Involvement of annexin A2 in anti-β2GPI/β2 GPI-induced tissue factor expression on monocytes

Dear Editor： Growing evidence demonstrates that β2-glycoprotein Ⅰ （β2GPI） is the key target for antiphospholipid antibodies which are closely associated with thrombotic events in antiphospholipid syndrome （APS） . Anti-β2GPI/β2GPI complex can bind to the surface membrane ofmonocytes and endothelial cells, promoting tissue factor （TF） activity on these cells, and thus increasing the risk of thrombosis.[第一段]     

β2GPI及其抗体与血栓形成的相关性研究

血栓形成是临床疾病中常见的一种病理过程,以血栓形成为基本病理特征的心、脑血管疾病已超过恶性肿瘤,成为威胁人类生命的第一杀手。如何有效防治血栓,也是临床治疗中比较棘手的一个问题。目前对血栓形成的机理还有待进一步阐明。β2糖蛋白I(β2GPI)及其抗体是血栓形成发生发展的重要因素之一,可影响内皮细胞、单核细胞、血小板和纤溶系统,促进血液凝固,导致血栓发生。如果能对β2GPI及其抗体进行有效控制,将有助于防治血栓性疾病。本文就近年来β2GPI及其抗体与血栓形成的相关性研究予以综述,希望能为寻找一种安全有效防治血栓性疾病的新途径提供可能。     

GPI微域与信号转导

许多真核细胞膜表面蛋白 (例如ＣＤ1 4、ＣＤ1 6ｂ、ＣＤ2 4、ＣＤ48、ＣＤ5 2、ＣＤ5 9、ＣＤ5 5 /ＤＡＦ、ＣＤ5 8 /ＬＦＡ 3、ＣＤ6 6、ＣＤ6 7、ＣＤ73、ＣＤ87、ＣＤ90 /Ｔｈｙ 1、ＣＤ1 5 7、Ｌｙ 6等 )通过糖基磷脂酰肌醇(ｇｌｙｃｏｓｙｌｐｈｏｓｐｈａｔｉｄｙｌｉｎｏｓｉｔｏｌ,ＧＰＩ)锚着于细胞膜上 ,称为ＧＰＩ锚定蛋白 (ＧＰＩ ａｎｃｈｏｒｅｄｐｒｏｔｅｉｎｓ,ＧＰＩ ＡＰ) ,它们没有跨膜区和胞内部分 ,不能直接与胞内发生联系。但用特异性抗体结合这些结构上不同的膜蛋白或膜糖鞘脂 (ｇｌｙｃｏｓｐｈｉｎｇｏｌｉｐｉ…     

Xenopus paraxial protocadherin inhibits Wnt/β-catenin signalling via casein kinase 2β

Xenopus paraxial protocadherin (PAPC) regulates cadherin-mediated cell adhesion and promotes the planar cell polarity (PCP) pathway. Here we report that PAPC functions in the Xenopus gastrula as an inhibitor of the Wnt/β-catenin pathway. The intracellular domain of PAPC interacts with casein kinase 2 beta (CK2β), which is part of the CK2 holoenzyme. The CK2α/β complex stimulates Wnt/β-catenin signalling, and the physical interaction of CK2β with PAPC antagonizes this activity. By this mechanism, PAPC restricts the expression of Wnt target genes during gastrulation. These experiments identify a novel function of protocadherins as regulators of the Wnt pathway.     

β3 Integrin Promotes TGF-β1/H2O2/HOCl-Mediated Induction of Metastatic Phenotype of Hepatocellular Carcinoma Cells by Enhancing TGF-β1 Signaling

In addition to being an important mediator of migration and invasion of tumor cells, β3 integrin can also enhance TGF-β1 signaling. However, it is not known whether β3 might influence the induction of metastatic phenotype of tumor cells, especially non-metastatic tumor cells which express low level of β3. Here we report that H₂O₂ and HOCl, the reactive oxygen species produced by neutrophils, could cooperate with TGF-β1 to induce metastatic phenotype of non-metastatic hepatocellular carcinoma (HCC) cells. TGF-β1/H₂O₂/HOCl, but not TGF-β1 or H₂O₂/HOCl, induced β3 expression by triggering the enhanced activation of p38 MAPK. Intriguingly, β3 in turn promoted TGF-β1/H₂O₂/HOCl-mediated induction of metastatic phenotype of HCC cells by enhancing TGF-β1 signaling. β3 promoted TGF-β1/H₂O₂/HOCl-induced expression of itself via positive feed-back effect on p38 MAPK activation, and also promoted TGF-β1/H₂O₂/HOCl-induced expression of α3 and SNAI2 by enhancing the activation of ERK pathway, thus resulting in higher invasive capacity of HCC cells. By enhancing MAPK activation, β3 enabled TGF-β1 to augment the promoting effect of H₂O₂/HOCl on anoikis-resistance of HCC cells. TGF-β1/H₂O₂/HOCl-induced metastatic phenotype was sufficient for HCC cells to extravasate from circulation and form metastatic foci in an experimental metastasis model in nude mice. Inhibiting the function of β3 could suppress or abrogate the promoting effects of TGF-β1/H₂O₂/HOCl on invasive capacity, anoikis-resistance, and extravasation of HCC cells. These results suggest that β3 could function as a modulator to promote TGF-β1/H₂O₂/HOCl-mediated induction of metastatic phenotype of non-metastatic tumor cells, and that targeting β3 might be a potential approach in preventing the induction of metastatic phenotype of non-metastatic tumor cells.     

What can GPI do for you?

Various functions for glycosylphosphatidylinositol (GPI) protein anchors have been described in mammalian and protozoan systems. These data suggest that some functions are common to higher and lower eukaryotes, whereas others may represent adaptations that are specifically advantageous to either unicellular or metazoan organisms. In this article, Mike Ferguson discusses the current theories of GPI function that have relevance to protozoan parasites and their mammalian hosts.     

神经元GPI锚定蛋白结构与功能研究进展

神经系统中的IgSF蛋白是一类重要的神经细胞表面分子,种类繁多,功能多样,其中一类分子缺乏跨膜区,通过GPI锚结合在细胞膜上,表现出结构和功能的特异性。本文对该类神经元GPI锚定蛋白分子作一系统介绍。根据结构特点,神经元GPI锚定蛋白分子可分为三类,各类分子通过Ig结构域与其自身或其它蛋白分子进行顺式或反式结合,调节神经细胞活动。     

Synthesis of 11β-3H-prostaglandin E2

11β-³H-Prostaglandin E₂ was synthesized by the stereoselective reduction of the PGD₂ derivative $\text{2}$ using sodium borotritide.     

MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK-3β/β-catenin signalling

Recent studies have demonstrated that one-carbon metabolism plays a significant role in cancer development. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme of one-carbon metabolism, has been reported to be dysregulated in many cancers. However, the specific role and mechanism of MTHFD2 in lung adenocarcinoma (LUAD) still remains unclear. In this study, we evaluated the clinicopathological and prognostic values of MTHFD2 in LUAD patients. We conducted a series of functional experiments in vivo and in vitro to explore novel mechanism of MTHFD2 in LUAD. The results showed that MTHFD2 was significantly up-regulated in LUAD tissues and predicted poor prognosis of LUAD patients. Knockdown of MTHFD2 dramatically inhibited cell proliferation and migration by blocking the cell cycle and inducing the epithelial-mesenchymal transition (EMT). In addition, MTHFD2 knockdown suppressed LUAD growth and metastasis in cell-derived xenografts. Mechanically, we found that MTHFD2 promoted LUAD cell growth and metastasis via AKT/GSK-3β/β-catenin signalling. Finally, we identified miR-30a-3p as a novel regulator of MTHFD2 in LUAD. Collectively, MTHFD2 plays an oncogenic role in LUAD progression and is a promising target for LUAD diagnosis and therapy.     

The oxidation of cat,human, and the cat-human hybrid hemoglobins α2Humanβ2Cat and α2Catβ2Human by copper(II)

The heme iron of the β chains of mammalian hemoglobins are rapidly and selectively oxidized in the presence of excess Cu(II) ions in a reaction that requires the presence of a free -SH groups on the β globin chain. The presence of freely reactive -SH groups on the α chains of cat and sheep hemoglobins does not alter the course of this reaction: only the β hemes are oxidized rapidly by Cu(II) in these hemoglobins. Two equivalents of copper are required for the rapid oxidation of the two β chain hemes per mole of cat hemoglobin, in contrast with the four equivalents that are required for reaction with human hemoglobin. The human-cat hybrid hemoglobins, α₂^Humanβ₂^Cat and α₂^Catβ₂^Human, required two and four equivalents of copper/mol, respectively, for the reaction. Thus, the kinetics and stoichimetry of the reaction are determined by the nature of the β subunit. Analysis of the esr spectra of the products of the reaction of Cu(II) with these hemoglobins indicate that human hemoglobin and the hybrid α₂^Catβ₂^Human contain tight binding sites for two equivalents of Cu(II) that are not involved in the oxidation reaction and are not present in cat hemoglobin or α₂^Humanβ₂^Cat. Cat β globin like others (sheep, bovine) that lack the tight binding site, has no histidine residue at 2β. It has phenylalanine in this position. These results support the suggestion of Rifkind et al. (Biochemistry 15,5337[1976]) that the tight binding site is near the amino terminal region of the β chain and is associated with histidine 2β.     

Crystal structure of 2-deoxy-β-d-lyxo-hexose (2-deoxy-β-d-galactose)

2-Deoxy-β-d-lyxo-hexose (2-deoxy-β-d-galactose, C₆H₁₂O₅), M_r = 164.16, is monoclinic, P2₁ with a = 9.811(1), b = 6.953(1), c = 5.315(1) Å, β = 91.58(2)°, V = 362.5(1) ų, Z = 2, and D_x = 1.504 g.cm^?3. The structure was solved by direct methods (MULTAN 79) and refined to R = 0.032 for 800 observed reflections. Each hydroxyl oxygen, acting both as donor and acceptor, is involved in a hydrogen-bonding system, which consists of infinite helical chains around the crystallographic screw axes. Moreover, weak interactions allow the incorporation of the ring-oxygen atoms into an interconnected network.     

神经元GPI锚定蛋白结构与功能研究进展

神经系统中的IsSF蛋白是一类重要的神经细胞表面分子,种类繁多,功能多样,其中一类分子缺乏跨膜区,通过GPI锚结合在细胞膜上,表现出结构和功能的特异性,本文对该类神经GPI锚定蛋白分子作一系统介绍,根据结构特点,神经元GPI锚定蛋白分子可分为三类,各类分子通过Ig结构域与其自身或其它蛋白分子进行顺式或反式结合,调节神经细胞活动。     

Intractable Headaches,Ischemic Stroke,and Seizures Are Linked to the Presence of Anti-β2GPI Antibodies in Patients with Systemic Lupus Erythematosus

Background

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common and potentially fatal manifestation of SLE. Antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA), anticardiolipin (aCL) and antibodies to β2glycoprotein I (anti-β2GPI), the most important aPL antigen, are thought to play a role in some forms of NPSLE. As of yet, their specific roles in NPSLE manifestations remain to be elucidated.

Methodology/Principal Findings

57 SLE patients (53 women) were assessed for LA, aCL and anti-β₂GPI twice, to determine persistent positivity. All patients were examined by neurology and psychiatry specialists. 69 healthy subjects were assessed as controls. NPSLE was diagnosed in 74% of patients. Headaches were the most prevalent manifestation of NPSLE (39%), followed by cerebrovascular disease (CVD) (23%), depressive disorders (19.0%), and seizures (14%). NPSLE and non-NPSLE patients showed comparable SLE activity and corticosteroid use. In 65% of patients neuropsychiatric manifestations preceded SLE diagnosis. aPL profiles of NPSLE patients and non-NPSLE patients were similar. Headaches and ischemic stroke were independently associated with anti-β₂GPI-IgM (OR=5.6; p<0.05), and seizures were linked to anti-β₂GPI-IgG (OR=11.3; p=0.01).

Conclusions

In SLE patients, neuropsychiatric manifestations occur frequently and early, often before the disease is diagnosed. Autoantibodies to β2GPI are linked to non-specific headaches, ischemic stroke and seizures, and show a better predictive value than aCL and LA. These findings may help to improve the diagnosis of NPSLE and should prompt further studies to characterize the role of anti-β2GPI in the pathogenesis of this condition.     

miR-637 Prevents Glioblastoma Progression by Interrupting ZEB2/WNT/β-catenin Cascades

Glioblastomas (GBMs) are the most frequent primary malignancies in the central nervous system. Aberrant activation of WNT/β-catenin signaling pathways is critical for GBM malignancy. However, the regulation of WNT/β-catenin signaling cascades remains unclear. Presently, we observed the increased expression of ZEB2 and the decreased expression of miR-637 in GBM. The expression of miR-637 was negatively correlated with ZEB2 expression. miR-637 overexpression overcame the ZEB2-enhanced cell proliferation and G1/S phase transition. Besides, miR-637 suppressed the canonical WNT/β-catenin pathways by targeting WNT7A directly. Gain- and loss-of-function experiments with U251 mice demonstrated that miR-637 inhibited cell proliferation and arrested the G1/S phase transition, leading to tumor growth suppression. The collective findings suggest that ZEB2 and WNT/β-catenin cascades merge at miR-637, and the ectopic expression of miR-637 disturbs ZEB2/WNT/β-catenin-mediated GBM growth. The findings provide new clues for improving β-catenin-targeted therapy against GBM.

     

MFAP2 promotes HSCs activation through FBN1/TGF-β/Smad3 pathway

Liver fibrosis is a chronic inflammatory process characterized by the accumulation of extracellular matrix (ECM), which contributes to cirrhosis and hepatocellular carcinoma. Increasing evidence suggests that the activation of hepatic stellate cells (HSCs) under an inflammatory state leads to the secretion of collagens, which can cause cirrhosis. In this study, we analysed data from the Gene Expression Omnibus (GEO) databases to identify differentially expressed genes (DEGs) between quiescent and fibrotic HSCs. We found that Microfibril Associated Protein 2 (MFAP2) was elevated in carbon tetrachloride (CCl4)-induced liver fibrosis and Transforming Growth Factor-Beta 1 (TGF-β1)-activated HSCs. Knockdown of MFAP2 inhibited HSC proliferation and partially attenuated TGF-β-stimulated fibrogenesis markers. Bioinformatics analysis revealed that Fibrillin-1 (FBN1) was correlated with MFAP2, and the expression of FBN1 was significantly upregulated after MFAP2 overexpression. Silencing MFAP2 partially attenuated the activation of HSCs by inhibiting HSC proliferation and decreasing collagen deposits. In vitro results showed that the inhibition of MFAP2 alleviated hepatic fibrosis by inhibiting the activation and inducing the apoptosis of active HSCs in a CCl4-induced mouse model. In conclusion, our results suggest that MFAP2 is a potential target for the clinical treatment of liver fibrosis.     

Ghrelin、KGF、TGF-β(β2、β3)在大鵟胃肠道中的表达

应用免疫组织化学方法和体视学半定量方法,检测了ghrelin、KGF、TGF-β(TGF-β_2,TGF-β_3)在大鵟(Buteo hemilasius)胃肠道中的表达,利用IPP专业图像分析软件对其表达强度进行了定量分析.结果表明,ghrelin免疫反应阳性物质分布在十二指肠、空肠、回肠、盲肠和直肠的黏膜层,主要分布于黏膜上皮、肠腺上皮和固有层.从十二指肠到盲肠阳性细胞的分布密度逐渐减小,直肠阳性细胞的分布密度高于盲肠.胃肠道呈KGF免疫反应阳性,胃内阳性物质分布于腺胃浅腺和深腺、肌胃黏膜、肌胃单管腺的上皮细胞;肠内阳性物质分布于固有层的血管、淋巴和平滑肌纤维.胃黏膜、腺胃深腺、肌胃单管腺、肠道黏膜、肠腺呈TGF-β_2及TGF-β_3免疫反应阳性,阳性物质分布于黏膜、肠腺上皮细胞胞质中.图像分析显示,KGF的阳性表达水平呈波浪形变化,在空肠和直肠处达到峰值;TGF-β2的阳性表达水平呈波浪形变化,分别在肌胃和空肠处有峰值;TGF-β_3从腺胃到空肠阳性表达水平逐渐增强,之后阳性表达水平又逐渐下降,到盲肠阳性表达水平回升.ghrelin、KGF、TGF-β_2和TGF-β_3的阳性表达强弱可能与胃肠道的消化能力有关,它们的协同表达调控鸟类胃肠道的生长和发育.