The Experts below are selected from a list of 13026 Experts worldwide ranked by ideXlab platform
Yasuo Yanagi - One of the best experts on this subject based on the ideXlab platform.
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aqueous humour proteins and treatment outcomes of anti vegf therapy in neovascular age related macular degeneration
PLOS ONE, 2020Co-Authors: Yusuke Arai, Shinichi Sakamoto, Hidenori Takahashi, Yuji Inoue, Yujiro Fujino, Hidetoshi Kawashima, Satoru Inoda, Yasuo YanagiAbstract:We aimed to construct a better model for predicting treatment outcomes of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration (nAMD) using the concentrations of aqueous humour proteins at baseline and during treatment. From the data of 48 treatment-naive nAMD eyes that received intravitreal ranibizumab pro re nata for up to 12 months, we used the aqueous humour concentrations of C-X-C motif chemokine ligand 1 (CXCL1), CXCL12, CXCL13, interferon-gamma-induced protein 10, monocyte chemoattractant protein 1 (MCP-1), C-C motif chemokine ligand 11, interleukin 6 (IL-6), IL-10, and matrix metalloproteinase 9 (MMP-9). After stepwise regression, multivariate analysis was performed to identify which predictors were significantly associated with best-corrected visual acuity (BCVA) changes and the number of injections. The results demonstrated that besides male sex (beta coefficient = -0.088, P = 0.040) and central retinal thickness (beta coefficient = 0.00051 per mum, P = 0.027), MCP-1 (beta coefficient = 0.44, P < 0.001) and IL-10 (beta coefficient = -0.16, P = 0.033) were significantly correlated with baseline BCVA. Additionally, high MCP-1 at baseline (beta coefficient = -0.20, P = 0.015) and low CXCL13 at baseline (beta coefficient = 0.10, P = 0.0054) were independently associated with better BCVA change at 12 months. High MMP-9 at the first injection (beta coefficient = 0.56, P = 0.01), CXCL12 at the third injection (beta coefficient = 0.10, P = 0.0002), and IL-10 at the third injection (beta coefficient = 1.3, P = 0.001) were predictor variables associated with the increased number of injections. In conclusion, aqueous humour protein concentrations may have predictive abilities of BCVA change over 12 months and the number of injections in pro re nata treatment of exudative nAMD.
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changes in multiple cytokine concentrations in the aqueous humour of neovascular age related macular degeneration after 2 months of ranibizumab therapy
British Journal of Ophthalmology, 2017Co-Authors: Shinichi Sakamoto, Hidenori Takahashi, Yuji Inoue, Yoko Nomura, Yusuke Arai, Yujiro Fujino, Hidetoshi Kawashima, Yasuo YanagiAbstract:Purpose To determine changes in multiple cytokine concentrations in the anterior chamber during the induction phase of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD). Methods This prospective study included 48 treatment-naive neovascular AMD eyes of 48 patients who received three consecutive monthly injections of ranibizumab at the Japan Community Health Care Organization Tokyo Shinjuku Medical Center between November 2010 and August 2012. We collected ~0.2 mL aqueous humour before the first and third (2 months later) injections. Controls were 80 eyes with cataracts without retinal disease. The cytokines C-X-C motif chemokine ligand 1 (CXCL1), interferon-γ-induced protein 10 (IP-10), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine ligand 13 (CXCL13), monocyte chemoattractant protein 1 (MCP-1), CCL11, C-C motif chemokine ligand 11 (CCL11), interleukin-6 (IL-6), interleukin-10 (IL-10) and matrix metalloproteinase 9 (MMP-9) were analysed using multiplex cytokine assays. Results Mean ages of the patients with AMD and controls were 73 and 75 years, respectively, and 31 (65%) and 37 (46%) subjects were men, respectively. Polypoidal choroidal vasculopathy was found in 27 eyes (56%). Mean concentrations of cytokines in aqueous humour in patients with neovascular AMD before the first and third ranibizumab injections were as follows (in pg/mL): CXCL1, 8.4 and 3.3; IP-10, 110 and 55; CXCL12, 480 and 240; CXCL13, 9.2 and 2.6; MCP-1, 620 and 220; CCL11, 7.1 and 2.8; IL-6, 5.9 and 1.6; IL-10, 0.15 and 0.015 (all p Conclusions After two monthly consecutive antivascular endothelial growth factor injections, inflammatory cytokine levels in the aqueous humour of the eyes with AMD were strongly suppressed, while MMP-9 levels increased.
Scott G Worthen - One of the best experts on this subject based on the ideXlab platform.
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il 17a and tnf α exert synergistic effects on expression of cxcl5 by alveolar type ii cells in vivo and in vitro
Journal of Immunology, 2011Co-Authors: Linda W Gonzales, Michael Favara, Scott G Worthen, Susan H Guttentag, Peggy Zhang, Kenneth C Malcolm, Guang Yang, Ping WangAbstract:CXCL5, a member of the CXC family of chemokines, contributes to neutrophil recruitment during lung inflammation, but its regulation is poorly understood. Because the T cell-derived cytokine IL-17A enhances host defense by triggering production of chemokines, particularly in combination with TNF-α, we hypothesized that IL-17A would enhance TNF-α–induced expression of CXCL5. Intratracheal coadministration of IL-17A and TNF-α in mice induced production of CXCL1, CXCL2, and CXCL5, which was associated with increased neutrophil influx in the lung at 8 and 24 h. The synergistic effects of TNF-α and IL17A were greatly attenuated in Cxcl5−/− mice at 24 h, but not 8 h, after exposure, a time when CXCL5 expression was at its peak in wild-type mice. Bone marrow chimeras produced using Cxcl5−/− donors and recipients demonstrated that lung-resident cells were the source of CXCL5. Using differentiated alveolar epithelial type II (ATII) cells derived from human fetal lung, we found that IL-17A enhanced TNF-α–induced CXCL5 transcription and stabilized TNF-α–induced CXCL5 transcripts. Whereas expression of CXCL5 required activation of NF-κB, IL-17A did not increase TNF-α–induced NF-κB activation. Apical costimulation of IL-17A and TNF-α provoked apical secretion of CXCL5 by human ATII cells in a transwell system, whereas basolateral costimulation led to both apical and basolateral secretion of CXCL5. The observation that human ATII cells secrete CXCL5 in a polarized fashion may represent a mechanism to recruit neutrophils in host defense in a fashion that discriminates the site of initial injury.
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cxcl5 regulates chemokine scavenging and pulmonary host defense to bacterial infection
Immunity, 2010Co-Authors: Michael Favara, Teshell K Greene, Scott G Worthen, Mortimer Poncz, Samithamby JeyaseelanAbstract:The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia coli pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation.
Yuji Inoue - One of the best experts on this subject based on the ideXlab platform.
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aqueous humour proteins and treatment outcomes of anti vegf therapy in neovascular age related macular degeneration
PLOS ONE, 2020Co-Authors: Yusuke Arai, Shinichi Sakamoto, Hidenori Takahashi, Yuji Inoue, Yujiro Fujino, Hidetoshi Kawashima, Satoru Inoda, Yasuo YanagiAbstract:We aimed to construct a better model for predicting treatment outcomes of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration (nAMD) using the concentrations of aqueous humour proteins at baseline and during treatment. From the data of 48 treatment-naive nAMD eyes that received intravitreal ranibizumab pro re nata for up to 12 months, we used the aqueous humour concentrations of C-X-C motif chemokine ligand 1 (CXCL1), CXCL12, CXCL13, interferon-gamma-induced protein 10, monocyte chemoattractant protein 1 (MCP-1), C-C motif chemokine ligand 11, interleukin 6 (IL-6), IL-10, and matrix metalloproteinase 9 (MMP-9). After stepwise regression, multivariate analysis was performed to identify which predictors were significantly associated with best-corrected visual acuity (BCVA) changes and the number of injections. The results demonstrated that besides male sex (beta coefficient = -0.088, P = 0.040) and central retinal thickness (beta coefficient = 0.00051 per mum, P = 0.027), MCP-1 (beta coefficient = 0.44, P < 0.001) and IL-10 (beta coefficient = -0.16, P = 0.033) were significantly correlated with baseline BCVA. Additionally, high MCP-1 at baseline (beta coefficient = -0.20, P = 0.015) and low CXCL13 at baseline (beta coefficient = 0.10, P = 0.0054) were independently associated with better BCVA change at 12 months. High MMP-9 at the first injection (beta coefficient = 0.56, P = 0.01), CXCL12 at the third injection (beta coefficient = 0.10, P = 0.0002), and IL-10 at the third injection (beta coefficient = 1.3, P = 0.001) were predictor variables associated with the increased number of injections. In conclusion, aqueous humour protein concentrations may have predictive abilities of BCVA change over 12 months and the number of injections in pro re nata treatment of exudative nAMD.
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changes in multiple cytokine concentrations in the aqueous humour of neovascular age related macular degeneration after 2 months of ranibizumab therapy
British Journal of Ophthalmology, 2017Co-Authors: Shinichi Sakamoto, Hidenori Takahashi, Yuji Inoue, Yoko Nomura, Yusuke Arai, Yujiro Fujino, Hidetoshi Kawashima, Yasuo YanagiAbstract:Purpose To determine changes in multiple cytokine concentrations in the anterior chamber during the induction phase of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD). Methods This prospective study included 48 treatment-naive neovascular AMD eyes of 48 patients who received three consecutive monthly injections of ranibizumab at the Japan Community Health Care Organization Tokyo Shinjuku Medical Center between November 2010 and August 2012. We collected ~0.2 mL aqueous humour before the first and third (2 months later) injections. Controls were 80 eyes with cataracts without retinal disease. The cytokines C-X-C motif chemokine ligand 1 (CXCL1), interferon-γ-induced protein 10 (IP-10), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine ligand 13 (CXCL13), monocyte chemoattractant protein 1 (MCP-1), CCL11, C-C motif chemokine ligand 11 (CCL11), interleukin-6 (IL-6), interleukin-10 (IL-10) and matrix metalloproteinase 9 (MMP-9) were analysed using multiplex cytokine assays. Results Mean ages of the patients with AMD and controls were 73 and 75 years, respectively, and 31 (65%) and 37 (46%) subjects were men, respectively. Polypoidal choroidal vasculopathy was found in 27 eyes (56%). Mean concentrations of cytokines in aqueous humour in patients with neovascular AMD before the first and third ranibizumab injections were as follows (in pg/mL): CXCL1, 8.4 and 3.3; IP-10, 110 and 55; CXCL12, 480 and 240; CXCL13, 9.2 and 2.6; MCP-1, 620 and 220; CCL11, 7.1 and 2.8; IL-6, 5.9 and 1.6; IL-10, 0.15 and 0.015 (all p Conclusions After two monthly consecutive antivascular endothelial growth factor injections, inflammatory cytokine levels in the aqueous humour of the eyes with AMD were strongly suppressed, while MMP-9 levels increased.
Hidenori Takahashi - One of the best experts on this subject based on the ideXlab platform.
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aqueous humour proteins and treatment outcomes of anti vegf therapy in neovascular age related macular degeneration
PLOS ONE, 2020Co-Authors: Yusuke Arai, Shinichi Sakamoto, Hidenori Takahashi, Yuji Inoue, Yujiro Fujino, Hidetoshi Kawashima, Satoru Inoda, Yasuo YanagiAbstract:We aimed to construct a better model for predicting treatment outcomes of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration (nAMD) using the concentrations of aqueous humour proteins at baseline and during treatment. From the data of 48 treatment-naive nAMD eyes that received intravitreal ranibizumab pro re nata for up to 12 months, we used the aqueous humour concentrations of C-X-C motif chemokine ligand 1 (CXCL1), CXCL12, CXCL13, interferon-gamma-induced protein 10, monocyte chemoattractant protein 1 (MCP-1), C-C motif chemokine ligand 11, interleukin 6 (IL-6), IL-10, and matrix metalloproteinase 9 (MMP-9). After stepwise regression, multivariate analysis was performed to identify which predictors were significantly associated with best-corrected visual acuity (BCVA) changes and the number of injections. The results demonstrated that besides male sex (beta coefficient = -0.088, P = 0.040) and central retinal thickness (beta coefficient = 0.00051 per mum, P = 0.027), MCP-1 (beta coefficient = 0.44, P < 0.001) and IL-10 (beta coefficient = -0.16, P = 0.033) were significantly correlated with baseline BCVA. Additionally, high MCP-1 at baseline (beta coefficient = -0.20, P = 0.015) and low CXCL13 at baseline (beta coefficient = 0.10, P = 0.0054) were independently associated with better BCVA change at 12 months. High MMP-9 at the first injection (beta coefficient = 0.56, P = 0.01), CXCL12 at the third injection (beta coefficient = 0.10, P = 0.0002), and IL-10 at the third injection (beta coefficient = 1.3, P = 0.001) were predictor variables associated with the increased number of injections. In conclusion, aqueous humour protein concentrations may have predictive abilities of BCVA change over 12 months and the number of injections in pro re nata treatment of exudative nAMD.
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changes in multiple cytokine concentrations in the aqueous humour of neovascular age related macular degeneration after 2 months of ranibizumab therapy
British Journal of Ophthalmology, 2017Co-Authors: Shinichi Sakamoto, Hidenori Takahashi, Yuji Inoue, Yoko Nomura, Yusuke Arai, Yujiro Fujino, Hidetoshi Kawashima, Yasuo YanagiAbstract:Purpose To determine changes in multiple cytokine concentrations in the anterior chamber during the induction phase of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD). Methods This prospective study included 48 treatment-naive neovascular AMD eyes of 48 patients who received three consecutive monthly injections of ranibizumab at the Japan Community Health Care Organization Tokyo Shinjuku Medical Center between November 2010 and August 2012. We collected ~0.2 mL aqueous humour before the first and third (2 months later) injections. Controls were 80 eyes with cataracts without retinal disease. The cytokines C-X-C motif chemokine ligand 1 (CXCL1), interferon-γ-induced protein 10 (IP-10), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine ligand 13 (CXCL13), monocyte chemoattractant protein 1 (MCP-1), CCL11, C-C motif chemokine ligand 11 (CCL11), interleukin-6 (IL-6), interleukin-10 (IL-10) and matrix metalloproteinase 9 (MMP-9) were analysed using multiplex cytokine assays. Results Mean ages of the patients with AMD and controls were 73 and 75 years, respectively, and 31 (65%) and 37 (46%) subjects were men, respectively. Polypoidal choroidal vasculopathy was found in 27 eyes (56%). Mean concentrations of cytokines in aqueous humour in patients with neovascular AMD before the first and third ranibizumab injections were as follows (in pg/mL): CXCL1, 8.4 and 3.3; IP-10, 110 and 55; CXCL12, 480 and 240; CXCL13, 9.2 and 2.6; MCP-1, 620 and 220; CCL11, 7.1 and 2.8; IL-6, 5.9 and 1.6; IL-10, 0.15 and 0.015 (all p Conclusions After two monthly consecutive antivascular endothelial growth factor injections, inflammatory cytokine levels in the aqueous humour of the eyes with AMD were strongly suppressed, while MMP-9 levels increased.
Krishna Rajarathnam - One of the best experts on this subject based on the ideXlab platform.
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molecular basis of chemokine cxcl5 glycosaminoglycan interactions
Journal of Biological Chemistry, 2016Co-Authors: Krishna Mohan Sepuru, Balaji Nagarajan, Umesh R Desai, Krishna RajarathnamAbstract:Abstract Chemokines, a large family of highly versatile small soluble proteins, play crucial roles in defining innate and adaptive immune responses by regulating the trafficking of leukocytes, and also play a key role in various aspects of human physiology. Chemokines share the characteristic feature of reversibly existing as monomers and dimers, and their functional response is intimately coupled to interaction with glycosaminoglycans (GAGs). Currently, nothing is known regarding the structural basis or molecular mechanisms underlying CXCL5-GAG interactions. To address this missing knowledge, we characterized the interaction of a panel of heparin oligosaccharides to CXCL5 using solution NMR, isothermal titration calorimetry, and molecular dynamics simulations. NMR studies indicated that the dimer is the high-affinity GAG binding ligand and that lysine residues from the N-loop, 40s turn, β3 strand, and C-terminal helix mediate binding. Isothermal titration calorimetry indicated a stoichiometry of two oligosaccharides per CXCL5 dimer. NMR-based structural models reveal that these residues form a contiguous surface within a monomer and, interestingly, that the GAG-binding domain overlaps with the receptor-binding domain, indicating that a GAG-bound chemokine cannot activate the receptor. Molecular dynamics simulations indicate that the roles of the individual lysines are not equivalent and that helical lysines play a more prominent role in determining binding geometry and affinity. Further, binding interactions and GAG geometry in CXCL5 are novel and distinctly different compared with the related chemokines CXCL1 and CXCL8. We conclude that a finely tuned balance between the GAG-bound dimer and free soluble monomer regulates CXCL5-mediated receptor signaling and function.
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CXCL1 mgsa is a novel glycosaminoglycan gag binding chemokine structural evidence for two distinct non overlapping binding domains
Journal of Biological Chemistry, 2016Co-Authors: Krishna Mohan Sepuru, Krishna RajarathnamAbstract:Abstract In humans, the chemokine CXCL1/MGSA (hCXCL1), plays fundamental and diverse roles in pathophysiology, from microbial killing to cancer progression, by orchestrating directed migration of immune and non-immune cells. Cellular trafficking is highly regulated and requires concentration gradients that are achieved by interactions with sulfated glycosaminoglycans (GAGs). However, very little is known regarding the structural basis underlying hCXCL1-GAG interactions. We have addressed this missing knowledge by characterizing the binding of GAG heparin oligosaccharides to hCXCL1 using nuclear magnetic resonance (NMR) spectroscopy. Binding experiments under conditions at which hCXCL1 exists as monomers and dimers indicate that the dimer is the high-affinity GAG ligand. NMR experiments and modeling studies indicate that lysine and arginine residues mediate binding, and are located in two non-overlapping domains. One domain, consisting of N-loop and C-helical residues (defined as α-domain) was also previously identified as the GAG-binding domain for the related chemokine CXCL8/IL-8. The second domain, consisting of residues from the N-terminus, 40s turn, and 3rd β-strand (defined as β-domain) is novel. Eliminating β-domain binding by mutagenesis does not perturb α-domain binding indicating two independent GAG-binding sites. It is known that N-loop and N-terminal residues mediate receptor activation, and we show that these residues are also involved in extensive GAG interactions. We also show that GAG-bound chemokine completely occludes receptor binding. We conclude that hCXCL1-GAG interactions provide stringent control over regulating chemokine levels and receptor accessibility and activation, and that chemotactic gradients mediate cellular trafficking to the target site.
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chemokine CXCL1 dimer is a potent agonist for the cxcr2 receptor
Journal of Biological Chemistry, 2013Co-Authors: Aishwarya Ravindran, Kirti V Sawant, Jose Sarmiento, Javier Navarro, Krishna RajarathnamAbstract:Abstract The CXCL1/CXCR2 axis plays a crucial role in recruiting neutrophils in response to microbial infection and tissue injury, and dysfunction in this process has been implicated in various inflammatory diseases. Chemokines exist as monomers and dimers, and compelling evidence now exists that both forms regulate in vivo function. Therefore, knowledge of the receptor activities of both CXCL1 monomer and dimer is essential to describe the molecular mechanisms by which they orchestrate neutrophil function. The monomer-dimer equilibrium constant (∼20 μm) and the CXCR2 binding constant (1 nm) indicate that WT CXCL1 is active as a monomer. To characterize dimer activity, we generated a trapped dimer by introducing a disulfide across the dimer interface. This disulfide-linked CXCL1 dimer binds CXCR2 with nanomolar affinity and shows potent agonist activity in various cellular assays. We also compared the receptor binding mechanism of this dimer with that of a CXCL1 monomer, generated by deleting the C-terminal residues that stabilize the dimer interface. We observe that the binding interactions of the dimer and monomer to the CXCR2 N-terminal domain, which plays an important role in determining affinity and activity, are essentially conserved. The potent activity of the CXCL1 dimer is novel: dimers of the CC chemokines CCL2 and CCL4 are inactive, and the dimer of the CXC chemokine CXCL8 (which is closely related to CXCL1) is marginally active for CXCR1 but shows variable activity for CXCR2. We conclude that large differences in dimer activity among different chemokine-receptor pairs have evolved for fine-tuned leukocyte function.
