• 【Tyro3,Axl和Mer酪氨酸激酶激动剂对胶原诱导的关节炎的治疗效果。】 复制标题 收藏 收藏
    DOI:10.1002/art.37786 复制DOI
    作者列表:van den Brand BT,Abdollahi-Roodsaz S,Vermeij EA,Bennink MB,Arntz OJ,Rothlin CV,van den Berg WB,van de Loo FA
    BACKGROUND & AIMS: OBJECTIVE:Hyperactivation of innate immunity by Toll-like receptors (TLRs) can contribute to the development of autoinflammatory or autoimmune diseases. This study evaluated the activation of Tyro3, Axl, Mer (TAM) receptors, physiologic negative regulators of TLRs, by their agonists, growth arrest-specific protein 6 (GAS-6) and protein S, in the prevention of collagen-induced arthritis (CIA). METHODS:Adenoviruses overexpressing GAS-6 and protein S were injected intravenously or intraarticularly into mice during CIA. Splenic T helper cell subsets from intravenously injected mice were studied by flow cytometry, and the knee joints of mice injected intravenously and intraarticularly were assessed histologically. Synovium from mice injected intraarticularly was evaluated for cytokine and suppressor of cytokine signaling (SOCS) expression. RESULTS:Protein S significantly reduced ankle joint swelling when overexpressed systemically. Further analysis of knee joints revealed a moderate reduction in pathologic changes in the joint and a significant reduction in the number of splenic Th1 cells when protein S was overexpressed systemically. Local overexpression of GAS-6 decreased joint inflammation and joint pathology. Protein S treatment showed a similar trend of protection. Consistently, GAS-6 and protein S reduced cytokine production in the synovium. Moreover, levels of messenger RNA for interleukin-12 (IL-12) and IL-23 were reduced by GAS-6 and protein S treatment, with a corresponding decrease in the production of interferon-γ and IL-17. TAM ligand overexpression was associated with an increase in SOCS-3 levels, which likely contributed to the amelioration of arthritis. CONCLUSION:This study provides the first evidence that TAM receptor stimulation by GAS-6 and protein S can be used to ameliorate arthritis when applied systemically or locally. TAM receptor stimulation limits proinflammatory signaling and adaptive immunity. This pathway provides a novel strategy by which to combat rheumatoid arthritis.
    背景与目标:
  • 【胶原: 酰胺I带手性二阶光学非线性的结构起源。】 复制标题 收藏 收藏
    DOI:10.1016/j.bpj.2012.10.017 复制DOI
    作者列表:Reiser KM,McCourt AB,Yankelevich DR,Knoesen A
    BACKGROUND & AIMS: :The molecular basis of nonlinear optical (NLO) chiral effects in the amide I region of type I collagen was investigated using sum-frequency generation vibrational spectroscopy; chiral and achiral tensor elements were separated using different input/output beam polarization conditions. Spectra were obtained from native rat tail tendon (RTT) collagen and from cholesteric liquid crystal-like (LC) type I collagen films. Although RTT and LC collagen both possess long-range order, LC collagen lacks the complex hierarchical organization of RTT collagen. Their spectra were compared to assess the role of such organization in NLO chirality. No significant differences were observed between RTT and LC with respect to chiral or achiral spectra. These findings suggest that amide I NLO chiral effects in type I collagen assemblies arise predominantly from the chiral organization of amide chromophores within individual collagen molecules, rather than from supramolecular structures. The study suggests that sum-frequency generation vibrational spectroscopy may be uniquely valuable in exploring fundamental aspects of chiral nonlinearity in complex macromolecular structures.
    背景与目标: : 使用和频产生振动光谱研究了I型胶原的酰胺I区域中非线性光学 (NLO) 手性效应的分子基础; 使用不同的输入/输出光束偏振条件分离手性和非手性张量元素。光谱是从天然的大鼠尾腱 (RTT) 胶原蛋白和胆甾型液晶样 (LC) I型胶原蛋白膜获得的。尽管RTT和LC胶原蛋白都具有长程顺序,但LC胶原蛋白缺乏RTT胶原蛋白的复杂层次组织。比较了它们的光谱,以评估这种组织在NLO手性中的作用。在手性或无手性光谱方面,RTT和LC之间未观察到显着差异。这些发现表明,I型胶原蛋白组装体中的酰胺I NLO手性作用主要来自单个胶原蛋白分子中酰胺发色团的手性组织,而不是超分子结构。研究表明,和频产生振动光谱在探索复杂大分子结构中手性非线性的基本方面可能具有独特的价值。
  • 【使用与I型胶原蛋白的C-端肽的8个氨基酸序列的异构化形式反应的抗体测量血清中的骨降解产物。】 复制标题 收藏 收藏
    DOI:10.1359/jbmr.1997.12.7.1028 复制DOI
    作者列表:Bonde M,Garnero P,Fledelius C,Qvist P,Delmas PD,Christiansen C
    BACKGROUND & AIMS: An enzyme-linked immunosorbent assay for measuring type I collagen degradation products in serum (S-ELISA) was developed. The assay uses a high affinity polyclonal antibody which reacts with an isomerized form of an 8 amino acid sequence of the C-telopeptides of type I collagen (EKAHD-beta-GGR). Cross-reactivity to a nonisomerized synthetic peptide form of the 8 amino acid sequence is less than 0.2%. Values obtained in a group of premenopausal women (age, 33.3 +/- 3.11 years) were 69 +/- 24 ng/ml(n = 22). In a group of early postmenopausal women (age, 51.8 +/- 1.88 years) values obtained were 125 +/- 43 ng/ml (n = 46), which represents an increase of 81% (p < 0.001). Values found in untreated patients with Paget's disease were 234 +/- 95 ng/ml (n = 15), and for primary hyperparathyroidism we found 335 +/- 82 ng/ml (n = 10). Intravenous administration of a bisphosphonate (Pamidronate) to Paget's disease patients for 3 days was reflected in the S-ELISA by a decrease in the values of 55% when compared with values before treatment (n = 15). Following treatment with another bisphosphonate (Alendronate) for 6 months, values were decreased to 48 +/- 19 ng/ml (n = 12), which corresponds to a 62% decrease. Clinical results presented in this context support that the assay is a sensitive and specific index of bone resorption. It may, therefore, prove useful in the follow up of treatment of patients with metabolic bone diseases and in the clinical investigation of osteoporosis.

    背景与目标: 开发了一种用于测量血清中I型胶原蛋白降解产物的酶联免疫吸附测定法 (S-ELISA)。该测定使用高亲和力多克隆抗体,该抗体与I型胶原蛋白 (EKAHD-β-GGR) 的C-端肽的8个氨基酸序列的异构化形式反应。对8个氨基酸序列的非异构化合成肽形式的交叉反应性小于0.2%。在一组绝经前妇女 (年龄,33.3 +/- 3.11岁) 中获得的值为69 +/- 24 ng/ml(n = 22)。在一组绝经后早期妇女 (年龄,51.8 +/- 1.88岁) 中,获得的值为125 +/- 43 ng/ml (n = 46),这表示增加了81% (p <0.001)。在未经治疗的Paget病患者中发现的值为234/- 95 ng/ml (n = 15),对于原发性甲状旁腺功能亢进,我们发现335/- 82 ng/ml (n = 10)。与治疗前的值相比 (n = 15),在S-ELISA中反映了将双膦酸盐 (帕米膦酸盐) 静脉给药至Paget病患者3天的55% 值降低。用另一种双膦酸盐 (阿仑膦酸盐) 治疗6个月后,值降低至48 +/- 19 ng/ml (n = 12),这对应于62% 降低。在这种情况下提出的临床结果支持该测定是骨吸收的敏感且特异性的指标。因此,它可能对代谢性骨病患者的治疗随访和骨质疏松症的临床研究有用。
  • 【瘦素的生理浓度增加了非永生化人肝星状细胞产生的胶原蛋白。】 复制标题 收藏 收藏
    DOI:10.1016/j.metabol.2006.05.016 复制DOI
    作者列表:Choudhury J,Mirshahi F,Murthy KS,Yager DR,Sanyal AJ
    BACKGROUND & AIMS: :The effects of leptin, in concentrations seen in obesity, on collagen production and turnover in non-immortalized human hepatic stellate cell (HSC), were unknown. The profibrogenic effects of leptin in these cells were studied. Hepatic stellate cells were obtained from resected livers. Collagen I/III gene expression and protein production were measured by quantitative real-time polymerase chain reaction and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, respectively. The signal transduction pathways involved were evaluated by specific blockers of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase kinase (MEK), and Janus kinase 2 (JAK2). The effects on matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were assessed by their gene transcript levels, collagenolytic activity of cell culture supernatants, and MMP-1 protein levels. At concentrations seen in nonobese individuals ([leptin] < 10 ng/mL), leptin did not affect collagen production. At concentrations seen in obesity (30-50 ng/mL), leptin increased collagen I and III messenger RNA (mRNA) transcript levels by 286% +/- 55% (P < .001) and 167% +/- 62% (P < .007) and protein production by 45.8% +/- .02% and 84.39% +/- .01%, respectively. These effects were blocked by JAK2 inhibition as well as PI3K inhibition. Although MEK inhibition blocked leptin-induced procollagen I and III mRNA levels, there were no significant effects on collagen I and III protein levels. Leptin (10-50 ng/mL) had no significant effects on MMP-1 or TIMP-1 mRNA levels, collagenolytic activity, or MMP-1 protein levels. In conclusion, leptin, at levels seen in obese individuals, produces an increase in collagen production by HSC acting through the JAK and PI3K pathways. At these concentrations, leptin does not affect MMP-1 or TIMP-1 expression or collagenolytic activity of HSC.
    背景与目标: : 瘦素 (在肥胖中观察到的浓度) 对非永生化人肝星状细胞 (HSC) 中胶原蛋白产生和周转的影响尚不清楚。研究了瘦素在这些细胞中的促纤维化作用。从切除的肝脏中获得肝星状细胞。通过定量实时聚合酶链反应和十二烷基硫酸钠-聚丙烯酰胺凝胶电泳分别测量胶原蛋白I/III基因表达和蛋白质产生。通过磷脂酰肌醇3-激酶 (PI3K),丝裂原活化蛋白激酶激酶 (MEK) 和Janus激酶2 (JAK2) 的特异性阻滞剂评估了所涉及的信号转导途径。通过其基因转录水平,细胞培养上清液的胶原分解活性和MMP-1蛋白水平评估了对基质金属蛋白酶1 (MMP-1) 和组织金属蛋白酶1 (TIMP-1) 的影响。在非肥胖个体中观察到的浓度 ([leptin] < 10 ng/mL),leptin不会影响胶原蛋白的产生。在肥胖中观察到的浓度 (30-50 ng/mL),瘦素通过286% +/- 55% (P < .001) 和167% +/- 62% (P < .007) 增加胶原蛋白I和III信使RNA (mRNA) 转录水平,并通过45.8% +/- .02% 和84.39% +/- .01% 增加蛋白质生产。这些作用被JAK2抑制和PI3K抑制所阻断。尽管MEK抑制抑制了瘦素诱导的胶原蛋白I和III mRNA水平,但对胶原蛋白I和III蛋白水平没有显着影响。瘦素 (10-50ng/mL) 对MMP-1或TIMP-1 mRNA水平,胶原蛋白分解活性或MMP-1蛋白水平没有显着影响。总之,在肥胖个体中观察到的瘦素水平,通过HSC通过JAK和PI3K途径起作用而增加胶原蛋白的产生。在这些浓度下,瘦素不影响HSC的MMP-1或TIMP-1表达或胶原分解活性。
  • 【胶原刚度调节细胞收缩和基质重塑基因表达。】 复制标题 收藏 收藏
    DOI:10.1002/jbm.a.31423 复制DOI
    作者列表:Karamichos D,Brown RA,Mudera V
    BACKGROUND & AIMS: :Cell-level mechanical and 3D spatial cues are essential to the organization and architecture of new tissues that form during growth, repair or in bioreactors. Fibroblast-seeded 3D collagen constructs have been used as bioartifical extracellular matrix (ECM) providing a 3D environment to embedded resident cells. As cells attach to scaffold fibrils, they generate quantifiable contractile forces which depend on cell type, cell attachment, cell density, growth factors, and matrix stiffness. The aim of this study was to quantify the cytomechanical and molecular responses of human dermal (HDF) and neonatal foreskin fibroblasts (HNFF) seeded in constructs of increased stiffness. We also tested the effect of blocking early attachment using serum starvation on these outputs. Constructs were placed under uniaxial strains of 0-10% to increase scaffold stiffness, prior to gel contraction, and force generation was monitored using a tensional culture force monitor (t-CFM). Increased matrix stiffness reduced generation of quantifiable cellular force (up to 70%) over 24 h in both cell types and delayed the onset of measurable contraction (upto sevenfold). The delay of measurable force generation was cell lineage dependent but not FCS dependent. Gene expression of MMP-2, TIMP-2, and collagen type III expression in HDFs were significantly upregulated in constructs of increased stiffness. HNFFs did not show any significant changes in these gene expressions indicating a lineage specific response.
    背景与目标: : 细胞水平的机械和3D空间线索对于在生长,修复或生物反应器中形成的新组织的组织和结构至关重要。成纤维细胞种子的3D胶原蛋白构建体已被用作生物人工细胞外基质 (ECM),为嵌入的常驻细胞提供3D环境。当细胞附着在支架原纤维上时,它们会产生可量化的收缩力,这取决于细胞类型,细胞附着,细胞密度,生长因子和基质刚度。这项研究的目的是量化接种在硬度增加的构建体中的人真皮 (HDF) 和新生儿包皮成纤维细胞 (HNFF) 的细胞机械和分子反应。我们还测试了使用血清饥饿阻断早期附着对这些输出的影响。在凝胶收缩之前,将构建体置于0-10% 的单轴应变下以增加支架刚度,并使用张力培养力监测器 (t-cfm) 监测力的产生。在两种细胞类型中,增加的基质刚度在24小时内减少了可量化的细胞力 (高达70%) 的产生,并延迟了可测量的收缩的开始 (高达7倍)。可测量的力产生的延迟与细胞谱系有关,但与FCS无关。在刚度增加的构建体中,HDFs中MMP-2,TIMP-2和III型胶原表达的基因表达显着上调。HNFFs在这些基因表达中未显示任何显着变化,表明谱系特异性反应。
  • 【A组链球菌胶原蛋白样蛋白1 Scl1通过靶向受伤组织中表达的含细胞纤连蛋白的额外结构域A变体来介导生物膜的形成。】 复制标题 收藏 收藏
    DOI:10.1111/mmi.12125 复制DOI
    作者列表:Oliver-Kozup H,Martin KH,Schwegler-Berry D,Green BJ,Betts C,Shinde AV,Van De Water L,Lukomski S
    BACKGROUND & AIMS: :Wounds are known to serve as portals of entry for group A Streptococcus (GAS). Subsequent tissue colonization is mediated by interactions between GAS surface proteins and host extracellular matrix components. We recently reported that the streptococcal collagen-like protein-1, Scl1, selectively binds the cellular form of fibronectin (cFn) and also contributes to GAS biofilm formation on abiotic surfaces. One structural feature of cFn, which is predominantly expressed in response to tissue injury, is the presence of a spliced variant containing extra domain A (EDA/EIIIA). We now report that GAS biofilm formation is mediated by the Scl1 interaction with EDA-containing cFn. Recombinant Scl1 proteins that bound cFn also bound recombinant EDA within the C-C' loop region recognized by the α(9)β(1) integrin. The extracellular 2-D matrix derived from human dermal fibroblasts supports GAS adherence and biofilm formation. Altogether, this work identifies and characterizes a novel molecular mechanism by which GAS utilizes Scl1 to specifically target an extracellular matrix component that is predominantly expressed at the site of injury in order to secure host tissue colonization.
    背景与目标: : 已知伤口是A组链球菌 (GAS) 的入口。随后的组织定植是由气体表面蛋白和宿主细胞外基质成分之间的相互作用介导的。我们最近报道了链球菌胶原蛋白样蛋白1 Scl1选择性地结合纤连蛋白 (cFn) 的细胞形式,并且还有助于在非生物表面上形成气体生物膜。cFn的一个结构特征主要是对组织损伤的反应,是存在包含额外结构域a (EDA/EIIIA) 的剪接变体。我们现在报告气体生物膜的形成是由Scl1与含EDA的cFn相互作用介导的。结合cFn的重组Scl1蛋白也结合了由 α(9)β(1) 整联蛋白识别的c-c' 环区域内的重组EDA。源自人类真皮成纤维细胞的细胞外2-D基质支持气体粘附和生物膜形成。总之,这项工作确定并表征了一种新的分子机制,通过该机制,GAS利用Scl1特异性靶向主要在损伤部位表达的细胞外基质成分,以确保宿主组织定植。
  • 【抑制Src激酶可阻断高葡萄糖诱导的肾小球系膜细胞EGFR反式激活和胶原合成,并预防小鼠糖尿病肾病。】 复制标题 收藏 收藏
    DOI:10.2337/db12-1010 复制DOI
    作者列表:Taniguchi K,Xia L,Goldberg HJ,Lee KW,Shah A,Stavar L,Masson EA,Momen A,Shikatani EA,John R,Husain M,Fantus IG
    BACKGROUND & AIMS: :Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor-α-converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose-stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose-induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE-heparin-binding epidermal growth factor-EGFR-MAPK-signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy.
    背景与目标: : 长期暴露于高糖会导致糖尿病肾病,其特征是系膜基质蛋白 (例如胶原蛋白) 积累增加。已经记录了伴随氧化应激的细胞信号和基因表达的改变。检查了对氧化应激敏感的酪氨酸激酶c-Src (Src) 的贡献。在存在和不存在Src抑制剂 (PP2,SU6656),Src小干扰RNA (siRNA) 和肿瘤坏死因子-α 转化酶 (TACE) 的情况下,将培养的大鼠肾小球系膜细胞暴露于高糖 (25 mmol/L) TAPI-2抑制剂。通过向链脲佐菌素 (STZ) 诱导的糖尿病DBA2/J小鼠施用PP2在体内研究了Src。高糖刺激Src,TACE,表皮生长因子受体 (EGFR),丝裂原活化蛋白激酶 (MAPKs),细胞外信号调节激酶 (ERK1/2,p38) 和胶原IV在系膜细胞中的积累。PP2和SU6656阻断了高糖刺激的Src Tyr-416、EGFR和MAPKs的磷酸化。这些抑制剂和siRNA的Src敲除以及TAPI-2也消除了高糖诱导的这些靶标的磷酸化和胶原IV的积累。在STZ糖尿病小鼠中,pp2抑制了蛋白尿,Src pTyr-416增加,TACE激活,ERK和EGFR磷酸化,肾小球胶原积累和足细胞丢失。这些数据表明Src在高葡萄糖-Src-TACE-肝素结合表皮生长因子-egfr-mapk信号通路中与胶原蛋白积累的作用。因此,Src可能为糖尿病肾病提供新的治疗靶标。
  • 【胶原基质在肿瘤血管生成和多形性胶质母细胞瘤进展中的作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.ajpath.2013.06.026 复制DOI
    作者列表:Mammoto T,Jiang A,Jiang E,Panigrahy D,Kieran MW,Mammoto A
    BACKGROUND & AIMS: :Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor β-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression.
    背景与目标: : 胶质母细胞瘤是一种高度血管化的脑肿瘤,抗血管生成治疗可改善其无进展生存期。然而,当前的抗血管生成疗法会引起严重的不良反应,包括神经元细胞毒性,肿瘤侵袭性和对治疗的抵抗力。尽管已经提出物理微环境在肿瘤血管生成和进展中起关键作用,但细胞外基质的物理特性控制肿瘤血管生成和胶质母细胞瘤进展的机制尚不完全清楚。在本文中,我们显示了人胶质母细胞瘤细胞系U87MG,U251的物理压实 (细胞聚集并聚集在一起并引起细胞形状和大小相关变化的过程),LN229诱导 ⅳ 型和 ⅵ 型胶原和胶原交联酶赖氨酰氧化酶的表达,并上调血管生成因子血管内皮生长因子的体外表达。在小鼠原位脑肿瘤模型中,赖氨酰氧化酶抑制剂 β-氨基丙腈破坏肿瘤中的胶原蛋白结构并抑制肿瘤血管生成和多形性胶质母细胞瘤的生长。同样,d-青霉胺通过消耗脑内铜来抑制赖氨酰氧化酶的酶活性,也对小鼠脑肿瘤生长表现出抗血管生成作用。这些发现表明,胶原结构控制的肿瘤微环境在肿瘤血管生成和脑肿瘤进展中很重要。
  • 【用于压力性尿失禁的非手术,射频胶原蛋白变性: 回顾性3年评估。】 复制标题 收藏 收藏
    DOI:10.1586/17434440.4.4.455 复制DOI
    作者列表:Appell RA,Singh G,Klimberg IW,Graham C,Juma S,Wells WG,Kanellos A,Reilley SF
    BACKGROUND & AIMS: :Transurethral radiofrequency collagen denaturation, a nonsurgical treatment for stress urinary incontinence, reduces regional dynamic tissue compliance without causing tissue necrosis or gross tissue shrinkage, unlike transvaginal radiofrequency tissue ablation. This retrospective study evaluated long-term safety and efficacy in 21 patients from a 12-month, randomized controlled trial utilizing 3-day diaries and the Incontinence Quality of Life (I-QOL) survey. Significant increases in overall I-QOL scores 3 years or more post treatment was the primary end point. Secondary end points were reductions in frequency and severity of incontinence episodes. After 3 years, mean overall I-QOL score improvement was 12.7 (+/-26); 56% of patients achieved 50% or more reduction in frequency. No new adverse events occurred. These results indicate that radiofrequency collagen denaturation is safe and provides durable efficacy.
    背景与目标: : 与经阴道射频组织消融不同,经尿道射频胶原变性是一种非手术治疗压力性尿失禁的方法,可降低局部动态组织顺应性,而不会引起组织坏死或大组织收缩。这项回顾性研究评估了一项为期12个月的随机对照试验中21例患者的长期安全性和有效性,该试验利用3天日记和尿失禁生活质量 (I-QOL) 调查。治疗后3年或更长时间的总体I-QOL评分显着增加是主要终点。次要终点是尿失禁发作频率和严重程度的降低。3年后,平均I-QOL评分改善12.7 (+/-26); 56% 的患者达到50% 或更多的频率降低。没有新的不良事件发生。这些结果表明,射频胶原蛋白变性是安全的,并提供持久的功效。
  • 【使用比率非线性光学显微镜对癌性食管组织中的胶原纤维进行无标记表征。】 复制标题 收藏 收藏
    DOI:10.1177/1535370220934039 复制DOI
    作者列表:Chen WC,Chen YJ,Lin ST,Hung WH,Chan MC,Wu IC,Wu MT,Kuo CT,Das S,Kao FJ,Zhuo GY
    BACKGROUND & AIMS: IMPACT STATEMENT:The issue of classifying esophageal cancer at various developmental stages is crucial for determining the optimized treatment protocol for the patients, as well as the prognosis. Precision improvement in staging esophageal cancer keeps seeking quantitative and analytical imaging methods that could augment histopathological techniques. In this work, we used nonlinear optical microscopy for ratiometric analysis on the intrinsic signal of two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) from single collagen fibers only in submucosa of esophageal squamous cell carcinoma (ESCC). The blind tests of TPEF/SHG and forward (F)/backward (B) SHG were demonstrated to compare with the histology conclusion. The discussion of sensitivity and specificity was provided via statistical comparison between the four stages of esophageal cancer. To the best of our knowledge, this is the first study of using these two ratios in combination for staging ESCC.
    背景与目标: 影响声明: 在各个发育阶段对食管癌进行分类对于确定患者的最佳治疗方案以及预后至关重要。食管癌分期的精度提高一直在寻求可以增强组织病理学技术的定量和分析成像方法。在这项工作中,我们使用非线性光学显微镜对食管鳞状细胞癌 (ESCC) 粘膜下层的双光子激发荧光 (TPEF) 和二次谐波产生 (SHG) 的固有信号进行了比率分析。TPEF/SHG和向前 (F)/向后 (B) SHG的盲测试被证明与组织学结论进行了比较。通过统计比较四个阶段的食管癌之间的敏感性和特异性的讨论。据我们所知,这是首次将这两种比率组合用于ESCC分期的研究。
  • 【小剂量IL-18联合IL-10通过下调炎症和Th1反应以及诱导Th2反应对胶原诱导的关节炎的治疗作用。】 复制标题 收藏 收藏
    DOI:10.1007/s00296-008-0732-3 复制DOI
    作者列表:Dai Q,Li Y,Zhang F,Yu H,Wang X
    BACKGROUND & AIMS: :To investigate the anti-inflammatory or pleiotropic immunomodulatory role of interleukin-18 (IL-18), collagen-induced arthritis (CIA) mice were administrated with IL-18 along or in combination with IL-10, IL-4 or IL-12. IL-18 treatment along had no therapeutic effect on onset or established CIA mice. However, the combined treatment of low-dose IL-18 with IL-10 ameliorated the disease progression. Th1 cytokine expression was significantly inhibited, whereas Th2 cytokine expression was up-regulated in the synovial tissue by the IL-18/IL-10 treatment when compared with that in control group. Interestingly, IL-18 receptor (IL-18R) alpha expression was down-regulated by the treatment. According to the development of Th2 responses, GATA-3 mRNA expression was significantly increased in the treatment group. Our results indicated that combined treatment of low-dose IL-18 with IL-10 can prevent the development of CIA, which may be mediated not only by inhibiting Th1 responses through IL-18/IL-18Ralpha signaling, but also by inducing anti-inflammatory mediators through a GATA-3-dependent mechanism.
    背景与目标: : 为了研究interleukin-18 (IL-18) 的抗炎或多效性免疫调节作用,将胶原诱导的关节炎 (CIA) 小鼠与IL-10,IL-4或IL-12一起或与之组合给予IL-18。IL-18治疗对发病或已建立的CIA小鼠没有治疗效果。然而,低剂量IL-18与IL-10的联合治疗改善了疾病进展。与对照组相比,IL-18/IL-10治疗在滑膜组织中Th1细胞因子表达被显着抑制,而Th2细胞因子表达在滑膜组织中被上调。有趣的是,IL-18受体 (IL-18R) α 表达被治疗下调。根据Th2反应的发展,治疗组GATA-3 mRNA表达显着增加。我们的结果表明,低剂量IL-18与IL-10的联合治疗可以防止CIA的发展,这不仅可以通过IL-18/IL-18Ralpha信号抑制Th1反应来介导,还可以通过GATA-3-dependent机制诱导抗炎介质来介导。
  • 【胶原生物学和肝纤维化的非侵入性生物标志物。】 复制标题 收藏 收藏
    DOI:10.1111/liv.14390 复制DOI
    作者列表:Karsdal MA,Daniels SJ,Holm Nielsen S,Bager C,Rasmussen DGK,Loomba R,Surabattula R,Villesen IF,Luo Y,Shevell D,Gudmann NS,Nielsen MJ,George J,Christian R,Leeming DJ,Schuppan D
    BACKGROUND & AIMS: :There is an unmet need for high-quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non-alcoholic fatty liver disease (NAFLD). In particular, there is a need for diagnostic and prognostic tools, as well as predictive biomarkers that reflect the efficacy of interventions, as described by the BEST criteria (Biomarkers, EndpointS, and other Tools Resource). This review covers the various liver collagens, their functional role in tissue homeostasis and delineates the common nomenclature for biomarkers based on BEST criteria. It addresses the common confounders affecting serological biomarkers, and describes defined collagen epitope biomarkers that originate from the dynamic processes of extracellular matrix (ECM) remodelling during liver injury.
    背景与目标: : 对高质量的液体生物标志物的需求尚未得到满足,这些生物标志物可以安全,可重复地预测纤维化的阶段和慢性肝病 (CLD) 的结果。由于非酒精性脂肪肝病 (NAFLD) 等疾病的全球患病率很高,因此对此类标志物的需求日益增加。特别地,需要诊断和预后工具,以及反映干预效果的预测性生物标志物,如最佳标准 (生物标志物、终点和其他工具资源) 所描述的。这篇综述涵盖了各种肝脏胶原蛋白,它们在组织稳态中的功能作用,并根据最佳标准描述了生物标志物的通用命名法。它解决了影响血清学生物标志物的常见混杂因素,并描述了定义的胶原蛋白表位生物标志物,这些标志物起源于肝损伤期间细胞外基质 (ECM) 重塑的动态过程。
  • 【由neurotrophin-3基因功能化的多通道胶原导管介导的横断脊髓轴突再生的改善。】 复制标题 收藏 收藏
    DOI:10.1038/gt.2013.42 复制DOI
    作者列表:Yao L,Daly W,Newland B,Yao S,Wang W,Chen BK,Madigan N,Windebank A,Pandit A
    BACKGROUND & AIMS: :Functionalized biomaterial scaffolds targeted at improving axonal regeneration by enhancing guided axonal growth provide a promising approach for the repair of spinal cord injury. Collagen neural conduits provide structural guidance for neural tissue regeneration, and in this study it is shown that these conduits can also act as a reservoir for sustained gene delivery. Either a G-luciferase marker gene or a neurotrophin-3-encoding gene, complexed to a non-viral, cyclized, PEGylated transfection vector, was loaded within a multichannel collagen conduit. The complexed genes were then released in a controlled fashion using a dual release system both in vitro and in vivo. For evaluation of their biological performance, the loaded conduits were implanted into the completely transected rat thoracic spinal cord (T8-T10). Aligned axon regeneration through the channels of conduits was observed one month post-surgery. The conduits delivering neurotrophin-3 polyplexes resulted in significantly increased neurotrophin-3 levels in the surrounding tissue and a statistically higher number of regenerated axons versus the control conduits (P<0.05). This study suggests that collagen neural conduits delivering a highly effective non-viral therapeutic gene may hold promise for repair of the injured spinal cord.
    背景与目标: : 旨在通过增强引导的轴突生长来改善轴突再生的功能化生物材料支架为修复脊髓损伤提供了一种有前途的方法。胶原神经导管为神经组织再生提供了结构指导,在这项研究中表明,这些导管也可以作为持续基因传递的储库。将与非病毒、环化、聚乙二醇化转染载体复合的G-荧光素酶标记基因或neurotrophin-3-encoding基因装载在多通道胶原导管内。然后使用体外和体内双重释放系统以受控方式释放复合基因。为了评估其生物学性能,将加载的导管植入完全横断的大鼠胸脊髓 (T8-T10) 中。术后一个月观察到通过导管通道对齐的轴突再生。递送neurotrophin-3多链体的导管导致周围组织中的neurotrophin-3水平显著增加,并且与对照导管相比具有统计学上更高数量的再生轴突 (P<0.05)。这项研究表明,提供高效非病毒治疗基因的胶原蛋白神经导管可能有望修复受伤的脊髓。
  • 【突变胶原蛋白I基因的转录是成牙本质细胞和成骨细胞分化的细胞类型和阶段特异性标记。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Schwarz M,Harbers K,Kratochwil K
    BACKGROUND & AIMS: :The Mov13 allele of the mouse alpha 1(I) collagen gene carries a retroviral insert in its first intron and had been reported to be transcriptionally silent. We have recently shown, however, that this mutant gene is expressed in odontoblasts of transplanted teeth derived from homozygous and heterozygous carrier embryos. The expression of the Mov13 allele has now been followed throughout in vivo development of mandibular teeth and bone in heterozygous animals, by in situ hybridization with a probe that specifically recognizes transcripts of the mutant gene. We show that the onset of its transcription precisely coincides with the final differentiation of odontoblasts and the onset of dentinogenesis, i.e. on day E16 for the incisor and at birth for the first molar. The mutant allele is also transcribed in osteoblasts of mandibular bone, again starting precisely with the onset of osteogenesis (day E13/14). No other cells were seen to transcribe the mutant gene. By these criteria, transcription of the Mov13 allele constitutes a true differentiation marker for odontoblasts and osteoblasts. Expression of the mutant allele in these two specialized cell types, in contrast to its transcriptional block in all other mesodermal cells ('fibroblasts'), suggests tissue-specific differences in the regulation of the alpha 1(I) collagen gene.
    背景与目标: : 小鼠 α1 (I) 胶原蛋白基因的Mov13等位基因在其第一个内含子中带有逆转录病毒插入物,据报道在转录上是沉默的。然而,我们最近表明,该突变基因在纯合和杂合载体胚胎衍生的移植牙齿的成牙本质细胞中表达。现在,通过与特异性识别突变基因转录本的探针进行原位杂交,在杂合子动物的下颌牙齿和骨骼的体内发育过程中,已经跟踪了Mov13等位基因的表达。我们表明,其转录的开始恰好与成牙本质细胞的最终分化和牙本质发生的开始相吻合,即在门牙的E16天和第一磨牙的出生时。突变等位基因也在下颌骨的成骨细胞中转录,再次从成骨的开始开始 (第E13/14天)。未见其他细胞转录突变基因。根据这些标准,Mov13等位基因的转录构成了成牙本质细胞和成骨细胞的真正分化标记。突变等位基因在这两种特殊细胞类型中的表达,与其在所有其他中胚层细胞 (“成纤维细胞”) 中的转录阻滞相反,表明 α1 (I) 胶原蛋白基因调控的组织特异性差异。
  • 【鉴定Tspan9为新型血小板四棘蛋白,胶原蛋白受体GPVI为四棘蛋白微区的组成部分。】 复制标题 收藏 收藏
    DOI:10.1042/BJ20081126 复制DOI
    作者列表:Protty MB,Watkins NA,Colombo D,Thomas SG,Heath VL,Herbert JM,Bicknell R,Senis YA,Ashman LK,Berditchevski F,Ouwehand WH,Watson SP,Tomlinson MG
    BACKGROUND & AIMS: :Platelets are essential for wound healing and inflammatory processes, but can also play a deleterious role by causing heart attack and stroke. Normal platelet activation is dependent on tetraspanins, a superfamily of glycoproteins that function as 'organisers' of cell membranes by recruiting other receptors and signalling proteins into tetraspanin-enriched microdomains. However, our understanding of how tetraspanin microdomains regulate platelets is hindered by the fact that only four of the 33 mammalian tetraspanins have been identified in platelets. This is because of a lack of antibodies to most tetraspanins and difficulties in measuring mRNA, due to low levels in this anucleate cell. To identify potentially platelet-expressed tetraspanins, mRNA was measured in their nucleated progenitor cell, the megakaryocyte, using serial analysis of gene expression and DNA microarrays. Amongst 19 tetraspanins identified in megakaryocytes, Tspan9, a previously uncharacterized tetraspanin, was relatively specific to these cells. Through generating the first Tspan9 antibodies, Tspan9 expression was found to be tightly regulated in platelets. The relative levels of CD9, CD151, Tspan9 and CD63 were 100, 14, 6 and 2 respectively. Since CD9 was expressed at 49000 cell surface copies per platelet, this suggested a copy number of 2800 Tspan9 molecules. Finally, Tspan9 was shown to be a component of tetraspanin microdomains that included the collagen receptor GPVI (glycoprotein VI) and integrin alpha6beta1, but not the von Willebrand receptor GPIbalpha or the integrins alphaIIbbeta3 or alpha2beta1. These findings suggest a role for Tspan9 in regulating platelet function in concert with other platelet tetraspanins and their associated proteins.
    背景与目标: 血小板对伤口愈合和炎症过程至关重要,但也可能通过引起心脏病发作和中风而发挥有害作用。正常的血小板活化依赖于tetaspanins,tetaspanins是一种糖蛋白的超家族,通过将其他受体和信号蛋白募集到富含tetaspanin的微域中而充当细胞膜的 “组织者”。但是,由于在血小板中仅鉴定了33种哺乳动物的四氮平蛋白中的四种,因此阻碍了我们对四氮平蛋白微结构域如何调节血小板的理解。这是因为缺乏针对大多数四棘蛋白的抗体,并且由于该无核细胞中的低水平而难以测量mRNA。为了鉴定潜在的血小板表达的四棘蛋白,使用基因表达和DNA微阵列的系列分析来测量其有核祖细胞 (巨核细胞) 中的mRNA。在巨核细胞中鉴定出的19种四棘蛋白中,Tspan9 (以前未鉴定的四棘蛋白) 对这些细胞相对特异。通过产生第一个Tspan9抗体,发现Tspan9表达在血小板中受到严格调节。CD9、CD151、Tspan9和CD63的相对水平分别为100、14、6和2。由于CD9以每血小板49000个细胞表面拷贝表达,这提示了2800个Tspan9分子的拷贝数。最后,Tspan9被证明是四棘蛋白微结构域的组成部分,其中包括胶原蛋白受体GPVI (糖蛋白VI) 和整联蛋白alpha6beta1,但不包括von Willebrand受体GPIbalpha或整联蛋白alphaIIbbeta3或alpha2beta1。这些发现表明Tspan9与其他血小板四aspanins及其相关蛋白协同调节血小板功能。

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