作者: Maasch, Christian ; Kellermann, Ute ; Klussmann, Sven ; Suttorp, Norbert ; Ahnert, Peter ; Vater, Axel ; Müller-Redetzky, Holger ; Gutbier, Birgitt ; Scholz, Markus ; Hellwig, Katharina ; Hoehlig, Kai ; Wienhold, Sandra-Maria ; Letsiou, Eleftheria ; Firsching, Theresa C. ; Witzenrath, Martin ; Reppe, Katrin ; Hoppe, Judith ; Tschernig, Thomas ; Lienau, Jasmin

AbstractBackgroundCommunity-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis.MethodsThe authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing l-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13).ResultsIn hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 ± 0.89 vs. 3.29 ± 2.34, mean ± SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 ± 1.17 vs. 7.31 ± 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury.ConclusionsSystemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

2018-08-01·Nephrology Dialysis Transplantation2区 · 医学

Complement C5a inhibition moderates lipid metabolism and reduces tubulointerstitial fibrosis in diabetic nephropathy

2区 · 医学

Article

作者: Sacks, Steven H ; Tang, Sydney C W ; Li, Rui Xi ; Wu, Hao Jia ; Chan, Kam Wa ; Yiu, Wai Han ; Wong, Dickson W L ; Chan, Loretta Y Y ; Lai, Kar Neng ; Leung, Joseph C K ; Zhou, Wuding

BackgroundComplement C5 mediates pro-inflammatory responses in many immune-related renal diseases. Given that the C5a level is elevated in diabetes, we investigated whether activation of C5a/C5aR signalling plays a pathogenic role in diabetic nephropathy (DN) and the therapeutic potential of C5a inhibition for renal fibrosis.MethodsHuman renal biopsies from patients with DN and control subjects were used for immunohistochemical staining of complement C5 components. Renal function and tubulointerstitial injury were compared between db/m mice, vehicle-treated mice and C5a inhibitor-treated db/db mice. A cell culture model of tubule epithelial cells (HK-2) was used to demonstrate the effect of C5a on the renal fibrotic pathway.ResultsIncreased levels of C5a, but not of its receptor C5aR, were detected in renal tubules from patients with DN. The intensity of C5a staining was positively correlated with the progression of the disease. In db/db mice, administration of a novel C5a inhibitor, NOX-D21, reduced the serum triglyceride level and attenuated the upregulation of diacylglycerolacyltransferase-1 and sterol-regulatory element binding protein-1 expression and lipid accumulation in diabetic kidney. NOX-D21-treated diabetic mice also had reduced serum blood urea nitrogen and creatinine levels with less glomerular and tubulointerstitial damage. Renal transforming growth factor beta 1 (TGF-β1), fibronectin and collagen type I expressions were reduced by NOX-D21. In HK-2 cells, C5a stimulated TGF-β production through the activation of the PI3K/Akt signalling pathway.ConclusionsBlockade of C5a signalling by NOX-D21 moderates altered lipid metabolism in diabetes and improved tubulointerstitial fibrosis by reduction of lipid accumulation and TGF-β-driven fibrosis in diabetic kidney.

2018-01-01·Analytical and Bioanalytical Chemistry2区 · 化学

Synthesis of multirecognition magnetic molecularly imprinted polymer by atom transfer radical polymerization and its application in magnetic solid-phase extraction

2区 · 化学

Article

作者: Dong, Lin-Yi ; Xu, Liang ; Lan, Yao-Han ; Liu, Hao-Long ; Dong, Qian ; Wang, Xian-Hua ; Chi, Shuai-Shuai ; Zheng, Chao ; Peng, Chao ; Kong, Xiang-Jin

In this work, we reported an effective method for the synthesis of a multirecognition magnetic molecularly imprinted polymer (MMIP) with atom transfer radical polymerization (ATRP), using 2,4-diamino-6-methyl-1,3,5-triazine as pseudo-template. The resulting MMIP was characterized in detail by Fourier transform-infrared (FT-IR) spectra, scanning electron microscopy (SEM), thermogravimetic analysis (TGA), and vibrating sample magnetometry (VSM). These results indicated the successful synthesis of MMIP with sufficient thermal stability and magnetic properties. The adsorption experiments were carried out to evaluate the specific selectivity of MMIP related to the spatial structure of target molecules. The MMIP exhibited multirecognition ability and excellent binding capability for melamine (MEL), cyromazine (CYR), triamterene (TAT), diaveridine (DVD), and trimethoprim (TME), and the apparent maximum number of binding sites (Q _max) was 77.5, 75.2, 72.5, 69.9, and 70.4 μmol g^-1, respectively. The multirecognition MMIP not only possessed adequate magnetic responsiveness for fast separation but also avoided the risk of template leakage on trace component analysis. Therefore, it was suitable for serving as a magnetic solid-phase extraction (MSPE) adsorbent. MSPE coupled with high-performance liquid chromatography analysis was applied to enrich and separate five target molecules from three samples. Recoveries for all target molecules ranged from 81.6 to 91.5% with relative standard deviations of no more than 4.1% (n = 3). Graphical abstract Multirecognition property of magnetic molecularly imprinted polymer prepared with pseudo template.

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床1期	德国	TME Pharma NV	-
疼痛	临床1期	德国	TME Pharma NV	-
杜氏肌营养不良症	临床前	德国	NOXXON Pharma AG	2017-05-01
杜氏肌营养不良症	临床前	日本	National Center of Neurology & Psychiatry	2017-05-01
糖尿病	临床前	德国	TME Pharma NV	-
炎症	临床前	德国	TME Pharma NV	-
肺炎	临床前	德国	TME Pharma NV	-
脓毒症	临床前	西班牙	University of Barcelona	-