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Journal articles on the topic 'MD-2'

Author: Grafiati

Published: 9 March 2023

Last updated: 10 March 2023

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1

Visintin, Alberto, Dimitar B. Iliev, Brian G. Monks, Kristen A. Halmen, and Douglas T. Golenbock. "MD-2." Immunobiology 211, no. 6-8 (September 2006): 437–47. http://dx.doi.org/10.1016/j.imbio.2006.05.010.

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2

Madsen, Karen. "MD-2." Inflammatory Bowel Diseases 17, no. 6 (June 2011): 1436–37. http://dx.doi.org/10.1002/ibd.21485.

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3

Choi, Soo-Ho, Jungsu Kim, Ayelet Gonen, Suganya Viriyakosol, and Yury I. Miller. "MD-2 binds cholesterol." Biochemical and Biophysical Research Communications 470, no. 4 (February 2016): 877–80. http://dx.doi.org/10.1016/j.bbrc.2016.01.126.

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4

Gitlin, Melvin C., and Marcos FeBornstein. "Opinion #2: Melvin C. Gitlin, MD, and Marcos FeBornstein, MD." Pain Medicine 2, no. 3 (September 2001): 234. http://dx.doi.org/10.1046/j.1526-4637.2001.01036-3.x.

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Gitlin, Melvin C., and Marcos FeBornstein. "Opinion #2: Melvin C. Gitlin, MD, and Marcos FeBornstein, MD." Pain Medicine 2, no. 3 (July 7, 2008): 234. http://dx.doi.org/10.1111/j.1526-4637.2001.1036-3.x.

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6

Hamaty, Daniel. "Opinion #2: Daniel Hamaty, MD." Pain Medicine 3, no. 2 (June 2002): 170.1–170. http://dx.doi.org/10.1046/j.1526-4637.2002.02021_3.x.

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7

Gordin, Vitaly. "Opinion #2: Vitaly Gordin, MD." Pain Medicine 3, no. 4 (December 2002): 350.1–350. http://dx.doi.org/10.1046/j.1526-4637.2002.02049_3.x.

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8

Villarreal, Armando. "Opinion #2: Armando Villarreal, MD." Pain Medicine 4, no. 3 (September 2003): 297.1–297. http://dx.doi.org/10.1046/j.1526-4637.2003.03026_3.x.

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9

Divanovic, Senad, Aurelien Trompette, Sowsan F. Atabani, Rajat Madan, Douglas T. Golenbock, Alberto Visintin, Robert W. Finberg, et al. "Inhibition of TLR-4/MD-2 signaling by RP105/MD-1." Journal of Endotoxin Research 11, no. 6 (December 1, 2005): 363–68. http://dx.doi.org/10.1179/096805105x67300.

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10

Divanovic, Senad, Aurelien Trompette, Sowsan F. Atabani, Rajat Madan, Douglas T. Golenbock, Alberto Visintin, Robert W. Finberg, et al. "Inhibition of TLR-4/MD-2 signaling by RP105/MD-1." Journal of Endotoxin Research 11, no. 6 (December 2005): 363–68. http://dx.doi.org/10.1177/09680519050110061201.

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11

Viriyakosol, Suganya, Peter S. Tobias, Richard L. Kitchens, and Theo N. Kirkland. "MD-2 Binds to Bacterial Lipopolysaccharide." Journal of Biological Chemistry 276, no. 41 (October 2001): 38044–51. http://dx.doi.org/10.1074/jbc.m105228200.

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12

Viriyakosol, S., T. N. Kirkland, K. Soldau, and P. S. Tobias. "MD-2 binds to bacterial lipopolysaccharide." Journal of Endotoxin Research 6, no. 6 (June 1, 2000): 489–91. http://dx.doi.org/10.1179/096805100101532379.

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13

Viriyakosol, S., T. N. Kirkland, K. Soldau, and P. S. Tobias. "MD-2 binds to bacterial lipopolysaccharide." Journal of Endotoxin Research 6, no. 6 (December 2000): 489–91. http://dx.doi.org/10.1177/09680519000060060201.

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14

Barata, Teresa S., Ian Teo, Steve Brocchini, Mire Zloh, and Sunil Shaunak. "Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses." PLoS Computational Biology 7, no. 6 (June 30, 2011): e1002095. http://dx.doi.org/10.1371/journal.pcbi.1002095.

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15

Roy, Sanhita, Yan Sun, and Eric Pearlman. "Interferon-γ-induced MD-2 Protein Expression and Lipopolysaccharide (LPS) Responsiveness in Corneal Epithelial Cells Is Mediated by Janus Tyrosine Kinase-2 Activation and Direct Binding of STAT1 Protein to the MD-2 Promoter." Journal of Biological Chemistry 286, no. 27 (May 13, 2011): 23753–62. http://dx.doi.org/10.1074/jbc.m111.219345.

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The inability of epithelial cells from the cornea and other tissues to respond to LPS is reportedly due to low expression of the TLR4 co-receptor MD-2. We generated MD-2−/− bone marrow chimeras, and showed that MD-2 expression on non-myeloid cells was sufficient to mediate LPS-induced corneal inflammation. As IFN-γ is produced during Pseudomonas aeruginosa corneal infection, we examined the role of this cytokine on MD-2 expression by primary human corneal epithelial (HCE) cells and HCE cell lines. Exogenous IFN-γ was found to induce MD-2 mRNA, MD-2 cell surface expression, and LPS responsiveness as determined by p65 translocation to the nucleus and production of IL-6, CXCL1, and CXCL8/IL-8. Incubation with either the AG490 JAK2 inhibitor or with STAT1 siRNA blocked STAT1 phosphorylation and MD-2 transcription. Furthermore, EMSA analysis demonstrated that STAT1 binds to the MD-2 promoter, indicating that STAT1 is an MD-2 transcription factor. Together, these findings demonstrate that IFN-γ induces MD-2 expression and LPS responsiveness in HCE cells by JAK-2-dependent STAT1 activation and direct binding to the MD-2 promoter. Furthermore, given our findings on LPS-induced corneal inflammation, it is likely that IFN-γ-induced MD-2 expression by corneal epithelial cells contributes to the host response in vivo, determining the extent of tissue damage and bacterial clearance.

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16

Akashi, Sachiko, Shin-ichiroh Saitoh, Yasutaka Wakabayashi, Takane Kikuchi, Noriaki Takamura, Yoshinori Nagai, Yutaka Kusumoto, et al. "Lipopolysaccharide Interaction with Cell Surface Toll-like Receptor 4-MD-2." Journal of Experimental Medicine 198, no. 7 (September 29, 2003): 1035–42. http://dx.doi.org/10.1084/jem.20031076.

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Toll-like receptors (TLRs) are innate recognition molecules for microbial products, but their direct interactions with corresponding ligands remain unclarified. LPS, a membrane constituent of gram-negative bacteria, is the best-studied TLR ligand and is recognized by TLR4 and MD-2, a molecule associated with the extracellular domain of TLR4. Although TLR4-MD-2 recognizes LPS, little is known about the physical interaction between LPS and TLR4-MD-2. Here, we demonstrate cell surface LPS–TLR4-MD-2 complexes. CD14 greatly enhances the formation of LPS–TLR4-MD-2 complexes, but is not coprecipitated with LPS–TLR4-MD-2 complexes, suggesting a role for CD14 in LPS loading onto TLR4-MD-2 but not in the interaction itself between LPS and TLR4-MD-2. A tentative dissociation constant (Kd) for LPS–TLR4-MD-2 complexes was ∼3 nM, which is ∼10–20 times lower than the reported Kd for LPS–MD-2 or LPS–CD14. The presence of detergent disrupts LPS interaction with CD14 but not with TLR4-MD-2. E5531, a lipid A antagonist developed for therapeutic intervention of endotoxin shock, blocks LPS interaction with TLR4-MD-2 at a concentration 100 times lower than that required for blocking LPS interaction with CD14. These results reveal direct LPS interaction with cell surface TLR4-MD-2 that is distinct from that with MD-2 or CD14.

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17

Leão, César, António Pedro Mendes, Catarina Custódio, Mafalda Ng, Nuno Ribeiro, Nuno Loureiro, João Pedro Araújo, José Afonso, Sílvia Rocha-Rodrigues, and Francisco Tavares. "Nutritional Intake and Training Load of Professional Female Football Players during a Mid-Season Microcycle." Nutrients 14, no. 10 (May 21, 2022): 2149. http://dx.doi.org/10.3390/nu14102149.

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Football (soccer) is a high-intensity intermittent sport with large energy demands. In a repeated-measures design, we analysed the nutritional intake and training load of fourteen female football players (22.50 ± 4.38 y; 57.23 ± 8.61 kg; 164 ± 6.00 cm; 18.33 ± 2.48% of fat mass and 23.71 ± 2.51 kg of muscle mass) competing in the highest female Football Portuguese League across a typical mid-season microcycle. The microcycle had one match day (MD), one recovery session (two days after the MD, MD+2), three training sessions (MD-3, MD-2, MD-1) and two rest days (MD+1). Energy intake and CHO (g.kg.BW−1) intake were lower on the days before the competition (MD+2, MD-3, MD-2 and MD-1 vs. MD; p < 0.05; ES: 0.60–1.30). Total distance, distance covered at high-speed running (HSRD) and the high metabolic distance load (HMLD) were lower on MD+2, MD-3 and MD-1 compared with MD (p < 0.05; ES: <0.2–5.70). The internal training load was lower in all training sessions before the competition (MD+2, MD-3, MD-2 and MD-1 vs. MD; p ≤ 0.01; ES: 1.28–5.47). Despite the small sample size and a single assessment in time, the results suggest that caloric and CHO intake were below the recommendations and were not structured based on the physical requirements for training sessions or match days.

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18

Belcher, John D., Ping Zhang, Julia Nguyen, Zachary Monroe Kiser, John O. Trent, and Gregory M. Vercellotti. "Identification of a Heme Activation Site on the MD-2/TLR4 Complex." Blood 134, Supplement_1 (November 13, 2019): 209. http://dx.doi.org/10.1182/blood-2019-123788.

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Lipopolysaccharide (LPS), the first-identified TLR4 agonist, binds myeloid differentiation factor-2 (MD-2) in association with TLR4 to initiate TLR4 signaling. LPS binds to a large hydrophobic pocket in MD-2 and directly bridges the MD-2/TLR4 heterodimer. The MD-2/TLR4 complex also recognizes a diverse number of endogenous molecules released from injured cells called damage-associated molecular patterns or DAMPs. One such DAMP is heme. Large amounts of heme can be released intravascularly by trauma, sepsis, malaria and red blood cell disorders such as sickle cell disease (SCD). Recent studies underscore the importance of heme-mediated MD-2/TLR4 activation in inflammation, vessel occlusion, lethality and pulmonary injury in SCD. Therefore, we examined human MD-2 for potential heme activation sites. Recombinant MD-2 (rMD-2) was produced by transfecting Chinese hamster ovary (CHO) cells with human MD-2 plasmids. After 72 hours, Western blots of the CHO-conditioned media demonstrated soluble rMD-2 was present. Heme was shown to bind rMD-2 using pull-down assays utilizing heme-agarose or biotin-heme with streptavidin-agarose coupled with MD-2 Western blots of the pellet. These pull-down assays of rMD2 were inhibited by excess heme, indicating specific binding of heme to rMD-2. UV/visible scanning spectroscopy (250 - 550 nm) of purified rMD-2 in the presence or absence of heme, confirmed specific rMD-2-heme binding. In silico analyses combining both structure and sequence-based methods, identified two potential heme docking sites on MD-2 near conserved amino acids W23/S33/Y34 and Y36/C37/I44 (Figure 1). To determine whether MD-2 mutations at these two sites affect heme-MD-2/TLR4 signaling, HEK293 cells were transfected with plasmids encoding human MD-2, TLR4, CD14 and an NF-κB luciferase reporter. After 24 hours, transfected cells were stimulated with heme (10 μM) or LPS (10 ng/ml) for 6 hours and NF-κB luciferase reporter activity was measured. Heme or LPS treatment elicited robust luciferase activity. The addition of both heme and LPS had an additive effect on NF-κB luciferase activity. Absence of an MD-2, TLR4 or CD14 plasmid abolished NF-κB luciferase reporter responses to heme and/or LPS. When plasmids encoding MD-2 point mutants W23A or Y34A were introduced into MD-2, heme-induced NF-κB luciferase activity was inhibited 91-92% compared to WT-MD-2. The S33A MD-2 mutant stimulated NF-κB luciferase activity by 40%. NF-κB activation by LPS was marginally affected by the same mutants. Biotin-heme/streptavidin-agarose pulled down 68% less W23A mutant MD-2 and 80% less W23A/S33A/Y34A mutant MD-2 than WT-MD-2. In contrast, at the other potential heme binding site, heme-induced NF-κB luciferase activity was increased in mutants Y36A (120%), C37A (121%) and I44A (230%) compared to WT-MD-2. These data suggest that amino acids W23 and Y34 on MD-2 are specific for heme binding and TLR4 signaling. This heme activation site was targeted for potential inhibitors using virtual screening. The virtual screen identified 60 potential inhibitors for screening in heme-stimulated primary human umbilical vein endothelial cells (HUVEC) and a human U-937 monocyte cell line. Four of these molecules inhibited Weibel-Palade body P-selectin and von Willebrand factor expression in HUVEC and IL-8 secretion by U-937 cells stimulated with heme. We conclude that heme activates MD-2/TLR4 signaling at residues W23 and Y34 on MD-2, which might be a drugable target in SCD and other hemolytic diseases. Disclosures Belcher: Mitobridge, an Astellas Company: Consultancy, Research Funding. Vercellotti:Mitobridge, an Astellas Company: Consultancy, Research Funding.

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19

Miyake, K. "Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2." International Immunopharmacology 3, no. 1 (January 2003): 119–28. http://dx.doi.org/10.1016/s1567-5769(02)00258-8.

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20

Fernandes, Renato, Rafael Oliveira, Alexandre D. Martins, and João Moreira de Brito. "Internal training and match load quantification of one-match week schedules in female first league Portugal soccer team." Cuadernos de Psicología del Deporte 21, no. 3 (September 23, 2021): 126–38. http://dx.doi.org/10.6018/cpd.469141.

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La cuantificación de la carga de entrenamiento (TL) permite a los entrenadores gestionar la carga durante el entrenamiento con el objetivo de estar en la mejor forma física para la próxima competición. El propósito de este estudio fue comparar la Percepción Subjetiva de Esfuerzo (s-RPE) y el Índice Hooper (HI) entre deportes y partidos de un solo equipo de fútbol de la principal liga femenina portuguesa. En este estudio participaron dieciséis jugadores con una media ± DE edad, altura y peso de 24,0 ± 2,9 años, 164 ± 4,1 cm y 58,5 ± 8,2 kg, respectivamente. Los participantes completaron ≥80% de las sesiones de entrenamiento durante la temporada 2019/20. Los datos evaluados fueron s-RPE y HI, que midieron la calidad de la grasa, la fatiga, el estrés y el dolor muscular (DOMS). Los datos se analizaron en relación al número de días durante un microciclo competitivo (semana de juego), es decir, menos día de juego (MD-) con tres sesiones de entrenamiento por semana (MD-5; MD-4; MD-2). El estudio analizó datos para un total de 12 juegos y 45 sesiones de entrenamiento con ANOVA de medidas repetidas, p≤0,05. Los resultados mostraron diferencias entre MD-5 (85,2 ± 0,3min) vs MD-4 (87,2 ± 0,4min) vs MD-2 (80,6 ± 0.6min) vs MD (62,8 ± 4,9min), todos p <0,05; s-RPE mostró valores más altos en MD-5 (503,8 ± 19,0ua) vs MD-4 (473,2 ± 14,8ua) vs MD-2 (362,1 ± 12,1ua) vs MD (468, 2 ± 40,5ua); El HI mostró valores más altos en MD-5 (13,4 ± 0,5ua) frente a MD-4 (13,4 ± 0,4ua) frente a MD-2 (12,7 ± 0,5ua) frente a MD (11, 9 ± 0,4ua); DOMS reveló diferencias entre MD-4 vs MD-2 (3,1 ± 0,2 vs 2,7 ± 0,2ua), p<0,05. Se ha demostrado que existe una mayor carga de entrenamiento en el MD-5 y MD-4 en comparación con el MD-2. Los resultados de HI mostraron que la grasa, la fatiga, el estrés y DOMS estaban bien controlados por el equipo técnico y los jugadores. Training load (TL) quantification allow coaches to a better load management during training sessions to be in the best physical fitness to the next match. The aim of this study was to compare session rated of perceived exertion (s-RPE) and Hooper Index (HI) between training and match days from the same women’s Portuguese League team. Sixteen players with a mean±SD age, height and weight of 24.0±2.9 years, 164±4.1 cm and 58.5±8.2 kg, respectively, participated in this study. The participants completed ≥80% of the training sessions during 2019/20 in-season. Data was collected through the s-RPE and the HI that measured sleep quality, fatigue, stress, and muscle soreness (DOMS). Data was analysed in relation to the number of days away from the competitive one-match week (i.e., match day minus, MD-) with three training sessions a week (MD-5; MD-4; MD-2). The study analysed data from a total of 12 matches and 45 training sessions with repeated measures ANOVA, p≤0.05. Results showed differences between MD-5 (85.2±0.3min) vs MD-4 (87.2±0.4min) vs MD-2 (80.6±0.6min) vs MD (62.8±4.9min), all p<0.05; s-RPE showed higher values on MD-5 (503.8±19.0au) vs MD-4 (473.2±14.8au) vs MD-2 (362.1±12.1au) vs MD (468.2±40.5au); HI showed higher values on MD-5 (13.4±0.5au) vs MD-4 (13.4±0.4au) vs MD-2 (12.7±0.5au) vs MD (11.9±0.4au); DOMS revealed difference between MD-4 vs MD-2 (3.1±0.2 vs 2.7±0.2au), p<0.05. It was shown that there is a higher TL on MD-5 and MD-4 compared with MD-2. Results from HI showed that sleep, fatigue, stress and DOMS was well fair controlled by coaches and staff. A quantificação da carga de treino (CT) permite aos treinadores uma melhor gestão da carga dos jogadores durante as sessões de treino para que estejam na melhor condição física para o próximo jogo. O objetivo deste estudo foi comparar os valores da perceção subjetiva de esforço (s-RPE) e o Índice Hooper (HI) entre dias de treino e de jogo numa equipa feminina de Futebol da principal Liga feminina portuguesa. Participaram neste estudo dezasseis jogadoras com média ± DP de idade, altura e peso de 24,0 ± 2,9 anos, 164 ± 4,1 cm e 58,5 ± 8,2 kg, respetivamente. As participantes completaram ≥80% das sessões de treino durante a temporada de 2019/20. Os dados avaliados foram o s-RPE e o HI que mediu a qualidade do sono, fadiga, stresse e dor muscular (DOMS). Os dados foram recolhidos através do s-RPE e do IH que avaliaram a qualidade do sono, fadiga, stress e dor muscular (DOMS). Os dados foram analisados em relação ao número de dias para o jogo competitivo (ou seja, dia de jogo menos, MD-) com três sessões de treino por semana (MD-5; MD-4; MD-2). O estudo analisou 12 jogos e 45 sessões de treino através de medidas repetidas ANOVA, p≤0,05. Os resultados mostraram diferenças entre MD-5 (85,2±0,3min) vs MD-4 (87,2±0,4min) vs MD-2 (80,6±0,6min) vs MD (62,8±4,9min), todos p<0,05; s-RPE mostrou valores mais altos em MD-5 (503,8±19,0au) vs MD-4 (473,2±14,8au) vs MD-2 (362,1±12,1au) vs MD (468,2±40,5au); HI mostrou valores mais altos em MD-5 (13,4±0,5au) vs MD-4 (13,4±0,4au) vs MD-2 (12,7±0,5au) vs MD (11,9±0,4au); DOMS revelou diferença entre MD-4 vs MD-2 (3,1±0,2 vs 2,7±0,2au), p<0,05. Foi demonstrado que existe uma maior CT no MD-5 e MD-4 em comparação com o MD-2. Os resultados do HI mostraram que o sono, fadiga, stress e DOMS foi bem controlado pelos treinadores e staff.

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21

Miao, Hui-Lai. "Significance of MD-2 and MD-2B expression in rat liver during acute cholangitis." World Journal of Hepatology 2, no. 6 (2010): 233. http://dx.doi.org/10.4254/wjh.v2.i6.233.

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22

Kimoto, Masao, Kohei Nagasawa, and Kensuke Miyake. "Role of TLR4/MD-2 and RP105/MD-1 in Innate Recognition of Lipopolysaccharide." Scandinavian Journal of Infectious Diseases 35, no. 9 (January 2003): 568–72. http://dx.doi.org/10.1080/00365540310015700.

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23

Gayer, Steven I., and Harry W. Flynn. "Discussion by Steven I. Gayer, MD 1 and Harry W. Flynn, Jr., MD 2." Ophthalmology 107, no. 1 (January 2000): 46–47. http://dx.doi.org/10.1016/s0161-6420(99)00061-5.

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24

Jain, Vishal, Annett Halle, Kristen A. Halmen, Egil Lien, Marie Charrel-Dennis, Sanjay Ram, Douglas T. Golenbock, and Alberto Visintin. "Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling." Blood 111, no. 9 (May 1, 2008): 4637–45. http://dx.doi.org/10.1182/blood-2007-11-126862.

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AbstractBoth Toll-like receptor 4 (TLR4)– and MD-2–deficient mice succumb to otherwise nonfatal Gram-negative bacteria inocula, demonstrating the pivotal role played by these proteins in antibacterial defense in mammals. MD-2 is a soluble endogenous ligand for TLR4 and a receptor for lipopolysaccharide (LPS). LPS-bound MD-2 transmits an activating signal onto TLR4. In this report, we show that both recombinant and endogenous soluble MD-2 bind tightly to the surface of live Gram-negative bacteria. As a consequence, MD-2 enhances cellular activation, bacterial internalization, and intracellular killing, all in a TLR4-dependent manner. The enhanced internalization of MD-2–coated bacteria was not observed in macrophages expressing Lpsd, a signaling-incompetent mutant form of TLR4, suggesting that the enhanced phagocytosis observed is dependent on signal transduction. The data confirm the notion that soluble MD-2 is a genuine opsonin that enhances proinflammatory opsonophagocytosis by bridging live Gram-negative bacteria to the LPS transducing complex. The presented results extend our understanding of the role of the TLR4/MD-2 signaling axis in bacterial recognition by phagocytes.

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25

Pugin, Jérôme, Sabine Stern-Voeffray, Bruno Daubeuf, Michael A. Matthay, Greg Elson, and Irène Dunn-Siegrist. "Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock." Blood 104, no. 13 (December 15, 2004): 4071–79. http://dx.doi.org/10.1182/blood-2003-04-1290.

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Abstract In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LPS activation of epithelial cells to levels measured with “septic” plasma, whereas soluble MD-2-depleted plasma lost its effects. The same “MD-2 activity” was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LPS but were not able to mediate LPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis. (Blood. 2004;104:4071-4079)

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26

Teghanemt, Athmane, Fabio Re, Polonca Prohinar, Richard Widstrom, Theresa L. Gioannini, and Jerrold P. Weiss. "Novel Roles in Human MD-2 of Phenylalanines 121 and 126 and Tyrosine 131 in Activation of Toll-like Receptor 4 by Endotoxin." Journal of Biological Chemistry 283, no. 3 (October 30, 2007): 1257–66. http://dx.doi.org/10.1074/jbc.m705994200.

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Potent mammalian cell activation by Gram-negative bacterial endotoxin requires sequential protein-endotoxin and protein-protein interactions involving lipopolysaccharide-binding protein, CD14, MD-2, and Toll-like receptor 4 (TLR4). TLR4 activation requires simultaneous binding of MD-2 to endotoxin (E) and the ectodomain of TLR4. We now describe mutants of recombinant human MD-2 that bind TLR4 and react with E·CD14 but do not support cellular responsiveness to endotoxin. The mutants F121A/K122A MD-2 and Y131A/K132A MD-2 react with E·CD14 only when co-expressed with TLR4. Single mutants K122A and K132A each react with E·CD14 ± TLR4 and promote TLR4-dependent cell activation by endotoxin suggesting that Phe121 and Tyr131 are needed for TLR4-independent transfer of endotoxin from CD14 to MD-2 and also needed for TLR4 activation by bound E·MD-2. The mutant F126A MD-2 reacts as well as wild-type MD-2 with E·CD14 ± TLR4. E·MD-2F126A binds TLR4 with high affinity (Kd ∼ 200 pm) but does not activate TLR4 and instead acts as a potent TLR4 antagonist, inhibiting activation of HEK/TLR4 cells by wild-type E·MD-2. These findings reveal roles of Phe121 and Tyr131 in TLR4-independent interactions of human MD-2 with E·CD14 and, together with Phe126, in activation of TLR4 by bound E·MD-2. These findings strongly suggest that the structural properties of E·MD-2, not E alone, determine agonist or antagonist effects on TLR4.

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Morgans, Ryland, Adam Owen, Dominic Doran, Barry Drust, and James P. Morton. "Prematch Salivary Secretory Immunoglobulin A in Soccer Players From the 2014 World Cup Qualifying Campaign." International Journal of Sports Physiology and Performance 10, no. 3 (April 2015): 401–3. http://dx.doi.org/10.1123/ijspp.2014-0046.

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Purpose:To monitor resting salivary secretory immunoglobulin A (SIgA) levels in international soccer players during the short-term training period that precedes international match play.Methods:In a repeated-measure design, saliva samples were obtained from 13 outfield soccer players who participated in the training camps preceding 7 games (5 home and 2 away) of the 2014 FIFA World Cup qualifying campaign. Samples were obtained daily for 4 d preceding each game (and analyzed for SIgA using the IPRO oral-fluid-collection system) at match day minus 1 (MD-1), minus 2 (MD-2), minus 3 (MD-3), and minus 4 (MD-4).Results:SIgA displayed a progressive decline (P = .01) during the 4-d training period (MD-4, 365 ± 127 μg/mL; MD-3, 348 ± 154 μg/mL; MD-2, 290 ± 138 μg/mL; MD-1, 256 ± 90 μg/mL) such that MD-1 values were significantly lower (P = .01) than both MD-4 and MD-3. The 95% confidence intervals for the differences between MD-1 and MD-4 were –191 to –26 and between MD-1 and MD-3 were –155 to –28.Conclusions:Data demonstrate that a short-term soccer-training camp in preparation for international competition induces detectable perturbations to mucosal immunity. Future studies should monitor SIgA (as a practical and noninvasive measure of immunity) alongside internal and external measures of training load in an attempt to strategically individualize training and nutritional strategies that may support optimal preparation for high-level competition.

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Nagai, Yoshinori, Shoichiro Ohta, Kensuke Miyake, and Kiyoshi Takatsu. "TLR4/MD-2 and RP105/MD-1 differentially regulate LPS responsiveness in B cells (135.4)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 135.4. http://dx.doi.org/10.4049/jimmunol.182.supp.135.4.

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Abstract [Aims] TLR4/MD-2 is an essential complex for LPS recognition. RP105/MD-1 is a homologue of TLR4/MD-2 and is expressed in mainly B cells. RP105 or MD-1-deficient B cells show impaired LPS responsiveness, suggesting that B cells require both TLR4/MD-2 and RP105/MD-1 signals for LPS responses. However, precise mechanisms that functionally couple with the two types of complex remain unclear. Furthermore, as LPS stimulation activates B cells through both receptors, it is difficult to analyze the signals via TLR4/MD-2 and RP105/MD-1 differentially. To resolve this, we used agonistic mAbs to TLR4 and RP105 to explore differential roles for TLR4/MD-2 and RP105/MD-1 in B cell responses to LPS. [Methods] Mouse splenic B cells were stimulated with αTLR4 mAb, αRP105 mAb, or LPS in combination with IL-4. Expression of CD86, BAFF receptors (TACI, BAFF-R, BMCA), and CD138 was analyzed by FACS. For proliferation analysis, the B cells were stimulated with vehicles for 3 days and pulsed with 0.5 μCi [3H]-TdR. The μ to γ1 class switch recombination (CSR) was examined by analyzing the proportion of surface IgG1+ cells by FACS. [Results and Discussion] The αTLR4 mAb and αRP105 mAb induced massive B cell proliferation like as LPS. Expression of CD86 and BAFF receptors was induced by low doses of αRP105 (10 ng/ml), whereas those expression was very low by αTLR4 stimulation even at high doses (1 μg/ml). Combination of αTLR4 + IL-4 as well as LPS + IL-4 forced B cells to induce sIgG1+ cells. In contrast, αRP105 + IL-4 never showed this activity. CD138 expression was induced on B cells stimulated with αTLR4 but not with αRP105. These findings suggest that TLR4 and RP105 differentially regulate B cell response to LPS.

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Miyake, K., H. Ogata, Y. Nagai, S. Akashi, and M. Kimoto. "Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1." Journal of Endotoxin Research 6, no. 5 (May 1, 2000): 389–91. http://dx.doi.org/10.1179/096805100101532324.

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Miyake, Kensuke, Hirotaka Ogata, Yoshinori Nagai, Sachiko Akashi, and Masao Kimoto. "Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1." Journal of Endotoxin Research 6, no. 5 (October 2000): 389–91. http://dx.doi.org/10.1177/09680519000060051001.

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An, Jian‐Ping, Xiao‐Wei Zhang, Chun‐Xiang You, Si‐Qi Bi, Xiao‐Fei Wang, and Yu‐Jin Hao. "Md WRKY 40 promotes wounding‐induced anthocyanin biosynthesis in association with Md MYB 1 and undergoes Md BT 2‐mediated degradation." New Phytologist 224, no. 1 (July 24, 2019): 380–95. http://dx.doi.org/10.1111/nph.16008.

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Y. Lorente, Gustavo. "Fertilizacion foliar en plantas de piña 'MD-2'." Sinergia Académica 2, no. 3 (November 21, 2020): 41–49. http://dx.doi.org/10.51736/sa.v2i3.30.

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La piña (Ananas comosus var. comosus) es una de las frutas más producidas; ocupa el tercer lugar en producción mundial después de las bananas y mangos. Se cultiva para satisfacer las necesidades nutricionales y es importante para la producción de conservas y venta de fruta fresca. Con un riego óptimo, el rendimiento depende de dos factores fundamentales, la densidad de la plantación y el suministro adecuado de fertilizantes. El objetivo del estudio fue determinar los efectos sobre el crecimiento vegetativo de plantas de piña 'MD-2' de tres diferentes sistemas de fertilización foliar (macro y micronutrientes) basados en los productos de la marca CODA (Agro Solution, España) [CODA], el habitual sistema utilizado para la fertilización de piña [UEB] y una combinación de elementos de ambos tratamientos [COMBINADO] en condiciones de campo. Los tratamientos se organizaron en un diseño de bloques al azar y cada tratamiento se replicó dos veces. En parcelas de 0,25 ha que contenían aproximadamente 16,250 plantas por réplica. Los indicadores de crecimiento vegetativo evaluados fueron: masa fresca de la planta (kg), longitud de la planta (cm), número de hojas, peso fresco y seco de la hoja "D" (g), longitud y ancho de la hoja "D" (cm). Las plantas cultivadas con el sistema CODA tuvieron mayor masa fresca de la planta, número de hojas, masa fresca, seca y longitud de la hoja "D", y alcanzaron la inducción floral con peso de 2.5 kg al menos un mes antes que los otros dos sistemas.

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GANGLOFF, M. "MD-2: the Toll ?gatekeeper? in endotoxin signalling." Trends in Biochemical Sciences 29, no. 6 (June 2004): 294–300. http://dx.doi.org/10.1016/j.tibs.2004.04.008.

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Teghanemt, Athmane, Richard L. Widstrom, Theresa L. Gioannini, and Jerrold P. Weiss. "Isolation of Monomeric and Dimeric Secreted MD-2." Journal of Biological Chemistry 283, no. 32 (June 2, 2008): 21881–89. http://dx.doi.org/10.1074/jbc.m800672200.

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Zimmer, Shanta M., Jin Liu, Jaime L. Clayton, David S. Stephens, and James P. Snyder. "Paclitaxel Binding to Human and Murine MD-2." Journal of Biological Chemistry 283, no. 41 (July 23, 2008): 27916–26. http://dx.doi.org/10.1074/jbc.m802826200.

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曹, 珍富. "关于Diophantus方程Cx~2+2~mD=y~p." Chinese Science Bulletin 37, no. 22 (November 1, 1992): 2106. http://dx.doi.org/10.1360/csb1992-37-22-2106.

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Yu, Liping, Rachel L. Phillips, DeSheng Zhang, Athmane Teghanemt, Jerrold P. Weiss, and Theresa L. Gioannini. "NMR Studies of Hexaacylated Endotoxin Bound to Wild-type and F126A Mutant MD-2 and MD-2·TLR4 Ectodomain Complexes." Journal of Biological Chemistry 287, no. 20 (March 20, 2012): 16346–55. http://dx.doi.org/10.1074/jbc.m112.343467.

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Yang, Huan, Haichao Wang, Zhongliang Ju, Ahmed A. Ragab, Peter Lundbäck, Wei Long, Sergio I. Valdes-Ferrer, et al. "MD-2 is required for disulfide HMGB1–dependent TLR4 signaling." Journal of Experimental Medicine 212, no. 1 (January 5, 2015): 5–14. http://dx.doi.org/10.1084/jem.20141318.

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Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2–deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2–HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4–MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness.

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Chen, Guirong, Chang Liu, Mingbo Zhang, Xiaobo Wang, and Yubin Xu. "Niloticin binds to MD-2 to promote anti-inflammatory pathway activation in macrophage cells." International Journal of Immunopathology and Pharmacology 36 (January 2022): 039463202211330. http://dx.doi.org/10.1177/03946320221133017.

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Objectives Niloticin is an active compound isolated from Cortex phellodendri with uncharacterized anti-inflammatory activity. We assessed the drug potential of niloticin and examined its ability to target myeloid differentiation protein 2 (MD-2) to ascertain the mechanism for its anti-inflammatory activity. Methods The Traditional Chinese Medicine Systems Pharmacology Database was used to evaluate niloticin. Bio-layer interferometry and molecular docking technologies were used to explore how niloticin targets MD-2, which mediates a series of toll-like receptor 4 (TLR4)-dependent inflammatory responses. The cytokines involved in the lipopolysaccharide (LPS)-TLR4/MD-2-NF-κB pathway were evaluated using ELISA, RT-qPCR, and western blotting. Results Niloticin could bind to MD-2 and had no evident effects on cell viability. Niloticin treatment significantly decreased the levels of NO, IL-6, TNF-α, and IL-1β induced by LPS ( p < 0.01). IL-1β, IL-6, iNOS, TNF-α, and COX-2 mRNA expression levels were decreased by niloticin (all p < 0.01). Compared with that in the control group, the increase in TLR4, p65, MyD88, p-p65, and iNOS expression levels induced by LPS were suppressed by niloticin (all p < 0.01). Conclusion Our results suggest that niloticin has therapeutic potential and binds to MD-2. Niloticin binding to MD-2 antagonized the effects of LPS binding to the TLR4/MD-2 complex, resulting in the inhibition of the LPS-TLR4/MD-2-NF-κB signaling pathway.

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Nagai, Yoshinori, Rintaro Shimazu, Hirotaka Ogata, Sachiko Akashi, Katsuko Sudo, Hidetoshi Yamasaki, Shin-Ichi Hayashi, Yoichiro Iwakura, Masao Kimoto, and Kensuke Miyake. "Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide." Blood 99, no. 5 (March 1, 2002): 1699–705. http://dx.doi.org/10.1182/blood.v99.5.1699.

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RP105 is a B-cell surface molecule that has been recently assigned as CD180. RP105 ligation with an antibody induces B-cell activation in humans and mice, leading to proliferation and up-regulation of a costimulatory molecule, B7.2/CD86. RP105 is associated with an extracellular molecule, MD-1. RP105/MD-1 has structural similarity to Toll-like receptor 4 (TLR4)/MD-2. TLR4 signals a membrane constituent of Gram-negative bacteria, lipopolysaccharide (LPS). MD-2 is indispensable for TLR4-dependent LPS responses because cells expressing TLR4/MD-2, but not TLR4 alone, respond to LPS. RP105 also has a role in LPS responses because B cells lacking RP105 show hyporesponsiveness to LPS. Little is known, however, regarding whether MD-1 is important for RP105-dependent LPS responses, as MD-2 is for TLR4. To address the issue, we developed mice lacking MD-1 and generated monoclonal antibodies (mAbs) to the protein. MD-1–null mice showed impairment in LPS-induced B-cell proliferation, antibody production, and B7.2/CD86 up-regulation. These phenotypes are similar to those of RP105-null mice. The similarity was attributed to the absence of cell surface RP105 on MD-1–null B cells. MD-1 is indispensable for cell surface expression of RP105. A role for MD-1 in LPS responses was further studied with anti–mouse MD-1 mAbs. In contrast to highly mitogenic anti-RP105 mAbs, the mAbs to MD-1 were not mitogenic but antagonistic on LPS-induced B-cell proliferation and on B7.2 up-regulation. Collectively, MD-1 is important for RP105 with respect to B-cell surface expression and LPS recognition and signaling.

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Su, Lijing, Muhammad Athamna, Ying Wang, Junmei Wang, Marina Freudenberg, Tao Yue, Jianhui Wang, et al. "Sulfatides are endogenous ligands for the TLR4–MD-2 complex." Proceedings of the National Academy of Sciences 118, no. 30 (July 21, 2021): e2105316118. http://dx.doi.org/10.1073/pnas.2105316118.

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Many endogenous molecules, mostly proteins, purportedly activate the Toll-like receptor 4 (TLR4)–myeloid differentiation factor-2 (MD-2) complex, the innate immune receptor for lipopolysaccharide (LPS) derived from gram-negative bacteria. However, there is no structural evidence supporting direct TLR4–MD-2 activation by endogenous ligands. Sulfatides (3-O-sulfogalactosylceramides) are natural, abundant sulfated glycolipids that have variously been shown to initiate or suppress inflammatory responses. We show here that short fatty acid (FA) chain sulfatides directly activate mouse TLR4–MD-2 independent of CD14, trigger MyD88- and TRIF-dependent signaling, and stimulate tumor necrosis factor α (TNFα) and type I interferon (IFN) production in mouse macrophages. In contrast to the agonist activity toward the mouse receptor, the tested sulfatides antagonize TLR4–MD-2 activation by LPS in human macrophage-like cells. The agonistic and antagonistic activities of sulfatides require the presence of the sulfate group and are inversely related to the FA chain length. The crystal structure of mouse TLR4–MD-2 in complex with C16-sulfatide revealed that three C16-sulfatide molecules bound to the MD-2 hydrophobic pocket and induced an active dimer conformation of the receptor complex similar to that induced by LPS or lipid A. The three C16-sulfatide molecules partially mimicked the detailed interactions of lipid A to achieve receptor activation. Our results suggest that sulfatides may mediate sterile inflammation or suppress LPS-stimulated inflammation, and that additional endogenous negatively charged lipids with up to six lipid chains of limited length might also bind to TLR4–MD-2 and activate or inhibit this complex.

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Ohnishi, Takahiro, Masashi Muroi, and Ken-ichi Tanamoto. "MD-2 Is Necessary for the Toll-Like Receptor 4 Protein To Undergo Glycosylation Essential for Its Translocation to the Cell Surface." Clinical Diagnostic Laboratory Immunology 10, no. 3 (May 2003): 405–10. http://dx.doi.org/10.1128/cdli.10.3.405-410.2003.

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ABSTRACT MD-2 has been reported to be required for the translocation of the Toll-like receptor 4 (TLR4) to the cell surface. However, the mechanism by which MD-2 promotes TLR4 translocation is unknown. We identified the presence of two forms of TLR4 with different molecular masses (approximately 110 and 130 kDa) when TLR4 was expressed together with MD-2. Expressing TLR4 alone produced only the 110-kDa form. Using a membrane-impermeable biotinylation reagent, we found that only the 130-kDa form of TLR4 was expressed on the cell surface. When a cellular extract prepared from cells expressing TLR4 and MD-2 was treated with N-glycosidase, the two forms of TLR4 converged into a single band whose size was smaller than the 110-kDa form of TLR4. Mutation of TLR4 at Asn526 or Asn575 resulted in the disappearance of the 130-kDa form and prevented TLR4 from being expressed on the cell surface without affecting the ability of TLR4 to associate with MD-2. These results indicate that TLR4 is able to undergo multiple glycosylations without MD-2 but that the specific glycosylation essential for cell surface expression requires the presence of MD-2.

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Jia, Hong Peng, Joel N. Kline, Andrea Penisten, Michael A. Apicella, Theresa L. Gioannini, Jerrold Weiss, and Paul B. McCray. "Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 2 (August 2004): L428—L437. http://dx.doi.org/10.1152/ajplung.00377.2003.

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The expression of inducible antimicrobial peptides, such as human β-defensin-2 (HBD-2) by epithelia, comprises a component of innate pulmonary defenses. We hypothesized that HBD-2 induction in airway epithelia is linked to pattern recognition receptors such as the Toll-like receptors (TLRs). We found that primary cultures of well-differentiated human airway epithelia express the mRNA for TLR-4, but little or no MD-2 mRNA, and display little HBD-2 expression in response to treatment with purified endotoxin ± LPS binding protein (LBP) and soluble CD14. Expression of endogenous MD-2 by transduction of airway epithelial cells with an adenoviral vector encoding MD-2 or extracellular addition of recombinant MD-2 both increased the responses of airway epithelia to endotoxin + LBP and sCD14 by >100-fold, as measured by NF-κB-luciferase activity and HBD-2 mRNA expression. MD-2 mRNA could be induced in airway epithelia by exposure of these cells to specific bacterial or host products (e.g., killed Haemophilus influenzae, the P6 outer membrane protein from H. influenzae, or TNF-α + IFN-γ). These findings suggest that MD-2, either coexpressed with TLR-4 or secreted when produced in excess of TLR-4 from neighboring cells, is required for airway epithelia to respond sensitively to endotoxin. The regulation of MD-2 expression in airway epithelia and pulmonary macrophages may serve as a means to modify endotoxin responsiveness in the airway.

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Esparza, Greg A., Athmane Teghanemt, De-Sheng Zhang, Theresa Gioannini, and Jerrold Weiss. "Essential role of albumin in CD14-independent activation of MD-2/TLR4 by endotoxin (135.20)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 135.20. http://dx.doi.org/10.4049/jimmunol.182.supp.135.20.

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Abstract Host response to endotoxin (E) depends on the ordered interactions of LBP, CD14, MD-2 and Toll-Like Receptor (TLR) 4. CD14 is required for efficient transfer of E monomers to MD-2 (/TLR4) and for induction of TRIF-dependent signaling by activated TLR4. At high E concentrations, MD-2/TLR4-dependent cell activation by E is possible without CD14 through an unknown mechanism. We now show that incubation of purified E aggregates (Mr = 20 million) in PBS with = 0.1% albumin in the absence of the divalent cations Ca2+ and Mg2+, yields monomeric E:albumin complexes (Mr ~70,000). E monomers transfer from E:albumin to MD-2 and to MD-2/TLR4 directly and induce MD-2/TLR4-dependent, CD14-independent cell activation. Our findings suggest for the first time a mechanistic basis for CD14-independent cell activation by E. E:CD14 and E:albumin complexes should provide valuable reagents for future studies of MyD88-dependent (CD14-independent) and TRIF-dependent (CD14-dependent) TLR4 signaling by E. Work supported by NIH/NIAID #AI59372.

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Schromm, Andra B., Egil Lien, Philipp Henneke, Jesse C. Chow, Atsutoshi Yoshimura, Holger Heine, Eicke Latz, et al. "Molecular Genetic Analysis of an Endotoxin Nonresponder Mutant Cell Line." Journal of Experimental Medicine 194, no. 1 (July 2, 2001): 79–88. http://dx.doi.org/10.1084/jem.194.1.79.

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Somatic cell mutagenesis is a powerful tool for characterizing receptor systems. We reported previously two complementation groups of mutant cell lines derived from CD14-transfected Chinese hamster ovary–K1 fibroblasts defective in responses to bacterial endotoxin. Both classes of mutants expressed a normal gene product for Toll-like receptor (TLR)4, and fully responded to stimulation by tumor necrosis factor (TNF)-α or interleukin (IL)-1β. We identified the lesion in one of the complementation groups in the gene for MD-2, a putative TLR4 coreceptor. The nonresponder phenotype of this mutant was reversed by transfection with MD-2. Cloning of MD-2 from the nonresponder cell line revealed a point mutation in a highly conserved region resulting in a C95Y amino acid exchange. Both forms of MD-2 colocalized with TLR4 on the cell surface after transfection, but only the wild-type cDNA reverted the lipopolysaccharide (LPS) nonresponder phenotype. Furthermore, soluble MD-2, but not soluble MD-2C95Y, functioned to enable LPS responses in cells that expressed TLR4. Thus, MD-2 is a required component of the LPS signaling complex and can function as a soluble receptor for cells that do not otherwise express it. We hypothesize that MD-2 conformationally affects the extracellular domain of TLR4, perhaps resulting in a change in affinity for LPS or functioning as a portion of the true ligand for TLR4.

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Wang, Ying, Lijing Su, Matthew D. Morin, Brian T. Jones, Landon R. Whitby, Murali M. R. P. Surakattula, Hua Huang, et al. "TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS." Proceedings of the National Academy of Sciences 113, no. 7 (February 1, 2016): E884—E893. http://dx.doi.org/10.1073/pnas.1525639113.

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Structurally disparate molecules reportedly engage and activate Toll-like receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and activation by dissimilar ligands remain unknown. We describe Neoseptins, chemically synthesized peptidomimetics that bear no structural similarity to the established TLR4 ligand, lipopolysaccharide (LPS), but productively engage the mouse TLR4 (mTLR4)/myeloid differentiation factor 2 (MD-2) complex. Neoseptin-3 activates mTLR4/MD-2 independently of CD14 and triggers canonical myeloid differentiation primary response gene 88 (MyD88)- and Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling. The crystal structure mTLR4/MD-2/Neoseptin-3 at 2.57-Å resolution reveals that Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic pocket of MD-2, inducing an active receptor complex similar to that induced by lipid A. However, Neoseptin-3 and lipid A form dissimilar molecular contacts to achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS.

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Zhu, Xiaolong, R. Davis Manning, Deyin Lu, Celso E. Gomez-Sanchez, Yiling Fu, Luis A. Juncos, and Ruisheng Liu. "Aldosterone stimulates superoxide production in macula densa cells." American Journal of Physiology-Renal Physiology 301, no. 3 (September 2011): F529—F535. http://dx.doi.org/10.1152/ajprenal.00596.2010.

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Two major factors which regulate tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole are release of superoxide (O2−) and nitric oxide (NO) by macula densa (MD) cells. MD O2− inactivates NO; however, among the factors that increase MD O2− release, the role of aldosterone is unclear. We hypothesize that aldosterone activates the mineralocorticoid receptor (MR) on MD cells, resulting in increased O2− production due to upregulation of cyclooxygenase-1 (COX-2) and NOX-2, and NOX-4, isoforms of NAD(P)H oxidase. Studies were performed on MMDD1 cells, a renal epithelial cell line with properties of MD cells. RT-PCR and Western blotting confirmed the expression of MR. Aldosterone (10−8 mol/l for 30 min) doubled MMDD1 cell O2− production, and this was completely blocked by MR inhibition with 10−5 mol/l eplerenone. RT-PCR, real-time PCR, and Western blotting demonstrated aldosterone-induced increases in COX-2, NOX-2, and NOX-4 expression. Inhibition of COX-2 (NS398), NADPH oxidase (apocynin), or a combination blocked aldosterone-induced O2− production to the same degree. These data suggest that aldosterone-stimulated MD O2− production is mediated by COX-2 and NADPH oxidase. Next, COX-2 small-interfering RNA (siRNA) specifically decreased COX-2 mRNA without affecting NOX-2 or NOX-4 mRNAs. In the presence of the COX-2 siRNA, the aldosterone-induced increases in COX-2, NOX-2, and NOX-4 mRNAs and O2− production were completely blocked, suggesting that COX-2 causes increased expression of NOX-2 and NOX-4. In conclusion 1) MD cells express MR; 2) aldosterone increases O2− production by activating MR; and 3) aldosterone stimulates COX-2, which further activates NOX-2 and NOX-4 and generates O2−. The resulting balance between O2− and NO in the MD is important in modulating TGF.

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Tissières, Pierre, Irène Dunn-Siegrist, Michela Schäppi, Greg Elson, Rachel Comte, Vandack Nobre, and Jérôme Pugin. "Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria." Blood 111, no. 4 (February 15, 2008): 2122–31. http://dx.doi.org/10.1182/blood-2007-06-097782.

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Myeloid differentiation factor-2 (MD-2) is a lipopolysaccharide (LPS)-binding protein usually coexpressed with and binding to Toll-like receptor 4 (TLR4), conferring LPS responsiveness of immune cells. MD-2 is also found as a soluble protein. Soluble MD-2 (sMD-2) levels are markedly elevated in plasma from patients with severe infections, and in other fluids from inflamed tissues. We show that sMD-2 is a type II acute-phase protein. Soluble MD-2 mRNA and protein levels are up-regulated in mouse liver after the induction of an acute-phase response. It is secreted by human hepatocytic cells and up-regulated by interleukin-6. Soluble MD-2 binds to Gram-negative but not Gram-positive bacteria, and sMD-2 secreted by hepatocytic cells is an essential cofactor for the activation of TLR4-expressing cells by Gram-negative bacteria. Soluble MD-2 opsonization of Gram-negative bacteria accelerates and enhances phagocytosis, principally by polymorphonuclear neutrophils. In summary, our results demonstrate that sMD-2 is a newly recognized type II acute-phase reactant, an opsonin for Gram-negative bacteria, and a cofactor essential for the activation of TLR4-expressing cells. This suggests that sMD-2 plays a key role in the host innate immune response to Gram-negative infections.

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Giovanni, Sartore, Burlina Silvia, Ragazzi Eugenio, Ferraresso Stefania, Valentini Romina, and Lapolla Annunziata. "Mediterranean Diet and Red Yeast Rice Supplementation for the Management of Hyperlipidemia in Statin-Intolerant Patients with or without Type 2 Diabetes." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/743473.

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Lipid profile could be modified by Mediterranean diet (MD) and by red yeast rice (RYR). We assessed the lipid-lowering effects of MD alone or in combination with RYR on dyslipidemic statin-intolerant subjects, with or without type 2 diabetes, for 24 weeks. We evaluated the low-density lipoprotein (LDL) cholesterol level, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride, liver enzyme, and creatinine phosphokinase (CPK) levels. We studied 171 patients: 46 type 2 diabetic patients treated with MD alone (Group 1), 44 type 2 diabetic patients treated with MD associated with RYR (Group 2), 38 dyslipidemic patients treated with MD alone (Group 3), and 43 dyslipidemic patients treated with MD plus RYR (Group 4). The mean percentage changes in LDL cholesterol from the baseline were-7.34±3.14% (P<0.05) for Group 1;-21.02±1.63% (P<0.001) for Group 2;-12.47±1.75% (P<0.001) for Group 3; and-22±2.19% (P<0.001) for Group 4 with significant intergroup difference (Group 1 versus Group 2,P<0.001; Group 3 versus Group 4,P>0.05). No significant increase in AST, ALT, and CPK levels was observed in all groups. Our results indicate that MD alone is effective in reducing LDL cholesterol levels in statin-intolerant patients with a presumably low cardiovascular risk, but associating MD with the administration of RYR improves patients’ LDL cholesterol levels more, and in patients with type 2 diabetes.

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Watanabe, Yasuharu, Yoshinori Nagai, Tomoya Nakamura, Shizuo Akira, Kensuke Miyake, and Kiyoshi Takatsu. "The Radioprotective 105/MD-1 Complex Contributes to Diet-induced Obesity and Adipose Tissue Inflammation (172.23)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 172.23. http://dx.doi.org/10.4049/jimmunol.188.supp.172.23.

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Abstract Accumulating evidence suggest that innate immunity is associated with obesity-induced chronic inflammation and metabolic disorders. For example, the TLR4/MD-2 complex recognizes free fatty acids (FAAs) derived from adipose tissue and promotes adipose tissue inflammation and insulin resistance. The RP105/MD-1 complex is a homolog of the TLR4/MD-2 complex. However, the roles of RP105/MD-1 complex in adipose tissue inflammation have remained elusive. We now report that the RP105/MD-1 complex contributes to high-fat diet (HFD)-induced obesity, adipose tissue inflammation, and insulin resistance independent of TLR4 signaling. RP105 mRNA expression is dramatically increased by HFD in stromal vascular fraction of epididymal white adipose tissue (eWAT) in wild-type (WT) mice. In human, RP105 mRNA expression is also increased in the visceral adipose tissue of obese subjects. The RP105/MD-1 complex is expressed by most adipose tissue macrophages (ATMs). HFD increases RP105/MD-1 expression on the M1 ATMs in eWAT. Increased RP105 and MD-1 mRNA expression in macrophages is induced by co-culture with 3T3L-1 adipocytes. RP105 KO and MD-1 KO mice have less HFD-induced adipose tissue inflammation, hepatic steatosis and insulin resistance compared to these in WT and TLR4 KO mice. Finally, the saturated FAAs palmitic and stearic acids activate TLR4/MD-2 but not RP105/MD-1. Thus, the RP105/MD-1 complex is a major mediator of adipose tissue inflammation independent of TLR4 signaling.

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