scholarly journals Functions of NF-κB1 and NF-κB2 in immune cell biology

2004 ◽  
Vol 382 (2) ◽  
pp. 393-409 ◽  
Author(s):  
Sören BEINKE ◽  
Steven C. LEY
Keyword(s):  
B Cell ◽  
Map Kinase ◽  
Cell Biology ◽  
B Lymphocyte ◽  
Immune Cell ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Tumour Progression ◽  
Mitogen Activated Protein Kinase ◽  
P100 Processing

Two members of the NF-κB (nuclear factor κB)/Rel transcription factor family, NF-κB1 and NF-κB2, are produced as precursor proteins, NF-κB1 p105 and NF-κB2 p100 respectively. These are proteolytically processed by the proteasome to produce the mature transcription factors NF-κB1 p50 and NF-κB2 p52. p105 and p100 are known to function additionally as IκBs (inhibitors of NF-κB), which retain associated NF-κB subunits in the cytoplasm of unstimulated cells. The present review focuses on the latest advances in research on the function of NF-κB1 and NF-κB2 in immune cells. NF-κB2 p100 processing has recently been shown to be stimulated by a subset of NF-κB inducers, including lymphotoxin-β, B-cell activating factor and CD40 ligand, via a novel signalling pathway. This promotes the nuclear translocation of p52-containing NF-κB dimers, which regulate peripheral lymphoid organogenesis and B-lymphocyte differentiation. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas. NF-κB1 has a distinct function from NF-κB2, and is important in controlling lymphocyte and macrophage function in immune and inflammatory responses. In contrast with p100, p105 is constitutively processed to p50. However, after stimulation with agonists, such as tumour necrosis factor-α and lipopolysaccharide, p105 is completely degraded by the proteasome. This releases associated p50, which translocates into the nucleus to modulate target gene expression. p105 degradation also liberates the p105-associated MAP kinase (mitogen-activated protein kinase) kinase kinase TPL-2 (tumour progression locus-2), which can then activate the ERK (extracellular-signal-regulated kinase)/MAP kinase cascade. Thus, in addition to its role in NF-κB activation, p105 functions as a regulator of MAP kinase signalling.

Suppression of LPS-induced inflammatory responses by inflexanin B in BV2 microglial cells

2013 ◽  
Vol 91 (2) ◽  
pp. 141-148 ◽  
Author(s):  
Ji-Youn Lim ◽  
Donggeun Sul ◽  
Bang Yeon Hwang ◽  
Kwang Woo Hwang ◽  
Ki-Yeol Yoo ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Bv2 Cells ◽  
Mitogen Activated Protein ◽  
Physiological Homeostasis ◽  
The Central Nervous System ◽  
Factor Α ◽  
Bv2 Microglial Cells

Microglia are a type of resident macrophage that functions as an inflammation modulator in the central nervous system. Over-activation of microglia by a range of stimuli disrupts the physiological homeostasis of the brain, and induces inflammatory response and degenerative processes, such as those implicated in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Therefore, we investigated the possible anti-inflammatory mechanisms of inflexanin B in murine microglial BV2 cells. Lipopolysaccharide (LPS) activated BV2 cells and induced the production of pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), and cytokines (interleukins-1β and -6, and tumour necrosis factor α). The LPS-induced production of pro-inflammatory mediators was associated with the enhancement of nuclear factor-kappaB (NF-κB) nuclear translocation and the activation of mitogen-activated protein kinase (MAPK) including ERK1/2 and JNK. Conversely, pretreatment of cells with inflexanin B (10 and 20 μg/mL) significantly reduced the production of pro-inflammatory mediators. This was accompanied with the reduced nuclear translocation of NF-κB and reduced activation of MAPKs. These results suggest that inflexanin B attenuated the LPS-induced inflammatory process by inhibiting the activation of NF-κB and MAPKs.

scholarly journals Myc stimulates B lymphocyte differentiation and amplifies calcium signaling

2007 ◽  
Vol 179 (4) ◽  
pp. 717-731 ◽  
Author(s):  
Tania Habib ◽  
Heon Park ◽  
Mark Tsang ◽  
Ignacio Moreno de Alborán ◽  
Andrea Nicks ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Target Genes ◽  
B Lymphocyte ◽  
Nuclear Translocation ◽  
Efflux Pump ◽  
Double Knockout ◽  
Activated T Cells ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

Deregulated expression of the Myc family of transcription factors (c-, N-, and L-myc) contributes to the development of many cancers by a mechanism believed to involve the stimulation of cell proliferation and inhibition of differentiation. However, using B cell–specific c-/N-myc double-knockout mice and Eμ-myc transgenic mice bred onto genetic backgrounds (recombinase-activating gene 2−/− and Btk−/− Tec−/−) whereby B cell development is arrested, we show that Myc is necessary to stimulate both proliferation and differentiation in primary B cells. Moreover, Myc expression results in sustained increases in intracellular Ca2+ ([Ca2+]i), which is required for Myc to stimulate B cell proliferation and differentiation. The increase in [Ca2+]i correlates with constitutive nuclear factor of activated T cells (NFAT) nuclear translocation, reduced Ca2+ efflux, and decreased expression of the plasma membrane Ca2+–adenosine triphosphatase (PMCA) efflux pump. Our findings demonstrate a revised model whereby Myc promotes both proliferation and differentiation, in part by a remarkable mechanism whereby Myc amplifies Ca2+ signals, thereby enabling the concurrent expression of Myc- and Ca2+-regulated target genes.

Chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of USP25

2017 ◽  
Vol 95 (5) ◽  
pp. 481-491 ◽  
Author(s):  
Changyu Ding ◽  
Fangfang Li ◽  
Yupeng Long ◽  
Jiang Zheng
Keyword(s):  
Macrophage Activation ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Ubiquitin Proteasome System ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Activation Of Transcription ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Ubiquitin Proteasome

Lipopolysaccharide (LPS) is a key pathogenic factor in sepsis, and its recognition by toll-like receptor 4 (TLR4) can activate two district signaling pathways, leading to activation of transcription factors including NF-κB and interferon regulatory factor 3 (IRF3). Chloroquine (CQ) has been shown to affect LPS–TLR4 colocalization and inhibit both MyD88-dependent and TRAM/TRIF-dependent pathways, though the mechanism involved is still poorly understood. Here, we found that the ubiquitin–proteasome system might be involved in this process. CQ increased USP25, a deubiquitinating enzyme, as well as mRNA and protein expression in a dose-dependent manner, which might to some degree be involved in CQ attenuation of LPS-induced macrophage activation. Overexpression of USP25 decreased LPS-induced inflammatory cytokines like TNF-α, IL-6, and IFN-β, while specific siRNA-mediated USP25 silencing increased TNF-α, IL-6, and IFN-β production and secretion. In addition, USP25 deletion strengthened mitogen-activated protein kinase (MAPKs) phosphorylation and IκB degradation. Moreover, USP25 interference increased NF-κB and IRF3 nuclear translocation. Taken together, our data demonstrated a new possible regulator of LPS-induced macrophage activation mediated by CQ, through upregulation of USP25.

scholarly journals Mitogen-Activated Protein Kinase-Dependent Interleukin-1α Intracrine Signaling Is Modulated by YopP during Yersinia enterocolitica Infection

2011 ◽  
Vol 80 (1) ◽  
pp. 289-297 ◽  
Author(s):  
Rumu Bose ◽  
Josephine Thinwa ◽  
Paola Chaparro ◽  
Youmin Zhong ◽  
Santanu Bose ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Yersinia Enterocolitica ◽  
Nuclear Translocation ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Virulence Plasmid ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
Interleukin 1Α

ABSTRACTYersinia enterocoliticais a food-borne pathogen that preferentially infects the Peyer's patches and mesenteric lymph nodes, causing an acute inflammatory reaction. Even thoughY. enterocoliticainduces a robust inflammatory response during infection, the bacterium has evolved a number of virulence factors to limit the extent of this response. We previously demonstrated that interleukin-1α (IL-1α) was critical for the induction of gut inflammation characteristic ofY. enterocoliticainfection. More recently, the known actions of IL-1α are becoming more complex because IL-1α can function both as a proinflammatory cytokine and as a nuclear factor. In this study, we tested the ability ofY. enterocoliticato modulate intracellular IL-1α-dependent IL-8 production in epithelial cells. Nuclear translocation of pre-IL-1α protein and IL-1α-dependent secretion of IL-8 into the culture supernatant were increased during infection with a strain lacking the 70-kDa virulence plasmid compared to the case during infection with the wild type, suggesting thatYersiniaouter proteins (Yops) might be involved in modulating intracellular IL-1α signaling. Infection of HeLa cells with a strain lacking theyopPgene resulted in increased nuclear translocation of pre-IL-1α and IL-1α-dependent secretion of IL-8 similar to what is observed with bacteria lacking the virulence plasmid. YopP is a protein acetylase that inhibits mitogen-activated protein kinase (MAP kinase)- and NF-κB-dependent signal transduction pathways. Nuclear translocation of pre-IL-1α and IL-1α-dependent secretion of IL-8 in response toYersinia enterocoliticainfection were dependent on extracellular signal-regulated kinase (ERK) and p38 MAP kinase signaling but independent of NF-κB. These data suggest thatY. enterocoliticainhibits intracellular pre-IL-1α signaling and subsequent proinflammatory responses through inhibition of MAP kinase pathways.

Negative cross-talk between interleukin-3 and interleukin-11 is mediated by suppressor of cytokine signalling-3 (SOCS-3)

2001 ◽  
Vol 353 (2) ◽  
pp. 223-230 ◽  
Author(s):  
Florence MAGRANGEAS ◽  
Olivier BOISTEAU ◽  
Sébastien DENIS ◽  
Yannick JACQUES ◽  
Stéphane MINVIELLE
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cross Talk ◽  
Nuclear Translocation ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Cell Potential ◽  
Interleukin 3 ◽  
Mitogen Activated Protein

Previous studies have shown that addition of interleukin-3 (IL-3) abrogated the B-cell potential of primary colonies supported by IL-11, erythropoietin, IL-7 and steel factor. However, the mechanism by which IL-3 exerts its inhibitory role is not understood. Using a variant of the mouse pro-B cell line Ba/F3 which expresses both IL-3 and IL-11 receptors, we showed that pretreatment of these cells with IL-3 before stimulation by IL-11 suppressed the tyrosine phosphorylation and nuclear translocation of STAT3 (signal transducer and activator of transcription 3). This inhibition occurred within 30min and required the synthesis of a negative regulator. The onset of IL-3-dependent inhibition was correlated temporally with the appearance of SOCS-3 (suppressor of cytokine signalling-3) protein. In addition, overexpression of SOCS-3 in the pro-B cell line effectively blocked STAT3 activation induced by IL-11. These findings establish that a cytokine (IL-3) that has been shown to modulate its own signal of activation is also able to down-regulate signalling activated by a different cytokine (IL-11). This cross-talk involves activation of the JAK (Janus kinase)/STAT signalling pathway, but not mitogen-activated protein kinase pathways, and is mediated, at least in part, by SOCS-3.

scholarly journals ETAS®50 Attenuates SARS-CoV-2 Spike Protein-Induced IL-6 and IL-1β Production by Suppressing p44/42 MAPK and Akt Phosphorylation in Murine Primary Macrophages

2021 ◽  
Author(s):  
Ken Shirato ◽  
Jun Takanari ◽  
Takako Kizaki
Keyword(s):  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Ultraviolet B ◽  
Asparagus Officinalis ◽  
Mitogen Activated Protein Kinase ◽  
Spike Protein ◽  
Dependent Manner ◽  
Simultaneous Treatment ◽  
Tlr4 Signaling

Excessive host inflammation following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with severity and mortality in coronavirus disease 2019 (COVID-19). We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) induces pro-inflammatory responses by activating toll-like receptor 4 (TLR4) signaling in macrophages. ETAS®50, a standardized extract of Asparagus officinalis stem, is a unique functional food that elicits anti-photoaging effects by suppressing pro-inflammatory signaling in hydrogen peroxide- and ultraviolet B-exposed skin fibroblasts. To elucidate its potential in preventing excessive inflammation in COVID-19, we examined the effects of ETAS®50 on pro-inflammatory responses in S1-stimulated murine peritoneal exudate macrophages. Co-treatment of the cells with ETAS®50 significantly attenuated S1-induced secretion of interleukin (IL)-6 in a concentration-dependent manner without reducing cell viability. ETAS®50 also markedly suppressed the S1-induced transcription of IL-6 and IL-1β. However, among the TLR4 signaling proteins, ETAS®50 did not affect the degradation of inhibitor κBα, nuclear translocation of nuclear factor-κB p65 subunit, and phosphorylation of c-Jun N-terminal kinase p54 subunit after S1 exposure. In contrast, ETAS®50 significantly suppressed S1-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and Akt. Attenuation of S1-induced transcription of IL-6 and IL-1β by the MAPK kinase inhibitor U0126 was greater than that by the Akt inhibitor perifosine, and the effects were potentiated by simultaneous treatment with both inhibitors. These results suggest that ETAS®50 attenuates S1-induced IL-6 and IL-1β production by suppressing p44/42 MAPK and Akt signaling in macrophages. Therefore, ETAS®50 may be beneficial in regulating excessive inflammation in patients with COVID-19.

scholarly journals Standardized Extract of Asparagus officinalis Stem Attenuates SARS-CoV-2 Spike Protein-Induced IL-6 and IL-1β Production by Suppressing p44/42 MAPK and Akt Phosphorylation in Murine Primary Macrophages

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6189
Author(s):  
Ken Shirato ◽  
Jun Takanari ◽  
Takako Kizaki
Keyword(s):  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Asparagus Officinalis ◽  
Mitogen Activated Protein Kinase ◽  
Spike Protein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Signaling Proteins ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Tlr4 Signaling

Excessive host inflammation following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with severity and mortality in coronavirus disease 2019 (COVID-19). We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) induces pro-inflammatory responses by activating toll-like receptor 4 (TLR4) signaling in macrophages. A standardized extract of Asparagus officinalis stem (EAS) is a unique functional food that elicits anti-photoaging effects by suppressing pro-inflammatory signaling in hydrogen peroxide and ultraviolet B-exposed skin fibroblasts. To elucidate its potential in preventing excessive inflammation in COVID-19, we examined the effects of EAS on pro-inflammatory responses in S1-stimulated macrophages. Murine peritoneal exudate macrophages were co-treated with EAS and S1. Concentrations and mRNA levels of pro-inflammatory cytokines were assessed using enzyme-linked immunosorbent assay and reverse transcription and real-time polymerase chain reaction, respectively. Expression and phosphorylation levels of signaling proteins were analyzed using western blotting and fluorescence immunomicroscopy. EAS significantly attenuated S1-induced secretion of interleukin (IL)-6 in a concentration-dependent manner without reducing cell viability. EAS also markedly suppressed the S1-induced transcription of IL-6 and IL-1β. However, among the TLR4 signaling proteins, EAS did not affect the degradation of inhibitor κBα, nuclear translocation of nuclear factor-κB p65 subunit, and phosphorylation of c-Jun N-terminal kinase p54 subunit after S1 exposure. In contrast, EAS significantly suppressed S1-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and Akt. Attenuation of S1-induced transcription of IL-6 and IL-1β by the MAPK kinase inhibitor U0126 was greater than that by the Akt inhibitor perifosine, and the effects were potentiated by simultaneous treatment with both inhibitors. These results suggest that EAS attenuates S1-induced IL-6 and IL-1β production by suppressing p44/42 MAPK and Akt signaling in macrophages. Therefore, EAS may be beneficial in regulating excessive inflammation in patients with COVID-19.

scholarly journals Discovery of Phenolic Glycoside from Hyssopus cuspidatus Attenuates LPS-Induced Inflammatory Responses by Inhibition of iNOS and COX-2 Expression through Suppression of NF-κB Activation

2021 ◽  
Vol 22 (22) ◽  
pp. 12128
Author(s):  
Xingyu Liu ◽  
Jie Su ◽  
Geng Wang ◽  
Lihua Zheng ◽  
Guannan Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Peritoneal Macrophages ◽  
Mitogen Activated Protein Kinase ◽  
Raw 264.7 Cells ◽  
Phenolic Glycoside ◽  
No Production ◽  
Cox 2 ◽  
Anti Inflammatory

It seems quite necessary to obtain effective substances from natural products against inflammatory response (IR) as there are presently clinical problems regarding accompanying side effects and lowered quality of life. This work aimed to investigate the abilities of hyssopuside (HY), a novel phenolic glycoside isolated from Hyssopus cuspidatus (H. cuspidatus), against IR in lipopolysaccharide (LPS)-induced RAW 264.7 cells and mouse peritoneal macrophages. The results indicated that HY could reduce nitric oxide (NO) production and inhibit the production and secretion of pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in LPS-stimulated macrophages. Moreover, data from the immunofluorescence study showed that HY suppressed nuclear translocation of nuclear factor-kappa B (NF-κB) upon LPS induction. The Western blot results suggested that HY reversed the LPS-induced degradation of IκB (inhibitor of NF-κB), which is normally required for the activation of NF-κB. Meanwhile, the overexpression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) diminished significantly with the presence of HY in response to LPS stimulation. On the other hand, HY had a negligible impact on the activation of mitogen-activated protein kinase (MAPK) pathways. Moreover, an in silico study of HY against four essential proteins/enzymes revealed that COX-2 was the most efficient enzyme for the interaction, and binding of residues Phe179, Asn351, and Ser424 with HY played crucial roles in the observed activity. The structure analysis indicated the typical characterizations with phenylethanoid glycoside contributed to the anti-inflammatory effects of HY. These results indicated that HY manipulated its anti-inflammatory effects mainly through blocking the NF-κB signal transduction pathways. Collectively, we believe that HY could be a potential alternative phenolic agent for alleviating excessive inflammation in many inflammation-associated diseases.

scholarly journals Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses to Pneumocystis murina Infection in Healthy Mice

2006 ◽  
Vol 13 (2) ◽  
pp. 193-201 ◽  
Author(s):  
David J. Feola ◽  
Beth A. Garvy
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Immune Cell ◽  
Lavage Fluid ◽  
Cell Phenotype ◽  
Cell Populations ◽  
Control Group

ABSTRACT We have previously shown that zidovudine plus sulfamethoxazole-trimethoprim exposure decreases immune cell populations in the bone marrow of healthy mice by inducing apoptosis. The hypothesis of the current work was that this toxicity would have an adverse impact on the immune response. To determine this, BALB/c mice were treated with zidovudine, sulfamethoxazole-trimethoprim, the combination of both drugs, or vehicle only (control) via oral gavage for 21 days. On day 4 after dosing completion, the mice were infected intratracheally with 1 × 107 Pneumocystis murina organisms. Immune cell populations (in lung digest, bronchoalveolar lavage fluid, tracheobronchial lymph node, and bone marrow samples), the lung Pneumocystis burden, and serum Pneumocystis-specific antibody titers were determined at days 6, 10, and 20 postinfection. While total bone marrow cellularity was recovered by day 6 postinfection in the combination exposure group, B-cell numbers did not recover until 10 days postinfection, primarily due to the persistent depletion of the late pre-B-cell phenotype. The numbers of CD4+ and CD8+ T cells, as well as the numbers of total B cells and activated B cells in tracheobronchial lymph nodes, were decreased at days 10 and 20 as a result of zidovudine plus sulfamethoxazole-trimethoprim exposure compared to the numbers in the control group. No significant differences in lung lavage or lung digest cell populations were observed. There was a trend of a delay in Pneumocystis clearance in the combination treatment group, and Pneumocystis-specific serum immunoglobulin G titers were reduced at day 20 postinfection. Together, these data indicate that the combination of zidovudine and sulfamethoxazole-trimethoprim adversely affects the humoral immune response to Pneumocystis.

scholarly journals Subanesthetic Isoflurane Reduces Zymosan-Induced Inflammation in Murine Kupffer Cells by Inhibiting ROS-Activated p38 MAPK/NF-κB Signaling

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Hui Wang ◽  
Lei Wang ◽  
Nan-lin Li ◽  
Jun-tang Li ◽  
Feng Yu ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Kupffer Cells ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Prostaglandin E ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Volatile anesthetic isoflurane (ISO) has immunomodulatory effects. The fungal component zymosan (ZY) induces inflammation through toll-like receptor 2 or dectin-1 signaling. We investigated the molecular actions of subanesthetic (0.7%) ISO against ZY-induced inflammatory activation in murine Kupffer cells (KCs), which are known as the resident macrophages within the liver. We observed that ISO reduced ZY-induced cyclooxygenase 2 upregulation and prostaglandin E2release, as determined by western blot and radioimmunoassay, respectively. ISO also reduced the production of tumor necrosis factor-α, interleukin-1β, IL-6, high-mobility group box-1, macrophage inflammatory protein-1α, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 as assessed by enzyme-linked immunosorbent assays. ISO blocked the ZY-induced nuclear translocation and DNA-binding activity of nuclear factor- (NF)-κB p65. Moreover, ISO attenuated ZY-induced p38 mitogen-activated protein kinase (MAPK) activation partly by scavenging reactive oxygen species (ROS); the interregulation that ROS activated p38 MAPK followed by NF-κB activation was crucial for the ZY-induced inflammatory responses in KCs. Anin vivostudy by peritoneal injection of ZY into BALB/C mice confirmed the anti-inflammatory properties of 0.7% ISO against ZY in KCs. These results suggest that ISO ameliorates ZY-induced inflammatory responses in murine KCs by inhibiting the interconnected ROS/p38 MAPK/NF-κB signaling pathways.

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