIM11) on cardiomyocytes I/R injury and its underlying mechanism. Cardiomyocytes AC16 were used to establish an I/R injury cell model. After TRIM11 downregulation in I/R cells, cell proliferation (0, 12, 24, and 48 h) and apoptosis at 48 h as well as the related molecular changes in oxidative stress-related pathways was detected. Further, after the treatment of TRIM11 overexpression, SP600125, or DUSP1 overexpression, cell proliferation, apoptosis, and related genes were detected again. As per our findings, it was determined that TRIM11 was highly expressed in the cardiomyocytes AC16 after I/R injury. Downregulation of TRIM11 was determined to have significantly reduced I/R-induced proliferation suppression and apoptosis. Besides, I/R-activated c-Jun N-terminal kinase (JNK) signaling and cleaved caspase 3 and Bax expression were significantly inhibited by TRIM11 downregulation. In addition, the overexpression of TRIM11 significantly promoted apoptosis in AC16 cells, and JNK1/2 inhibition and DUSP1 overexpression potently counteracted the induction of TRIM11 overexpression in AC16 cells. These suggested that the downregulation of TRIM11 attenuates apoptosis in AC16 cells after I/R injury probably through the DUSP1-JNK1/2 pathways.     

8-Br-cADPR, a TRPM2 ion channel antagonist,inhibits renal ischemia–reperfusion injury

The transient receptor potential melastatin-2 (TRPM2) channel belongs to the transient receptor potential channel superfamily and is a cation channel permeable to Na⁺ and Ca ²⁺. The TRPM2 ion channel is expressed in the kidney and can be activated by various molecules such as hydrogen peroxide, calcium, and cyclic adenosine diphosphate (ADP)-ribose (cADPR) that are produced during acute kidney injury. In this study, we investigated the role of 8-bromo-cyclic ADP-ribose (8-Br-cADPR; a cADPR antagonist) in renal ischemia–reperfusion injury using biochemical and histopathological parameters. CD38, cADPR, tumor necrosis factor-α, interleukin-1β, and myeloperoxidase (inflammatory markers), urea and creatinine, hydrogen peroxide (oxidant), and catalase (antioxidant enzyme) levels that increase with ischemia–reperfusion injury decreased in the groups treated with 8-Br-cADPR. In addition, renin levels were elevated in the groups treated with 8-Br-cADPR. Histopathological examination revealed that 8-Br-cADPR reduced renal damage and the expression of caspase-3 and TRPM2. Our results suggest that the inhibition of TRPM2 ion channel may be a new treatment modality for ischemic acute kidney injury.