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Takayoshi Kaida, Hidetoshi Nitta, Yuki Kitano, Kensuke Yamamura, Kota Arima, Daisuke Izumi, Takaaki Higashi, Junji Kurashige, Katsunori Imai, Hiromitsu Hayashi, Masaaki Iwatsuki, Takatsugu Ishimoto, Daisuke Hashimoto, Yoichi Yamashita, Akira Chikamoto, Takahisa Imanura, Takatoshi Ishiko, Toru Beppu, Hideo Baba
PURPOSE: Anaphylatoxin C5a is a strong chemoattractant of the complement system that binds the C5a receptor (C5aR). The expression of C5aR is associated with poor prognosis in several cancers. However, the role of C5aR in gastric cancer (GC) is unknown. The aim of this study was to examine the role of C5aR on GC cell motility and invasion. EXPERIMENTAL DESIGN: The mechanism of invasion via C5aR was assessed by analyzing cytoskeletal rearrangement and RhoA activity after C5a treatment...
October 14, 2016: Oncotarget
Yu Ma, Cheng-Chao Ruan, Yu Zhang, Qian Ge, Qi-Hong Wu, Ling-Ran Kong, Ping-Jin Gao
OBJECTIVE: Women with preeclampsia (PE) display excessive activation of complement system. However, little is known about the detailed cellular and molecular mechanism of complement activation in the development of PE. Here, we hypothesized that whether complement C5a contributes to the onset of PE through its effect on trophoblasts. DESIGN AND METHOD: In this study, 23 women with established PE and 32 normotensive women were recruited. At entry, peripheral and central blood pressure and pulse wave velocity (PWV) were performed...
September 2016: Journal of Hypertension
Erika van der Maten, Cynthia M de Bont, Ronald de Groot, Marien I de Jonge, Jeroen D Langereis, Michiel van der Flier
Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population...
October 6, 2016: Cytokine
Bangqing Yuan, Fenlan Fu, Shaokuan Huang, Chuangan Lin, Guang Yang, Kunlong Ma, Hui Shi, Zhao Yang
Intracerebral hemorrhage (ICH) is a serious emergency with high mortality and morbidity. Up to date, a limited understanding of ICH pathogenesis is difficult to implement effective therapeutic strategy. Much evidence demonstrates that the complement cascade is activated after experimental ICH. However, the exact mechanism has not been well studied in ICH. In the current study, C57BL/6J mice were injected with autologous whole blood. C5a/C5aR levels, microglia infiltration, inflammatory cytokine, and fibrinogen-like protein 2 (Fgl-2) expression in the perihematomal region were analyzed following ICH...
October 5, 2016: Molecular Neurobiology
Shunsuke Tawara, Takumi Sakai, Osamu Matsuzaki
BACKGROUND: Thrombomodulin (TM) alfa, a recombinant human soluble TM, enhances activation of pro-carboxypeptidase B2 (pro-CPB2) by thrombin. Activated pro-CPB2 (CPB2) exerts anti-inflammatory and anti-fibrinolytic activities. Therefore, TM alfa may also have anti-inflammatory and anti-fibrinolytic effects through CPB2. However, these effects of TM alfa have not been elucidated. In the present study, we investigated the effects of TM alfa on inactivation of complement component C5a as an anti-inflammatory effect and prolongation of clot lysis time as an anti-fibrinolytic effect via CPB2 in vitro...
September 17, 2016: Thrombosis Research
Nathalie Niyonzima, Bente Halvorsen, Bjørnar Sporsheim, Peter Garred, Pål Aukrust, Tom Eirik Mollnes, Terje Espevik
In the host a diverse collection of endogenous danger signals is constantly generated consisting of waste material as protein aggregates or crystalline materials that are recognized and handled by soluble pattern recognition receptors and phagocytic cells of the innate immune system. These signals may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation...
September 28, 2016: Molecular Immunology
Hidetoshi Nitta, Takayuki Shimose, Yasunori Emi, Takahisa Imamura, Koji Ohnishi, Tetsuya Kusumoto, Manabu Yamamoto, Kengo Fukuzawa, Ikuo Takahashi, Hidefumi Higashi, Akihito Tsuji, Yoshito Akagi, Eiji Oki, Yoshihiko Maehara, Hideo Baba
The C5a receptor (C5aR) expressed in various types of cancers is involved in C5a-induced cancer cell invasion. However, its role in gastric cancer has not yet been fully elucidated. Therefore, we studied the clinical significance of C5aR expression in gastric cancer. The association of C5aR expression in gastric cancer, determined by immunostaining using the anti-C5aR antibody, with clinicopathological parameters and outcomes was evaluated in 148 patients. Further, the association of C5aR expression in liver metastatic sites with clinicopathological parameters was investigated in a separate cohort of 58 patients who underwent hepatectomy...
November 2016: Medical Oncology
Chiara Agostinis, Tamara Stampalija, Dionne Tannetta, Claudia Loganes, Liza Vecchi Brumatti, Francesco De Seta, Claudio Celeghini, Oriano Radillo, Ian Sargent, Francesco Tedesco, Roberta Bulla
PROBLEM: We have previously found that C1q is constitutively expressed by invading trophoblast and endothelial cells of decidua and contributes to vascular and tissue remodeling. Based on these findings, we sought to determine whether there were changes in the circulating level of C1q that may be used as a diagnostic and predictive marker of preeclampsia. METHOD OF STUDY: We measured the levels of C1q, C4, and complement activation products in serum or plasma of normal pregnant women and preeclamptic patients from different cohorts...
September 26, 2016: American Journal of Reproductive Immunology: AJRI
Xiaowu Wu, Michael A Dubick, Martin G Schwacha, Andrew P Cap, Daniel N Darlington
INTRODUCTION: Severe trauma, hemorrhage and resuscitation can lead to a trauma related acute lung injury that involves rapid infiltration of immune cells and platelets. This infiltration involves exymatic degradation of matrix proteins, including plasmin, and causes loss of barrier function. Since tranexamic acid (TXA) inhibits plasminogen/ plasmin binding to target substrates, it may attenuate loss of barrier function after severe trauma, hemorrhage and resuscitation. METHODS: Sprague-Dawley rats were subjected to polytrauma (laparotomy, and trauma to intestines, liver, right leg skeletal muscle and right femur fracture), then bled 40% of their blood volume...
September 19, 2016: Shock
Isaak Quast, Christian W Keller, Falk Hiepe, Björn Tackenberg, Jan D Lünemann
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic autoimmune neuropathy. While both cell-mediated and humoral mechanisms contribute to its pathogenesis, the rapid clinical response to plasmapheresis implicates a circulating factor responsible for peripheral nerve injury. We report that treatment-naïve patients with CIDP show increased serum and CSF levels of the anaphylatoxin C5a and the soluble terminal complement complex (sTCC). Systemic terminal complement activation correlates with clinical disease severity as determined by the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale...
September 2016: Annals of Clinical and Translational Neurology
Nicolas Gaudenzio, Riccardo Sibilano, Thomas Marichal, Philipp Starkl, Laurent L Reber, Nicolas Cenac, Benjamin D McNeil, Xinzhong Dong, Joseph D Hernandez, Ronit Sagi-Eisenberg, Ilan Hammel, Axel Roers, Salvatore Valitutti, Mindy Tsai, Eric Espinosa, Stephen J Galli
Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules...
October 3, 2016: Journal of Clinical Investigation
Yu Ma, Cheng-Chao Ruan, Yu Zhang, Qian Ge, Qi-Hong Wu, Ling-Ran Kong, Ping-Jin Gao
OBJECTIVE: Women with preeclampsia (PE) display excessive activation of complement system. However, little is known about the detailed cellular and molecular mechanism of complement activation in the development of PE. Here, we hypothesized that whether complement C5a contributes to the onset of PE through its effect on trophoblasts. DESIGN AND METHOD: In this study, 23 women with established PE and 32 normotensive women were recruited. At entry, peripheral and central blood pressure and pulse wave velocity (PWV) were performed...
September 2016: Journal of Hypertension
Ling-Ling An, Jacob V Gorman, Geoffrey Stephens, Bonnie Swerdlow, Paul Warrener, Jessica Bonnell, Tomas Mustelin, Michael Fung, Roland Kolbeck
Severe bacterial infection results in both uncontrolled inflammation and immune suppression in septic patients. Although there is ample evidence that complement activation provokes overwhelming pro-inflammatory responses, whether or not it plays a role in immune suppression in this case is unclear. Here, we identify that complement C5a directly participates in negative regulation of immune responses to bacteria-induced inflammation in an ex vivo model of human whole blood. Challenge of whole blood with heat-killed Pseudomonas aeruginosa induces PD-L1 expression on monocytes and the production of IL-10 and TGF-β, which we show to be inhibited by C5a blockade...
2016: Scientific Reports
Ramakrishna Edukulla, Kira Lee Rehn, Bo Liu, Jaclyn W McAlees, Gurjit K Hershey, Yui Hsi Wang, Ian Lewkowich, Andrew W Lindsley
INTRODUCTION: Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis. METHODS: Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo...
September 2016: Immunity, Inflammation and Disease
Kerstin A Heyl, Christian M Karsten, Hortense Slevogt
Changes in the glycosylation of immunoglobulins have been shown to modulate immune homeostasis and disease pathology. In this sense it has been shown that highly galactosylated but not agalactosylated IgG1 immune complexes (ICs) inhibit C5aR-mediated pro-inflammatory immune responses via the assembly of FcγRIIB-Dectin-1 receptor complexes. In this study we demonstrated that Galectin-3, a galactose-binding lectin that is known to cross-link proteins on cell-surfaces via binding their N-glycans, bound to highly-galactosylated, but not agalactosylated IgG1...
October 7, 2016: Biochemical and Biophysical Research Communications
Yongqiong Deng, Hong Zhao, Jiyuan Zhou, Linlin Yan, Guiqiang Wang
PURPOSE: To investigate the association between serum complement 5a (C5a) concentration and liver fibrosis and cirrhosis in a large cohort of patients chronically infected with hepatitis B virus (HBV). METHODS: Five hundred and eight patients with chronic HBV infection undergoing liver biopsy were included. Serum concentrations of C5a was measured by Luminex screening system. Ishak histological system was obtained. RESULTS: C5a levels were negatively associated with liver fibrosis stages and significantly declined in patients with severe fibrosis and cirrhosis (P < 0...
September 7, 2016: Infection
Damien Noone, Diane Hebert, Christoph Licht
The antineutrophil cytoplasm autoantibody (ANCA)-associated vasculitides (AAV), although rare in childhood, can have devastating effects on affected organs, especially the kidney. In this review we present an update on the pathogenesis and treatment of ANCA vasculitis, with a particular emphasis on the role of the alternative pathway of complement. The rationale and evidence for the current treatment strategies are summarized. Targeting the activation of neutrophils by the anaphylatoxin C5a may serve as an additional therapeutic strategy, however the results of clinical studies are awaited...
September 5, 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Jean F Regal, Megan E Strehlke, Jenna M Peterson, Cameron R Wing, Jordan E Parker, Noel Fernando Nieto, Lynne T Bemis, Jeffrey S Gilbert, Sherry D Fleming
Preeclampsia is characterized by development of hypertension during pregnancy and reduced placental perfusion. Previous studies in a rat model of placental ischemia-induced hypertension demonstrated that inhibiting complement activation attenuated increased maternal blood pressure with C3a and C5a identified as the important products of complement activation. Given that in other forms of ischemia both natural IgM and antigen antibody complexes initiate complement activation, we hypothesized that placental ischemia exposes neoepitopes recognized by IgM to cause local complement activation and hypertension...
October 2016: Molecular Immunology
Mingde Ji, Yanlai Lu, Chenhui Zhao, Wenxing Gao, Fengxia He, Jing Zhang, Dan Zhao, Wen Qiu, Yingwei Wang
Inflammatory response has been reported to contribute to the renal lesions in rat Thy-1 nephritis (Thy-1N) as an animal model of human mesangioproliferative glomerulonephritis (MsPGN). Besides C5b-9 complex, C5a is also a potent pro-inflammatory mediator and correlated to severity of various nephritic diseases. However, the role of C5a in mediating pro-inflammatory cytokine production in rats with Thy-1N is poorly defined. In the present studies, the levels of C5a, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were first determined in the renal tissues of rats with Thy-1N...
2016: PloS One
(no author information available yet)
This policy statement provides recommendations for the prevention of serogroup B meningococcal disease through the use of 2 newly licensed serogroup B meningococcal vaccines: MenB-FHbp (Trumenba; Wyeth Pharmaceuticals, a subsidiary of Pfizer, Philadelphia, PA) and MenB-4C (Bexsero; Novartis Vaccines, Siena, Italy). Both vaccines are approved for use in persons 10 through 25 years of age. MenB-FHbp is licensed as a 2- or 3-dose series, and MenB-4C is licensed as a 2-dose series for all groups. Either vaccine is recommended for routine use in persons 10 years and older who are at increased risk of serogroup B meningococcal disease (category A recommendation)...
September 2016: Pediatrics
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