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https://www.readbyqxmd.com/read/29156357/generation-of-complement-molecular-complex-c5b-9-c5b-9-in-response-to-poly-traumatic-hemorrhagic-shock-and-evaluation-of-c5-cleavage-inhibitors-in-non-human-primates
#1
R Madelaine Paredes, Sarah Reyna, Philip Vernon, Douglas K Tadaki, Jurandir J Dallelucca, Forest Sheppard
Severe trauma initiates a systemic inflammatory cascade and that involves early activation of complement and cleavage of C5 into C5a (anaphylatoxin) and C5b (C5b-9 membrane attack complex). We examined activation of C5 in non-human primate (NHP) models of hemorrhagic shock. Blood plasma concentrations of C5b-9 were significantly increased in NHPs in response to hemorrhage alone and were further increased with the addition of tissue trauma. The onset of increased C5 cleavage was accelerated in NHPs that experienced decompensated poly-traumatic hemorrhagic shock...
November 17, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29155837/reduced-order-modeling-and-analysis-of-the-human-complement-system
#2
Adithya Sagar, Wei Dai, Mason Minot, Rachel LeCover, Jeffrey D Varner
Complement is an important pathway in innate immunity, inflammation, and many disease processes. However, despite its importance, there are few validated mathematical models of complement activation. In this study, we developed an ensemble of experimentally validated reduced order complement models. We combined ordinary differential equations with logical rules to produce a compact yet predictive model of complement activation. The model, which described the lectin and alternative pathways, was an order of magnitude smaller than comparable models in the literature...
2017: PloS One
https://www.readbyqxmd.com/read/29155219/complement-anaphylatoxins-c3a-and-c5a-emerging-roles-in-cancer-progression-and-treatment
#3
REVIEW
Daniel Ajona, Sergio Ortiz-Espinosa, Ruben Pio
Recent insights into the role of complement anaphylatoxins C3a and C5a in cancer provide new opportunities for the development of innovative biomarkers and therapeutic strategies. These two complement activation products can maintain chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and increase the motility and metastatic potential of cancer cells. Still, the diverse heterogeneity of responses mediated by these peptides poses a challenge both to our understanding of the role played by these molecules in cancer progression and to the development of effective treatments...
November 16, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29154963/macrophage-scavenger-receptor-1-contributes-to-pathogenesis-of-fulminant-hepatitis-via-neutrophil-mediated-complement-activation
#4
Yuan Tang, Huifang Li, Junru Li, Yunzhi Liu, Yanli Li, Jing Zhou, Jia Zhou, Xiao Lu, Wei Zhao, Jinlin Hou, Xiang-Yang Wang, Zhengliang Chen, Daming Zuo
BACKGROUND & AIMS: The macrophage scavenger receptor 1 (Msr1, also called SRA)is a pattern recognition receptor primarily expressed on myeloid cells, playing an important role in the maintenance of immune homeostasis. Since MSR1 expression was up-regulated in the livers of patients with fulminant hepatitis (FH), we investigated the functional mechanism of Msr1 as related to FH pathogenesis. METHODS: Msr1-deficient (Msr1(-/-)) mice and their wild-type (WT) littermates were infected with mouse hepatitis virus strain-A59 (MHV-A59) to induce FH, and the levels of tissue damage, serum alanine aminotransferase (ALT), inflammatory cytokines and complement C5a were measured and compared...
November 14, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/29146705/complement-c3-is-a-novel-modulator-of-the-anti-fviii-immune-response
#5
Julie Rayes, Mathieu Ing, Sandrine Delignat, Ivan Peyron, Laurent Gilardin, Carl-Wilhelm Vogel, David C Fritzinger, Véronique Frémeaux-Bacchi, Srinivas V Kaveri, Lubka T Roumenina, Sébastien Lacroix-Desmazes
Development of neutralizing antibodies against therapeutic factor VIII (FVIII) is the most serious complication of the treatment of hemophilia A. Increasing evidence shows the multifactorial origin of the anti-FVIII immune response, combining both genetic and environmental factors. While a role for the complement system on innate as well as adaptive immunity has been documented, the implication of complement activation on the onset of the anti-FVIII immune response is unknown. Here, using in vitro assays for FVIII endocytosis by human monocyte-derived dendritic cells and presentation to T cells, as well as animal models of in vivo complement depletion, we show a novel role for complement C3 in enhancing the immune response against therapeutic FVIII...
November 16, 2017: Haematologica
https://www.readbyqxmd.com/read/29143341/a-toxicogenomics-approach-to-screen-chlorinated-flame-retardants-tris-2-chloroethyl-phosphate-and-tris-2-chloroisopropyl-phosphate-for-potential-health-effects
#6
Boris V Krivoshiev, Gerrit T S Beemster, Katrien Sprangers, Ronny Blust, Steven J Husson
Tris(2-chloroethyl) phosphate (TCEP) is a pervasive flame retardant that has been identified as a chemical of concern given its health effects and therefore its use has since been tightly regulated. Tris(2-chloroisopropyl) phosphate (TCIPP), an analogue of TCEP, is believed to be its replacement. However, compared to TCEP, little is known of the toxicological impacts of TCIPP. We used RNA sequencing as unbiased and sensitive tool to identify and compare effects on a transcriptome level of TCEP and TCIPP in the human hepatocellular carcinoma cell line, HepG2...
November 16, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/29141676/platelets-are-activated-in-anca-associated-vasculitis-via-thrombin-pars-pathway-and-can-activate-the-alternative-complement-pathway
#7
Di Miao, Dan-Yang Li, Min Chen, Ming-Hui Zhao
BACKGROUND: In this study, we investigated the mechanism of platelet activation in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), as well as the activation of the alternative complement pathway by platelets in AAV. METHODS: CD62P and platelet-leukocyte aggregates in AAV patients were tested by flow cytometry. Platelets were stimulated by plasma from active AAV patients. The effect of the thrombin-protease-activated receptors (PARs) pathway was evaluated by blocking thrombin or PAR1 antagonists...
November 15, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/29123963/blocking-c5ar-signaling-promotes-the-anti-tumor-efficacy-of-pd-1-pd-l1-blockade
#8
Haoran Zha, Xiao Han, Ying Zhu, Fei Yang, Yongsheng Li, Qijing Li, Bo Guo, Bo Zhu
Anti-PD-1/PD-L1 therapy has achieved great success in the clinic; however, only a small fraction of cancer patient benefit from PD-1/PD-L1 blockade therapy, and overcoming resistance to PD-1/PD-L1 blockade has thus become a primary priority. In this study, we demonstrated that administration of PD-1/PD-L1 antibodies resulted in the activation of the complement system and massive generation of C5a. Generation of C5a did not change the accumulation of MDSCs in either the tumor or spleen but enhanced their inhibitory potential...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29123203/respiratory-syncytial-virus-exacerbates-ova-mediated-asthma-in-mice-through-c5a-c5ar-regulating-cd4-t-cells-immune-responses
#9
Xinyue Hu, Xiaozhao Li, Chengping Hu, Ling Qin, Ruoxi He, Lisha Luo, Wei Tang, Juntao Feng
Asthma exacerbation could be induced by respiratory syncytial virus (RSV), and the underlying pathogenic mechanism is related to complement activation. Although complement might regulate CD4(+)T cells immune responses in asthma model, this regulation existed in RSV-induced asthma model remains incompletely characterrized. In this study, we assessed the contribution of C5a-C5aR to CD4(+)T cell immune responses in RSV-infected asthma mice. Female BALB/C mice were sensitized and challenged with ovalbumin (OVA) while treated with RSV infection and C5a receptor antagonist (C5aRA) during challenge period...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29121655/experimental-blunt-chest-trauma-induced-myocardial-inflammation-and-alteration-of-gap-junction-protein-connexin-43
#10
Miriam Kalbitz, Elisa Maria Amann, Belinda Bosch, Annette Palmer, Anke Schultze, Jochen Pressmar, Birte Weber, Martin Wepler, Florian Gebhard, Hubert Schrezenmeier, Rolf Brenner, Markus Huber-Lang
OBJECTIVE: Severe blunt chest trauma in humans is associated with high mortality rates. Whereas lung tissue damage and lung inflammation after blunt chest trauma have extensively been investigated, the traumatic and posttraumatic effects on the heart remain poorly understood. Therefore, the purpose of this study was to define cardiac injury patterns in an experimental blunt chest trauma model in rats. METHODS: Experimental blunt chest trauma was induced by a blast wave in rats, with subsequent analysis of its effects on the heart...
2017: PloS One
https://www.readbyqxmd.com/read/29118090/complement-activation-via-a-c3a-receptor-pathway-alters-cd4-t-lymphocytes-and-mediates-lung-cancer-progression
#11
Jeff W Kwak, Jennifer Laskowski, Howard Y Li, Maria V McSharry, Trisha R Sippel, Bonnie L Bullock, Amber M Johnson, Joanna M Poczobutt, Alexander J Neuwelt, Stephen P Malkoski, Mary C Weiser-Evans, John Lambris, Eric T Clambey, Joshua M Thurman, Raphael A Nemenoff
The complement cascade is a part of the innate immune system which acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/- mice), with tumors undetectable in many subjects...
November 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/29116124/monocytes-from-patients-with-primary-ciliary-dyskinesia-show-enhanced-inflammatory-properties-and-produce-higher-levels-of-pro-inflammatory-cytokines
#12
M Cockx, M Gouwy, P Ruytinx, I Lodewijckx, A Van Hout, S Knoops, N Pörtner, I Ronsse, L Vanbrabant, V Godding, K De Boeck, J Van Damme, M Boon, S Struyf
Patients with Primary Ciliary Dyskinesia (PCD) suffer from recurrent upper and lower airway infections due to defects in the cilia present on the respiratory epithelium. Since chronic inflammatory conditions can cause changes in innate immune responses, we investigated whether monocytes isolated from the peripheral blood of pediatric PCD patients respond differently to inflammatory stimuli, compared to monocytes from healthy children and adults. The receptor for C5a (C5aR) was upregulated in PCD, whereas expression levels of the leukocyte chemoattractant receptors CCR1, CCR2, CCR5, BLT1 and FPR1 on PCD monocytes were similar to those on monocytes from healthy individuals...
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29098911/targeted-treatments-for-hidradenitis-suppurativa-a-review-of-the-current-literature-and-ongoing-clinical-trials
#13
Melody Maarouf, Ashley K Clark, Dylan E Lee, Vivian Y Shi
PURPOSE: Targeted, immune-modulating drugs are at the forefront of therapy for HS, and a comprehensive clinical trial registry is needed to facilitate data pooling and clinical efficacy comparison. MATERIALS AND METHODS: A systematic review of the ClinicalTrials.gov database was searched for planned, in-progress, completed, or terminated trials investigating the effect of targeted biologic therapies for hidradenitis suppurativa (HS). When results of RCTs were not available, case reports or series were included...
November 10, 2017: Journal of Dermatological Treatment
https://www.readbyqxmd.com/read/29096100/layered-double-hydroxide-nanoparticles-impact-on-vascular-cells-blood-cells-and-the-complement-system
#14
Zi Gu, Shiyu Yan, Soshan Cheong, Zhenbang Cao, Huali Zuo, Anita C Thomas, Barbara E Rolfe, Zhi Ping Xu
The mounting interest in layered double hydroxide (LDH) nanoparticles as drug carriers and bio-imaging contrast agents makes biosafety evaluation of LDH essential. Considering the important role of blood circulation in bio-distribution of nanoparticles, the present work evaluated the impact of MgAl-LDHs on key components of the circulatory system, including vascular cells (vascular smooth muscle cells (SMCs) and endothelial cells (HUVECs)), red blood cells (RBCs), and complement activation. The results showed that LDH had no effects on SMCs and HUVECs at concentrations up to 500 and 10 µg/mL respectively, in terms of cell proliferation and viability...
October 19, 2017: Journal of Colloid and Interface Science
https://www.readbyqxmd.com/read/29078325/necroptosis-controls-net-generation-and-mediates-complement-activation-endothelial-damage-and-autoimmune-vasculitis
#15
Adrian Schreiber, Anthony Rousselle, Jan Ulrich Becker, Anne von Mässenhausen, Andreas Linkermann, Ralph Kettritz
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes life-threatening autoimmune diseases affecting every organ, including the kidneys, where they cause necrotizing crescentic glomerulonephritis. ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Better understanding of neutrophil-mediated AAV disease mechanisms may reveal novel treatment strategies. Here we report that ANCA induces neutrophil extracellular traps (NETs) via receptor-interacting protein kinase (RIPK) 1/3- and mixed-lineage kinase domain-like (MLKL)-dependent necroptosis...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29070810/complement-receptors-c5ar1-and-c5ar2-act-differentially-during-the-early-immune-response-after-bone-fracture-but-are-similarly-involved-in-bone-repair
#16
Anna Kovtun, Stephanie Bergdolt, Yvonne Hägele, Rebekka Matthes, John D Lambris, Markus Huber-Lang, Anita Ignatius
Severely injured patients frequently suffer compromised fracture healing because of systemic post-traumatic inflammation. An important trigger of the posttraumatic immune response is the complement anaphylatoxin C5a, which acts via two receptors, C5aR1 and C5aR2, expressed on immune and bone cells. The blockade of C5a-mediated inflammation during the early inflammatory phase was demonstrated to improve fracture healing after severe injury. However, the distinct roles of the two complement receptors C5aR1 and C5aR2 in bone has to date not been studied...
October 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29046976/the-complement-system-and-preeclampsia
#17
REVIEW
Jean F Regal, Richard M Burwick, Sherry D Fleming
PURPOSE OF REVIEW: Preeclampsia affects 3-4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed. RECENT FINDINGS: Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities and/or the maternal symptoms which characterize preeclampsia...
October 18, 2017: Current Hypertension Reports
https://www.readbyqxmd.com/read/29040213/importance-of-the-complement-alternative-pathway-in-serum-chemotactic-activity-during-sepsis
#18
Ganqiong Xu, Yan Feng, Dan Li, Qichang Zhou, Wei Chao, Lin Zou
Serum chemotactic activity is important in regulating neutrophil migration. The ability of neutrophils to migrate to infectious site is crucial for host effective pathogen control, but unregulated neutrophil activation can also cause tissue damage. During bacterial sepsis, the complement alternative pathway (AP) is massively activated in blood and tissues and reportedly contributes to sepsis pathogenesis. Complement factor B (FB) is an essential component of the AP activation. However, the impact of FB/AP activation on blood chemotactic activity during bacterial infection is unclear...
October 16, 2017: Shock
https://www.readbyqxmd.com/read/29036225/human-plasma-derived-c1-esterase-inhibitor-concentrate-has-limited-effect-on-house-dust-mite-induced-allergic-lung-inflammation-in-mice
#19
Ingrid Stroo, Jack Yang, Adam A Anas, J Daan de Boer, Gerard van Mierlo, Dorina Roem, Diana Wouters, Ruchira Engel, Joris J T H Roelofs, Cornelis van 't Veer, Tom van der Poll, Sacha Zeerleder
C1 esterase inhibitor (C1-INH) can inhibit multiple pathways (complement, contact-kinin, coagulation, and fibrinolysis) that are all implicated in the pathophysiology of asthma. We explored the effect of human plasma-derived C1-INH on allergic lung inflammation in a house dust mite (HDM) induced asthma mouse model by daily administration of C1-INH (15 U) during the challenge phase. NaCl and HDM exposed mice had comparable plasma C1-INH levels, while bronchoalveolar lavage fluid (BALF) levels were increased in HDM exposed mice coinciding with slightly reduced activation of complement (C5a)...
2017: PloS One
https://www.readbyqxmd.com/read/29031586/complement-c5a-c5ar-pathway-potentiates-the-pathogenesis-of%C3%A2-gastric-cancer-by-down-regulating-p21-expression
#20
Jian Chen, Gui-Qing Li, Li Zhang, Ming Tang, Xu Cao, Gui-Lian Xu, Yu-Zhang Wu
Although the complement C5a/C5aR pathway is suggested to play a critical role in tumor pathogenesis, the underlying mechanism has yet to be fully elucidated. In the present study, we found that in patients with gastric cancer in different clinical stages (from stageⅠto stage Ⅳ), both C5aR and p-PI3K/AKT levels were significantly higher in tumoral tissues than in adjacent non-tumoral tissues. In contrast, p21/p-p21 levels were significantly lower in tumoral tissues than in adjacent non-tumoral tissues. In vitro recombinant C5a administration remarkably promoted p-PI3K/p-AKT expression, but inhibited p21/p-p21 expression...
October 12, 2017: Cancer Letters
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