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Alternative complement pathway

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https://www.readbyqxmd.com/read/29237166/kallikrein-cleaves-c3-and-activates-complement
#1
Sarah Irmscher, Nadia Döring, Luke D Halder, Emeraldo A H Jo, Isabell Kopka, Christine Dunker, Ilse D Jacobsen, Shanshan Luo, Hortense Slevogt, Stefan Lorkowski, Niklas Beyersdorf, Peter F Zipfel, Christine Skerka
The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein-kinin, the coagulation, and the fibrinolytic systems. Previous work shows that the contact system also activates complement, and that plasma enzymes like kallikrein, plasmin, thrombin, and FXII are involved in the activation process. Here, we show for the first time that kallikrein cleaves the central complement component C3 directly to yield active components C3b and C3a...
December 14, 2017: Journal of Innate Immunity
https://www.readbyqxmd.com/read/29234687/delivery-of-cr2-fh-using-aav-vector-therapy-as-treatment-strategy-in-the-mouse-model-of-choroidal-neovascularization
#2
Gloriane Schnabolk, Nathaniel Parsons, Elisabeth Obert, Balasubramaniam Annamalai, Cecile Nasarre, Stephen Tomlinson, Alfred S Lewin, Bärbel Rohrer
Complement activation plays a significant role in age-related macular degeneration (AMD) pathogenesis, and polymorphisms interfering with factor H (fH) function, a complement alternative pathway (AP) inhibitor, are associated with increased AMD risk. We have previously validated an AP inhibitor, a fusion protein consisting of a complement receptor 2 fragment linked to the inhibitory domain of fH (CR2-fH) as an efficacious treatment for choroidal neovascularization (CNV) when delivered intravenously. Here we tested an alternative approach of AAV-mediated delivery (AAV5-VMD2-CR2-fH or AAV5-VMD2-mCherry) using subretinal delivery in C57BL/6J mice...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29233958/complement-c3a-signaling-facilitates-skeletal-muscle-regeneration-by-regulating-monocyte-function-and-trafficking
#3
Congcong Zhang, Chunxiao Wang, Yulin Li, Takashi Miwa, Chang Liu, Wei Cui, Wen-Chao Song, Jie Du
Regeneration of skeletal muscle following injury is accompanied by transient inflammation. Here we show that complement is activated in skeletal muscle injury and plays a key role during regeneration. Genetic ablation of complement C3 or its inactivation with Cobra Venom Factor (CVF) result in impaired muscle regeneration following cardiotoxin-induced injury in mice. The effect of complement in muscle regeneration is mediated by the alternative pathway and C3a receptor (C3aR) signaling, as deletion of Cfb, a key alternative pathway component, or C3aR leads to impaired regeneration and reduced monocyte/macrophage infiltration...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29230019/metabolic-profiling-of-zebrafish-danio-rerio-embryos-by-nmr-spectroscopy-reveals-multifaceted-toxicity-of-%C3%AE-methylamino-l-alanine-bmaa
#4
Upasana Roy, Laura Conklin, Jürgen Schiller, Jörg Matysik, John P Berry, A Alia
β-methylamino-L-alanine (BMAA) has been linked to several interrelated neurodegenerative diseases. Despite considerable research, specific contributions of BMAA toxicity to neurodegenerative diseases remain to be fully resolved. In the present study, we utilized state-of-the-art high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR), applied to intact zebrafish (Danio rerio) embryos, as a model of vertebrate development, to elucidate changes in metabolic profiles associated with BMAA exposure...
December 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29218045/factor-h-c-terminal-domains-are-critical-for-regulation-of-platelet-granulocyte-aggregate-formation
#5
Adam Z Blatt, Gurpanna Saggu, Claudio Cortes, Andrew P Herbert, David Kavanagh, Daniel Ricklin, John D Lambris, Viviana P Ferreira
Platelet/granulocyte aggregates (PGAs) increase thromboinflammation in the vasculature, and PGA formation is tightly controlled by the complement alternative pathway (AP) negative regulator, Factor H (FH). Mutations in FH are associated with the prothrombotic disease atypical hemolytic uremic syndrome (aHUS), yet it is unknown whether increased PGA formation contributes to the thrombosis seen in patients with aHUS. Here, flow cytometry assays were used to evaluate the effects of aHUS-related mutations on FH regulation of PGA formation and characterize the mechanism...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29214442/shiga-toxin-triggers-endothelial-and-podocyte-injury-the-role-of-complement-activation
#6
REVIEW
Carlamaria Zoja, Simona Buelli, Marina Morigi
Shiga toxin (Stx)-producing Escherichia coli (STEC) is the offending agent in post-diarrhea-associated hemolytic uremic syndrome (HUS), a disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney failure, with thrombi occluding the renal microvasculature. Endothelial dysfunction has been recognized as the trigger event in the development of microangiopathic processes. Glomerular endothelial cells are susceptible to the toxic effects of Stxs that, via nuclear factor kappa B (NF-κB) activation, induce the expression of genes encoding for adhesion molecules and chemokines, culminating in leukocyte adhesion and platelet thrombus formation on the activated endothelium...
December 6, 2017: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/29212897/genetic-variants-contributing-to-circulating-matrix-metalloproteinase-8-levels-and-their-association-with-cardiovascular-diseases-a-genome-wide-analysis
#7
Aino Salminen, Efthymia Vlachopoulou, Aki S Havulinna, Taina Tervahartiala, Wolfgang Sattler, Marja-Liisa Lokki, Markku S Nieminen, Markus Perola, Veikko Salomaa, Juha Sinisalo, Seppo Meri, Timo Sorsa, Pirkko J Pussinen
BACKGROUND: Matrix metalloproteinase 8 (MMP-8) is a proinflammatory enzyme expressed mainly by neutrophils. Elevated serum and plasma concentrations of MMP-8 are associated with the risk for and outcome of cardiovascular diseases (CVDs). The origin of circulating MMP-8 is not completely clear. METHODS AND RESULTS: We performed a genome-wide association study of serum MMP-8 levels in 2 populations comprising altogether 6049 individuals. Moreover, we studied whether MMP-8-associated variants are linked to increased risk of CVDs and overall mortality in >20 000 subjects...
December 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/29208412/impact-of-the-surface-charge-of-polydiacetylene-micelles-on-their-interaction-with-human-innate-immune-protein-c1q-and-the-complement-system
#8
Nicole M Thielens, Agathe Belime, Edmond Gravel, Sarah Ancelet, Charlotte Caneiro, Eric Doris, Wai Li Ling
Polydiacetylene (pDA) micelles have been demonstrated to be effective drug carriers for cancer therapy in mouse model. However, little is known about their interaction with the human complement system, which constitutes an important part of the innate immune system and can cause severe hypersensitivity reactions. Herein, we investigate the influence of micelle surface charge on the binding of complement protein C1q, the target recognition unit that activates the classical complement pathway and performs a range of other important physiological functions...
December 2, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/29208248/kidney-diseases-associated-with-alternative-complement-pathway-dysregulation-and-potential-treatment-options
#9
REVIEW
Prateek Sanghera, Mythili Ghanta, Fatih Ozay, Venkatesh K Ariyamuthu, Bekir Tanriover
Atypical hemolytic uremic syndrome and C3 glomerulopathy (dense deposit disease and C3 glomerulonephritis) are characterized as inappropriate activation of the alternative complement pathway. Genetic mutations affecting the alternative complement pathway regulating proteins (complement factor H, I, membrane cofactor protein and complement factor H-related proteins) and triggers (such as infection, surgery, pregnancy and autoimmune disease flares) result in the clinical manifestation of these diseases. A decade ago, prognosis of these disease states was quite poor, with most patients developing end-stage renal disease...
December 2017: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/29203414/complement-activation-in-vitro-and-reactogenicity-of-low-molecular-weight-dextran-coated-spions-in-the-pig-carpa-model-correlation-with-physicochemical-features-and-clinical-information
#10
Tamás Fülöp, Réka Nemes, Tamás Mészáros, Rudolf Urbanics, Robbert Jan Kok, Joshua A Jackman, Namjoon Cho, Gert Storm, János Szebeni
The unique magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) have led to their increasing use in drug delivery and imaging applications. Some polymer-coated SPIONs, however, share with many other nanoparticles the potential of causing hypersensitivity reactions known as complement (C) activation-related pseudoallergy (CARPA). In order to explore the roles of iron core composition and particle surface coating in SPION-induced CARPA, we measured C activation by 6 different SPIONs in a human serum that is known to react to nanoparticles (NPs) with strong C activation...
December 1, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29193757/effects-of-the-consumption-of-milk-biofortified-with-selenium-vitamin-e-and-different-fatty-acid-profile-on-immune-response-in-the-elderly
#11
Karina Pfrimer, Eduardo Ferriolli, Paula Lumy Takeuchi, Márcia Msv Salles, Arlindo Saran-Netto, Marcus A Zanetti, Luiz C Roma-Junior, Camila Bitu Moreno Braga, Fernanda A Domenici, Yara Ml Valim, Adriana Bp Paschoalato, Larissa F Marchi, Ana Ecs Azzolini, Eduardo A Donadi, Edson Martinez, Helio Vannucchi
SCOPE: Nutrition is a major contributing factor for immunocompetence. The aim was to assess the immune status of older after consuming a milk produced by lactating cows fed with one of the following diets: control diet(C), C+vitaminE+selenium(C+A), C+sunfloweroil(C+O), orC+sunflower oil+vitaminE+selenium(A+O). METHODS AND RESULTS: 60elderly received one of these biofortified milks during 12weeks. Immune response was assessed by measurement of the expression of COX-1,2, MCP-1, PPAR(δ,α and β/δ)genes, neutrophil production of oxygen reactive species induced by immune complexes, neutrophil phagocytosis and lytic activity of the alternative pathway of the complement system and cytokine levels...
November 28, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/29190743/crystal-structure-of-a-tripartite-complex-between-c3dg-c-terminal-domains-of-factor-h-and-ospe-of-borrelia-burgdorferi
#12
Robert Kolodziejczyk, Kornelia M Mikula, Tommi Kotila, Vincent L G Postis, T Sakari Jokiranta, Adrian Goldman, Taru Meri
Complement is an important part of innate immunity. The alternative pathway of complement is activated when the main opsonin, C3b coats non-protected surfaces leading to opsonisation, phagocytosis and cell lysis. The alternative pathway is tightly controlled to prevent autoactivation towards host cells. The main regulator of the alternative pathway is factor H (FH), a soluble glycoprotein that terminates complement activation in multiple ways. FH recognizes host cell surfaces via domains 19-20 (FH19-20). All microbes including Borrelia burgdorferi, the causative agent of Lyme borreliosis, must evade complement activation to allow the infectious agent to survive in its host...
2017: PloS One
https://www.readbyqxmd.com/read/29187587/modulation-of-the-alternative-pathway-of-complement-by-murine-factor-h-related-proteins
#13
Alexandra H Antonioli, Janice White, Frances Crawford, Brandon Renner, Kevin J Marchbank, Jonathan P Hannan, Joshua M Thurman, Philippa Marrack, V Michael Holers
Factor H (FH) is a key alternative pathway regulator that controls complement activation both in the fluid phase and on specific cell surfaces, thus allowing the innate immune response to discriminate between self and foreign pathogens. However, the interrelationships between FH and a group of closely related molecules, designated the FH-related (FHR) proteins, are currently not well understood. Whereas some studies have suggested that human FHR proteins possess complement regulatory abilities, recent studies have shown that FHR proteins are potent deregulators...
November 29, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29174517/longitudinal-associations-of-the-alternative-and-terminal-pathways-of-complement-activation-with-adiposity-the-codam-study
#14
Ying Xin, Elisabeth Hertle, Carla J H van der Kallen, Casper G Schalkwijk, Coen D A Stehouwer, Marleen M J van Greevenbroek
OBJECTIVE: To investigate longitudinal associations of components of the alternative (C3, C3a, Bb, factor D [FD], factor H [FH], and properdin) and the terminal complement pathway (C5a, sC5b-9) with adiposity. METHODS: A prospective human cohort study (n=574 at baseline, n=489 after 7 years follow-up) was analyzed. Generalized estimating equations were used to evaluate the longitudinal associations between complement components (standardized values) and adiposity (main outcome BMI [kg/m2])...
November 21, 2017: Obesity Research & Clinical Practice
https://www.readbyqxmd.com/read/29167939/the-properdin-pathway-an-alternative-activation-pathway-or-a-critical-amplification-loop-for-c3-and-c5-activation
#15
REVIEW
Richard A Harrison
This review is not intended to cover in detail all aspects of the discovery and evolution of our understanding of the "alternative pathway" of complement activation, there are many excellent reviews that do this (see Fearon (CRC Crit Rev Immunol 1:1-32, 1979), Pangburn and Müller-Eberhard (Springer Semin Immunopathol 7:163-192, 1984)), but instead to give sufficient background for current concepts to be put in context. The prevailing textbook view, of components having a primary role as an alternative "pathway" for C3 activation, is challenged, with an argument developed for the primary role of the system being that of providing a surface-dependent amplification loop for both C3 and C5 activation...
November 22, 2017: Seminars in Immunopathology
https://www.readbyqxmd.com/read/29166869/multimodal-imaging-of-retinal-pigment-epithelial-detachments-in-patients-with-c3-glomerulopathy-case-report-and-review-of-the-literature
#16
Valeria Kheir, Ali Dirani, Matthieu Halfon, Jean-Pierre Venetz, Georges Halabi, Yan Guex-Crosier
BACKGROUND: To describe the optical coherence tomography angiograhy (OCTA) of drusenoid pigment epithelial detachments (PEDs) in a woman affected by Complement 3 (C3) glomerulopathy, which represents a spectrum of glomerular diseases characterized on fluorescent microscopy by C3 accumulation with absent, or scanty, immunoglobulin deposits. It is due to acquired or genetically defective alternative pathway control and is generally associated with drusen-like deposits in Bruch's membrane, as well as choriocapillaris...
November 22, 2017: BMC Ophthalmology
https://www.readbyqxmd.com/read/29157988/de-novo-thrombotic-microangiopathy-after-kidney-transplantation
#17
REVIEW
Neetika Garg, Helmut G Rennke, Martha Pavlakis, Kambiz Zandi-Nejad
Thrombotic microangiopathy (TMA) is a serious complication of transplantation that adversely affects kidney transplant recipient and allograft survival. Post-transplant TMA is usually classified into two categories: 1) recurrent TMA and 2) de novo TMA. Atypical hemolytic uremic syndrome (aHUS) resulting from dysregulation and over-activation of the alternate complement pathway is a rare disease but the most common diagnosis associated with recurrence in the allografts. De novo TMA, on the other hand, represents an overwhelming majority of the cases of post-transplant TMA and is a substantially more heterogeneous entity than recurrent aHUS...
November 4, 2017: Transplantation Reviews
https://www.readbyqxmd.com/read/29155837/reduced-order-modeling-and-analysis-of-the-human-complement-system
#18
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/29151252/dominant-c3-glomerulopathy-new-roles-for-an-old-actor-in-renal-pathology
#19
REVIEW
Nicola Pirozzi, Antonella Stoppacciaro, Paolo Menè
Recently, a number of reports have described dominant C3 deposits in renal biopsies of patients with infection-related glomerulonephritis (GN). While acute post-infectious GN and membranoproliferative GN are commonly characterized by immune deposits containing C3 and/or C4, the absence of immunoglobulin (Ig) and/or immune complexes at light or electron microscopy is a rather unusual observation. Dominant C3 deposition is believed to result from the alternative pathway of complement activation via the C3bBb "tickover" convertase...
November 18, 2017: Journal of Nephrology
https://www.readbyqxmd.com/read/29150548/defense-against-reactive-carbonyl-species-involves-at-least-three-subcellular-compartments-where-individual-components-of-the-system-respond-to-cellular-sugar-status
#20
Jessica Schmitz, Isabell C Dittmar, Jörn D Brockmann, Marc Schmidt, Meike Hüdig, Alessandro W Rossoni, Veronica G Maurino
Methylglyoxal (MGO) and glyoxal (GO) are toxic reactive carbonyl species generated as by-products of glycolysis. The pre-emption pathway for detoxification of these products, the glyoxalase (GLX) system, involves two consecutive reactions catalyzed by GLXI and GLXII. In Arabidopsis thaliana, the GLX system is encoded by three homologs of GLXI and three homologs of GLXII, from which several predicted GLXI and GLXII isoforms can be derived through alternative splicing. We identified the physiologically relevant splice forms using sequencing data and demonstrated that the resulting isoforms have different subcellular localizations...
November 17, 2017: Plant Cell
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