The therapeutic potential of Annexin A1,an important member of the Annexin superfamily,has become evident in results of experiments with multiple human systems and animal models.The anti-inflammatory and pro-resolving...The therapeutic potential of Annexin A1,an important member of the Annexin superfamily,has become evident in results of experiments with multiple human systems and animal models.The anti-inflammatory and pro-resolving effects of Annexin A1 are characteristic of pathologies involving the nervous system.In this review,we initially describe the expression sites of Annexin A1,then outline the mechanisms by which Annexin A1 maintains the neurological homeostasis through either formyl peptide receptor 2 or other molecular approaches;and,finally,we discuss the neuroregenerative potential qualities of Annexin A1.The eye and the nervous system are anatomically and functionally connected,but the association between visual system pathogenesis,especially in the retina,and Annexin A1 alterations has not been well summarized.Therefore,we explain the beneficial effects of Annexin A1 for ocular diseases,especially for retinal diseases and glaucoma on the basis of published findings,and we explore present and future delivery strategies for Annexin A1 to the retina.展开更多
BACKGROUND Hepatic fibrosis is a common pathological process of chronic liver diseases with various causes,which can progress to cirrhosis.AIM To evaluate the effect and mechanism of action annexin(Anx)A1 in liver fib...BACKGROUND Hepatic fibrosis is a common pathological process of chronic liver diseases with various causes,which can progress to cirrhosis.AIM To evaluate the effect and mechanism of action annexin(Anx)A1 in liver fibrosis and how this could be targeted therapeutically.METHODS CCl4(20%)and active N-terminal peptide of AnxA1(Ac2-26)and N-formylpeptide receptor antagonist N-Boc-Phe-Leu-Phe-Leu-Phe(Boc2)were injected intraperitoneally to induce liver fibrosis in eight wild-type mice/Anxa1 knockout mice,and to detect expression of inflammatory factors,collagen deposition,and the role of the Wnt/β-catenin pathway in hepatic fibrosis.RESULTS Compared with the control group,AnxA1,transforming growth factor(TGF)-β1,interleukin(IL)-1βand IL-6 expression in the liver of mice with hepatic fibrosis induced by CCl4 was significantly increased,which promoted collagen deposition and expression ofα-smooth muscle actin(α-SMA),collagen type I and connective tissue growth factor(CTGF),and increased progressively with time.CCl4 induced an increase in TGF-β1,IL-1βand IL-6 in liver tissue of AnxA1 knockout mice,and the degree of liver inflammation and fibrosis and expression ofα-SMA,collagen I and CTGF were significantly increased compared with in wild-type mice.After treatment with Ac2-26,expression of liver inflammatory factors,degree of collagen deposition and expression of a-SMA,collagen I and CTGF were decreased compared with before treatment.Boc2 inhibited the anti-inflammatory and antifibrotic effects of Ac2-26.AnxA1 downregulated expression of the Wnt/β-catenin pathway in CCl4-induced hepatic fibrosis.In vitro,lipopolysaccharide(LPS)induced hepatocyte and hepatic stellate cell(HSC)expression of AnxA1.Ac2-26 inhibited LPS-induced RAW264.7 cell activation and HSC proliferation,decreased expression ofα-SMA,collagen I and CTGF in HSCs,and inhibited expression of the Wnt/β-catenin pathway after HSC activation.These therapeutic effects were inhibited by Boc2.CONCLUSION AnxA1 inhibited liver fibrosis in mice,and its mechanism may be related to inhibition of HSC Wnt/β-catenin pathway activation by targeting formylpeptide receptors to regulate macrophage function.展开更多
目的探究负载膜联蛋白A2(ANXA2)的骨髓间充质干细胞(BMSC)来源的外泌体(Exo-ANXA2)对前列腺癌细胞增殖、侵袭与迁移以及前列腺癌移植瘤生长的影响,并研究巨噬细胞是否参与该过程。方法分离与培养BALB/c裸鼠BMSC,采用负载ANXA2的慢病毒...目的探究负载膜联蛋白A2(ANXA2)的骨髓间充质干细胞(BMSC)来源的外泌体(Exo-ANXA2)对前列腺癌细胞增殖、侵袭与迁移以及前列腺癌移植瘤生长的影响,并研究巨噬细胞是否参与该过程。方法分离与培养BALB/c裸鼠BMSC,采用负载ANXA2的慢病毒质粒感染BMSC,并分离外泌体;加入外泌体处理THP-1巨噬细胞,ELISA检测细胞上清培养液肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)、IL-6和IL-10的水平;将外泌体处理的巨噬细胞与前列腺癌细胞共培养后,CCK-8法检测细胞增殖活性,Transwell^(TM)小室检测细胞侵袭与迁移。通过注射PC-3人前列腺癌细胞构建前列腺癌裸鼠移植瘤模型,将建模后的裸鼠随机分为对照组和实验组,每组8只,实验组裸鼠尾静脉注射1 mL Exo-ANXA2,对照组注射等量PBS,于注射后第0、3、6、9、12、15、18、21天,使用游标卡尺测量计算肿瘤体积,21 d处死裸鼠并测量肿瘤组织质量,免疫组织化学染色法检测肿瘤组织中抗原KI-67(ki67)和CD163表达。结果骨髓分离的细胞表面CD90和CD44呈高表达,CD34和CD45呈低表达,且成骨成脂分化能力较强,成功获得BMSC;负载ANXA2的慢病毒质粒感染后,BMSC中有较强的绿色荧光蛋白表达,并成功分离到Exo-ANXA2;经Exo-ANXA2处理后,THP-1细胞中TNF-α和IL-6的水平显著升高而IL-10和IL-13的水平显著下降;Exo-ANXA2处理巨噬细胞后,显著抑制Exo-ANXA2促进PC-3细胞增殖活性、侵袭与迁移的作用;经过给予前列腺癌移植瘤裸鼠注射Exo-ANXA2后,裸鼠在第6、9、12、15、18、21天的肿瘤组织体积显著减小,21 d时裸鼠肿瘤体质量也显著减少,此外,肿瘤组织内ki67和CD163的阳性表达率均显著降低。结论Exo-ANXA2能够抑制前列腺癌细胞增殖、侵袭与迁移,并抑制裸鼠前列腺癌移植瘤生长,M2型巨噬细胞减少。展开更多
基金supported by the National Natural Science Foundation of China,Nos.31800868(to YZ),32271037(to XL)and 82271090(to HZ).
文摘The therapeutic potential of Annexin A1,an important member of the Annexin superfamily,has become evident in results of experiments with multiple human systems and animal models.The anti-inflammatory and pro-resolving effects of Annexin A1 are characteristic of pathologies involving the nervous system.In this review,we initially describe the expression sites of Annexin A1,then outline the mechanisms by which Annexin A1 maintains the neurological homeostasis through either formyl peptide receptor 2 or other molecular approaches;and,finally,we discuss the neuroregenerative potential qualities of Annexin A1.The eye and the nervous system are anatomically and functionally connected,but the association between visual system pathogenesis,especially in the retina,and Annexin A1 alterations has not been well summarized.Therefore,we explain the beneficial effects of Annexin A1 for ocular diseases,especially for retinal diseases and glaucoma on the basis of published findings,and we explore present and future delivery strategies for Annexin A1 to the retina.
基金a Grant-in-Aid for Scientific Research from National Natural Science Foundation of China,No. 81860120 and 81860104Guangxi Natural Science Foundation,No. 2017GXNSFBA198134, 2017GXNSFAA198299 and 2015GXNSFCA139024
文摘BACKGROUND Hepatic fibrosis is a common pathological process of chronic liver diseases with various causes,which can progress to cirrhosis.AIM To evaluate the effect and mechanism of action annexin(Anx)A1 in liver fibrosis and how this could be targeted therapeutically.METHODS CCl4(20%)and active N-terminal peptide of AnxA1(Ac2-26)and N-formylpeptide receptor antagonist N-Boc-Phe-Leu-Phe-Leu-Phe(Boc2)were injected intraperitoneally to induce liver fibrosis in eight wild-type mice/Anxa1 knockout mice,and to detect expression of inflammatory factors,collagen deposition,and the role of the Wnt/β-catenin pathway in hepatic fibrosis.RESULTS Compared with the control group,AnxA1,transforming growth factor(TGF)-β1,interleukin(IL)-1βand IL-6 expression in the liver of mice with hepatic fibrosis induced by CCl4 was significantly increased,which promoted collagen deposition and expression ofα-smooth muscle actin(α-SMA),collagen type I and connective tissue growth factor(CTGF),and increased progressively with time.CCl4 induced an increase in TGF-β1,IL-1βand IL-6 in liver tissue of AnxA1 knockout mice,and the degree of liver inflammation and fibrosis and expression ofα-SMA,collagen I and CTGF were significantly increased compared with in wild-type mice.After treatment with Ac2-26,expression of liver inflammatory factors,degree of collagen deposition and expression of a-SMA,collagen I and CTGF were decreased compared with before treatment.Boc2 inhibited the anti-inflammatory and antifibrotic effects of Ac2-26.AnxA1 downregulated expression of the Wnt/β-catenin pathway in CCl4-induced hepatic fibrosis.In vitro,lipopolysaccharide(LPS)induced hepatocyte and hepatic stellate cell(HSC)expression of AnxA1.Ac2-26 inhibited LPS-induced RAW264.7 cell activation and HSC proliferation,decreased expression ofα-SMA,collagen I and CTGF in HSCs,and inhibited expression of the Wnt/β-catenin pathway after HSC activation.These therapeutic effects were inhibited by Boc2.CONCLUSION AnxA1 inhibited liver fibrosis in mice,and its mechanism may be related to inhibition of HSC Wnt/β-catenin pathway activation by targeting formylpeptide receptors to regulate macrophage function.
文摘目的探究负载膜联蛋白A2(ANXA2)的骨髓间充质干细胞(BMSC)来源的外泌体(Exo-ANXA2)对前列腺癌细胞增殖、侵袭与迁移以及前列腺癌移植瘤生长的影响,并研究巨噬细胞是否参与该过程。方法分离与培养BALB/c裸鼠BMSC,采用负载ANXA2的慢病毒质粒感染BMSC,并分离外泌体;加入外泌体处理THP-1巨噬细胞,ELISA检测细胞上清培养液肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)、IL-6和IL-10的水平;将外泌体处理的巨噬细胞与前列腺癌细胞共培养后,CCK-8法检测细胞增殖活性,Transwell^(TM)小室检测细胞侵袭与迁移。通过注射PC-3人前列腺癌细胞构建前列腺癌裸鼠移植瘤模型,将建模后的裸鼠随机分为对照组和实验组,每组8只,实验组裸鼠尾静脉注射1 mL Exo-ANXA2,对照组注射等量PBS,于注射后第0、3、6、9、12、15、18、21天,使用游标卡尺测量计算肿瘤体积,21 d处死裸鼠并测量肿瘤组织质量,免疫组织化学染色法检测肿瘤组织中抗原KI-67(ki67)和CD163表达。结果骨髓分离的细胞表面CD90和CD44呈高表达,CD34和CD45呈低表达,且成骨成脂分化能力较强,成功获得BMSC;负载ANXA2的慢病毒质粒感染后,BMSC中有较强的绿色荧光蛋白表达,并成功分离到Exo-ANXA2;经Exo-ANXA2处理后,THP-1细胞中TNF-α和IL-6的水平显著升高而IL-10和IL-13的水平显著下降;Exo-ANXA2处理巨噬细胞后,显著抑制Exo-ANXA2促进PC-3细胞增殖活性、侵袭与迁移的作用;经过给予前列腺癌移植瘤裸鼠注射Exo-ANXA2后,裸鼠在第6、9、12、15、18、21天的肿瘤组织体积显著减小,21 d时裸鼠肿瘤体质量也显著减少,此外,肿瘤组织内ki67和CD163的阳性表达率均显著降低。结论Exo-ANXA2能够抑制前列腺癌细胞增殖、侵袭与迁移,并抑制裸鼠前列腺癌移植瘤生长,M2型巨噬细胞减少。
