更新于：2024-11-01

PLG x DNase I

更新于：2024-11-01

基本信息

关联

项与 PLG x DNase I 相关的药物

Streptokinase/streptodornase

靶点

DNase I x PLG

作用机制

DNase I刺激剂 [+1]

在研机构

Hanmi Pharmaceutical Co., Ltd.

原研机构

Hanmi Pharmaceutical Co., Ltd.

在研适应症

急性支气管炎

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期1800-01-20

项与 PLG x DNase I 相关的临床试验

NCT04252963 / Unknown status临床4期

Double-blind, Randomized, Placebo Controlled, Multicenter, Phase IV Clinical Trial to Assess the Efficacy and Safety of MUCOLASE Tablet (Streptokinase • Streptodornase) in Patients With Acute Upper Respiratory Infection or Acute Bronchitis

A phase 4 study to evaluate efficacy and safety of MUCOLASE tablet (streptokinase • streptodornase)

开始日期2018-11-02

申办/合作机构

Hanmi Pharmaceutical Co., Ltd.

100 项与 PLG x DNase I 相关的临床结果

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100 项与 PLG x DNase I 相关的转化医学

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0 项与 PLG x DNase I 相关的专利（医药）

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项与 PLG x DNase I 相关的文献（医药）

2009-02-01·The FEBS Journal3区 · 生物学

Murine serum nucleases – contrasting effects of plasmin and heparin on the activities of DNase1 and DNase1‐like 3 (DNase1l3)

3区 · 生物学

Article

作者: Thomas Klöckl ; Hans G. Mannherz ; Jamal Mezrhab ; Sebastian Ludwig ; Markus Napirei

DNase1 is regarded as the major serum nuclease; however, a systematic investigation into the presence of additional serum nuclease activities is lacking. We have demonstrated directly that serum contains DNase1‐like 3 (DNase1l3) in addition to DNase1 by an improved denaturing SDS‐PAGE zymography method and anti‐murine DNase1l3 immunoblotting. Using DNA degradation assays, we compared the activities of recombinant murine DNase1 and DNase1l3 (rmDNase1, rmDNase1l3) with the serum of wild‐type and DNase1 knockout mice. Serum and rmDNase1 degrade chromatin effectively only in cooperation with serine proteases, such as plasmin or thrombin, which remove DNA‐bound proteins. This can be mimicked by the addition of heparin, which displaces histones from chromatin. In contrast, serum and rmDNase1l3 degrade chromatin without proteolytic help and are directly inhibited by heparin and proteolysis by plasmin. In previous studies, serum DNase1l3 escaped detection because of its sensitivity to proteolysis by plasmin after activation of the plasminogen system in the DNA degradation assays. In contrast, DNase1 is resistant to plasmin, probably as a result of its di‐N‐glycosylation, which is lacking in DNase1l3. Our data demonstrate that secreted rmDNase1 and murine parotid DNase1 are mixtures of three different di‐N‐glycosylated molecules containing two high‐mannose, two complex N‐glycans or one high‐mannose and one complex N‐glycan moiety. In summary, serum contains two nucleases, DNase1 and DNase1l3, which may substitute or cooperate with each other during DNA degradation, providing effective clearance after exposure or release from dying cells.

2004-06-01·Arthritis & Rheumatism

Chromatin breakdown during necrosis by serum Dnase1 and the plasminogen system

Article

作者: Hans Georg Mannherz ; Swantje Wulf ; Markus Napirei

AbstractObjectiveDnase1‐deficient mice with the 129 × C57BL/6 genetic background develop symptoms of systemic lupus erythematosus, such as high titers of antinuclear autoantibodies directed against nucleosomes. In this study we analyzed a potential molecular pathomechanism leading to this autoimmunity, by exploring the influence of extracellular Dnase1 present in serum on the breakdown of chromatin in necrotic cells in vitro.MethodsHuman breast adenocarcinoma cells (MCF‐7) and other cell lines were subjected to necrosis induced by hydrogen peroxide, streptolysin O, or freeze‐thawing. Subsequently, the influence of sera from Dnase1‐deficient and wild‐type mice as well as the influence of purified enzymes present in the culture medium on the process of necrotic chromatin breakdown was investigated.ResultsNecrotic chromatin breakdown resembled apoptotic DNA laddering and was catalyzed by serum Dnase1 in conjunction with plasmin. During necrosis, Dnase1 and plasminogen penetrated the cell and accumulated in the cytoplasm and nucleus. Plasminogen bound to the cytoskeleton and nuclear structures, was activated to plasmin by either tissue‐type or urokinase‐type plasminogen activator, and degraded histone H1, thereby facilitating internucleosomal DNA cleavage by Dnase1.ConclusionOur results suggest that serum Dnase1 in cooperation with the plasminogen system guarantees a fast and effective breakdown of chromatin during necrosis by the combined cleavage of DNA as well as of DNA binding proteins. The failure of such a clearance mechanism might lead to antinuclear autoimmunity similar to that observed in the Dnase1‐deficient mouse.

Frontiers in Immunology2区 · 医学

Deoxyribonuclease 1-Mediated Clearance of Circulating Chromatin Prevents From Immune Cell Activation and Pro-inflammatory Cytokine Production, a Phenomenon Amplified by Low Trap1 Activity: Consequences for Systemic Lupus Erythematosus

2区 · 医学

ArticleOA

作者: Breckler, Magali ; Rammensee, Hans-Georg ; Erbacher, Annika ; Mannherz, Hans Georg ; Napirei, Markus ; Hervé, Roxane ; Lemeiter, Delphine ; Decker, Patrice ; Felux, Jasmin

Increased concentrations of circulating chromatin, especially oligo-nucleosomes, are observed in sepsis, cancer and some inflammatory autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, circulating nucleosomes mainly result from increased apoptosis and decreased clearance of apoptotic cells. Once released, nucleosomes behave both as an autoantigen and as a damage-associated molecular pattern (DAMP) by activating several immune cells, especially pro-inflammatory cells. Deoxyribonuclease 1 (DNase1) is a major serum nuclease whose activity is decreased in mouse and human lupus. Likewise, the mitochondrial chaperone tumor necrosis factor (TNF) receptor-associated protein-1 (Trap1) protects against oxidative stress, which is increased in SLE. Here, using wild type, DNase1-deficient and DNase1/Trap1-deficient mice, we demonstrate that DNase1 is a major serum nuclease involved in chromatin degradation, especially when the plasminogen system is activated.In vitrodegradation assays show that chromatin digestion is strongly impaired in serum from DNase1/Trap1-deficient mice as compared to wild type mice.In vivo, after injection of purified chromatin, clearance of circulating chromatin is delayed in DNase1/Trap1-deficient mice in comparison to wild type mice. Since defective chromatin clearance may lead to chromatin deposition in tissues and subsequent immune cell activation, spleen cells were stimulatedin vitrowith chromatin. Splenocytes were activated by chromatin, as shown by interleukin (IL)-12 secretion and CD69 up-regulation. Moreover, cell activation was exacerbated when Trap1 is deficient. Importantly, we also show that cytokines involved in lupus pathogenesis down-regulate Trap1 expression in splenocytes. Therefore, combined low activities of both DNase1 and Trap1 lead to an impaired degradation of chromatinin vitro, delayed chromatin clearancein vivoand enhanced activation of immune cells. This situation may be encountered especially, but not exclusively, in SLE by the negative action of cytokines on Trap1 expression.