scholarly journals Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

2020 ◽  
Author(s):  
Lei Li ◽  
Xiang-Hui Wu ◽  
Xiao-Jing Zhao ◽  
Lu Xu ◽  
Cai-Long Pan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mapk Signaling ◽  
Amyloid Deposition ◽  
Microglial Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Therapeutic Effects ◽  
Inflammatory Phenotype ◽  
Β Amyloid ◽  
Anti Inflammatory ◽  
Behavioral Impairments

Abstract Background : Alzheimer’s disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. Methods : The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, Nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence and flow cytometry analysis. Results : Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro . After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. Conclusions : Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

scholarly journals Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

2019 ◽  
Author(s):  
Lei Li ◽  
Xiang-Hui Wu ◽  
Xiao-Jing Zhao ◽  
Lu Xu ◽  
Cai-Long Pan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Amyloid Deposition ◽  
Microglial Cells ◽  
Therapeutic Effects ◽  
Inflammatory Phenotype ◽  
Β Amyloid ◽  
Anti Inflammatory ◽  
Behavioral Impairments

Abstract Background: Alzheimer’s disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. Methods: The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated. Results: Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. Conclusions: Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

scholarly journals Anemoside B4 ameliorates TNBS-induced colitis through S100A9/MAPK/NF-κB signaling pathway

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yong Zhang ◽  
Zhengxia Zha ◽  
Wenhua Shen ◽  
Dan Li ◽  
Naixin Kang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Tca Cycle ◽  
Mapk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Trinitrobenzene Sulfonic Acid ◽  
Therapeutic Effects ◽  
Triterpenoid Saponin ◽  
Label Free

Abstract Background Despite the increased morbidity of ulcerative colitis (UC) in the developing countries, available treatments remain unsatisfactory. Therefore, it is urgent to discover more effective therapeutic strategies. Pulsatilla chinensis was widely used for the treatment of inflamed intestinal diseases including UC for thousands of years in China. Anemoside B4, the most abundant triterpenoid saponin isolated from P. chinensis, exerts anti-inflammatory and antioxidant effects and may be the most active compounds, which is responsible for the therapeutic effects. However, the mechanism how anemoside B4 executes its biological functions is still elusive. Methods Here, we used the 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model to evaluate the therapeutic effect of anemoside B4. Blood samples of colitis rats were collected for hematology analysis. The inflammation-associated factors were investigated by enzyme-linked immunosorbent assay (ELISA). Cell proliferation and apoptosis was determined with EdU cell proliferation assay and TUNEL assay. The proteins regulated by anemoside B4 were identified by label-free quantitative proteomics. The significantly down-regulated proteins were verified by Western blotting analysis. mRNA expression was analyzed by quantitative real-time RT-PCR. Results The results showed that anemoside B4 ameliorated TNBS-induced colitis symptoms, including tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine production, apoptosis and slowed proliferation in colon. Quantitative proteomic analyses discovered that 56 proteins were significantly altered by anemoside B4 in the TNBS-induced rats. These proteins mainly clustered in tricarboxylic acid (TCA) cycle and respiratory electron transport chain. Among the altered proteins, S100A9 is one of the most significantly down-regulated proteins and associated with NF-κB and MAPK signaling pathways in the pathogenesis of UC. Further experiments revealed that anemoside B4 suppressed the expression of S100A9 and its downstream genes including TLR4 and NF-κB in colon. In vitro, anemoside B4 could inhibit the NF-κB signaling pathway induced by recombinant S100A9 protein in human intestinal epithelial Caco-2 cells. Moreover, anemoside B4 inhibits neutrophils recruitment and activation in colon induced by TNBS. Conclusions Our results demonstrate that anemoside B4 prevents TNBS-induced colitis by inhibiting the NF-κB signaling pathway through deactivating S100A9, suggesting that anemoside B4 is a promising therapeutic candidate for colitis.

scholarly journals Anemoside B4 ameliorates TNBS-induced colitis through S100A9/MAPK/NF-κB signaling pathway

2020 ◽  
Author(s):  
Yong Zhang ◽  
Zhengxia Zha ◽  
Wenhua Shen ◽  
Dan Li ◽  
Naixin Kang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Tca Cycle ◽  
Mapk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Trinitrobenzene Sulfonic Acid ◽  
Therapeutic Effects ◽  
Triterpenoid Saponin ◽  
Label Free ◽  
Altered Proteins

Abstract Background: Despite the increased morbidity of ulcerative colitis (UC) in the developing countries, available treatments remain unsatisfactory. Therefore, it is urgent to discover more effective therapeutic strategies. Pulsatilla chinensis was widely used for the treatment of inflamed intestinal diseases including UC for thousands of years in China. Anemoside B4, the most abundant triterpenoid saponin isolated from P. chinensis, exerts anti-inflammatory and antioxidant effects and may be the most active compounds, which is responsible for the therapeutic effects. However, the mechanism how anemoside B4 executes its biological functions is still elusive.Methods: Here, we used the 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model to evaluate the therapeutic effect of anemoside B4. Blood samples of colitis rats were collected for hematology analysis. The inflammation-associated factors were investigated by enzyme-linked immunosorbent assay (ELISA). Cell proliferation and apoptosis was determined with EdU cell proliferation assay and TUNEL assay. The proteins regulated by anemoside B4 were identified by label-free quantitative proteomics. The significantly down-regulated proteins were verified by Western blotting analysis. mRNA expression was analyzed by quantitative real-time RT-PCR.Results: The results showed that anemoside B4 ameliorated TNBS-induced colitis symptoms, including tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine production, apoptosis and slowed proliferation in colon. Quantitative proteomic analyses discovered that 56 proteins were significantly altered by anemoside B4 in the TNBS-induced rats. These proteins mainly clustered in tricarboxylic acid (TCA) cycle and respiratory electron transport chain. Among the altered proteins, S100A9 is one of the most significantly down-regulated proteins and associated with NF-κB and MAPK signaling pathways in the pathogenesis of UC. Further experiments revealed that anemoside B4 suppressed the expression of S100A9 and its downstream genes including TLR4 and NF-κB in colon. In vitro, anemoside B4 could inhibit the NF-κB signaling pathway induced by recombinant S100A9 protein in human intestinal epithelial Caco-2 cells. Moreover, anemoside B4 inhibits neutrophils recruitment and activation in colon induced by TNBS.Conclusions: Our results demonstrate that anemoside B4 prevents TNBS-induced colitis by inhibiting the NF-κB signaling pathway through deactivating S100A9, suggesting that anemoside B4 is a promising therapeutic candidate for colitis.

scholarly journals Anti-Inflammatory Effect of Simonsinol on Lipopolysaccharide Stimulated RAW264.7 Cells through Inactivation of NF-κB Signaling Pathway

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3573
Author(s):  
Lian-Chun Li ◽  
Zheng-Hong Pan ◽  
De-Sheng Ning ◽  
Yu-Xia Fu
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathway ◽  
Morphological Changes ◽  
Raw264.7 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Oxide Synthase ◽  
Necrosis Factor

Simonsinol is a natural sesqui-neolignan firstly isolated from the bark of Illicium simonsii. In this study, the anti-inflammatory activity of simonsinol was investigated with a lipopolysaccharide (LPS)-stimulated murine macrophages RAW264.7 cells model. The results demonstrated that simonsinol could antagonize the effect of LPS on morphological changes of RAW264.7 cells, and decrease the production of nitric oxide (NO), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW264.7 cells, as determined by Griess assay and enzyme-linked immunosorbent assay (ELISA). Furthermore, simonsinol could downregulate transcription of inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 as measured by reverse transcription polymerase chain reaction (RT-PCR), and inhibit phosphorylation of the alpha inhibitor of NF-κB (IκBα) as assayed by Western blot. In conclusion, these data demonstrate that simonsinol could inhibit inflammation response in LPS-stimulated RAW264.7 cells through the inactivation of the nuclear transcription factor kappa-B (NF-κB) signaling pathway.

scholarly journals Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/β-Catenin Signaling Pathway

2018 ◽  
Vol 51 (6) ◽  
pp. 2575-2590 ◽  
Author(s):  
Gang Zhong ◽  
Ruiming Liang ◽  
Jun Yao ◽  
Jia Li ◽  
Tongmeng Jiang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cruciate Ligament ◽  
Interleukin 1 ◽  
Cartilage Degradation ◽  
Chondrocyte Apoptosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Viability Assay ◽  
Necrosis Factor Alpha ◽  
Anti Inflammatory

Background/Aims: Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/β-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. Methods: The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1β)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. Results: ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/β-catenin signaling pathway, suggesting that it might serve as a Wnt/β-catenin antagonist to reduce inflammation and prevent cartilage degradation. Conclusion: In conclusion, ART alleviates IL-1β-mediated inflammatory response and OA progression by regulating the Wnt/β-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA.

scholarly journals PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2420
Author(s):  
Minju Lee ◽  
Gee-Hye Kim ◽  
Miyeon Kim ◽  
Ji Min Seo ◽  
Yu Mi Kim ◽  
...  
Keyword(s):  
Scale Up ◽  
Therapeutic Effects ◽  
Arginase 1 ◽  
Inflammatory Phenotype ◽  
Monosodium Iodoacetate ◽  
M1 Phenotype ◽  
Interleukin 1Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Inflammatory Macrophages

Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.

scholarly journals Integrated Network and Experimental Pharmacology for Deciphering the Medicinal Substances and Multiple Mechanisms of Duhuo Jisheng Decoction in Osteoarthritis Therapy

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Wenyu Xiao ◽  
Weibing Sun ◽  
Hui Lian ◽  
Juexin Shen
Keyword(s):  
Signaling Pathway ◽  
Mapk Signaling ◽  
Herbal Remedies ◽  
Chondrocyte Apoptosis ◽  
Therapeutic Effects ◽  
Integrated Network ◽  
Experimental Pharmacology ◽  
Joint Disorder ◽  
Medicinal Substances ◽  
Long Time

Osteoarthritis (OA) is currently the most common joint disorder worldwide. In last decades, herbal remedies have achieved a significant advancement in the treatment of OA. Duhuo Jisheng Decoction (DHJS), an herbal formula consisting of 15 medicinal herbs, has a long-time practice in OA therapy in China. However, its therapeutic mechanisms have not been comprehensively elucidated. In the present work, integrated network and experimental pharmacology were performed for investigating the therapeutic substances and mechanisms of DHJS. Based on network analysis, the contribution of each herb to OA therapy was evaluated. Furthermore, a series of potential targets and signaling pathways were enriched, which could be involved in the therapeutic effects and mechanisms of DHJS. Further experimental results indicated that DHJS attenuated TNFα, IL-6, MMP-1, MMP-9, MMP-13, and ADAMTs-5 expression, inhibited NF-κB and p38 MAPK signaling pathway, activated AMPK-SIRT1 signaling pathway, and suppressed chondrocyte apoptosis, which synergistically contributed to OA therapy. Our work demonstrated that DHJS could be very promising for OA therapy through synergistically acting on multitargets and multipathways.

Fermented ginseng attenuates lipopolysaccharide-induced inflammatory responses by activating the TLR4/MAPK signaling pathway and remediating gut barrier

2021 ◽  
Author(s):  
Jingjing Fan ◽  
Sitong Liu ◽  
Zhiyi Ai ◽  
Yiying Chen ◽  
Yonghong Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Mapk Signaling ◽  
Physiological Effect ◽  
Mapk Signaling Pathway ◽  
Gut Barrier ◽  
Fermented Ginseng ◽  
Anti Inflammatory

Generally, ginsenosides have the physiological effect of an anti-inflammatory immunity.

Glia Maturation Factor-Gamma Negatively Modulates Fatty Acid-Induced Inflammation in Macrophages Via PI3K/AKT Pathway

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1096-1096
Author(s):  
Wulin Aerbajinai ◽  
Kyung Chin ◽  
Jianqiong Zhu ◽  
Griffin P Rodgers
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Enzyme Linked Immunosorbent Assay ◽  
Glia Maturation Factor ◽  
Endogenous Expression ◽  
Maturation Factor ◽  
Tnf Α

Abstract Abstract 1096 The macrophage-mediated inflammatory response plays a critical role in the development of obesity-related tissue inflammation and insulin resistance. Free-fatty acids (FFAs) are well-characterized factors causing production of inflammatory factors and insulin resistance. Glia maturation factor-gamma (GMFG), a member of the ADF/cofilin family of proteins that regulate actin cytoskeleton reorganization, is preferentially expressed in inflammatory cells, but its function in the macrophages immune response remains unclear. In this study, we investigated whether GMFG may affect FFAs-induced inflammatory reaction in macrophages. We show here that silencing of GMFG (80% inhibition of the endogenous expression levels) by transfected with GMFG siRNA significantly enhanced FFAs-induced production of proinflammatory cytokines and chemokines, including TNF-α, IL-6 and IL-8 compared to transfected non-targeting silencing siRNA in human peripheral blood monocytes-derived macrophage (1.2 × 104 ± 224.2 vs. 4.6 × 103 ± 98.4 molecules/ng, P < 0.001; 1.2 × 103 ± 56.1 vs. 2.3 × 102 ± 8.4 molecules/ng, P =0.001; 1.3 × 107 ± 5.8 × 105 vs. 4.9 × 106 ± 2.8 × 105 molecules/ng, P < 0.001) as determined by quantitative real time-PCR and confirmed by enzyme-linked immunosorbent assay (TNF-α: 9.4 × 102 ± 38.6 vs. 5.6 × 102 ± 31.1 ng/mL, P < 0.01; IL-6: 4.5 × 102 ± 31.3 vs. 2.2 × 102 ± 22.7 ng/mL, P < 0.01; IL-8: 2.2 × 103 ± 205.5 vs. 1.3 × 103 ± 113.9 ng/mL, P < 0.01). These increased inflammatory cytokines resulted from an increased activation of NF-κB and the ERK1/2 MAPK signaling pathway (based on increased NF-κB p65 phosphorylation, IκBα loss and enhanced phosphorylation of ERK1/2 in Western blot analysis) and a reduced phosphorylation of the PI3K/Akt/GSK3-β pathway following FFAs stimulation. Overexpression of GFP-GMFG in GMFG-silenced cells abrogated enhanced phosphorylation of NF-κB p65, ERK1/2 MAPK and reduced phosphorylation of Akt and GSK3-β. Furthermore, in cells in which GMFG was knockdown, FFAs induced an increase in the expression of SHIP1, a phosphatase that negatively regulates the PI3K signaling pathway, suggesting increased SHIP1 expression may be responsible for the augmentation of inflammatory cytokines following FFAs stimulation. We also show that silencing of GMFG enhances the oxidized low density lipoprotein (oxLDL) induced expression of TNF-α and IL-6 (2.9 × 104 ± 204.8 vs. 1.3 × 104 ± 153.9 molecules/ng, P < 0.01; 2.5 × 103 ± 31.3 vs. 9.2 × 102 ± 22.7 ng/mL, P < 0.01) in MDM. Taking together with the data that GMFG is constitutively expressed in macrophages and its expression is down-regulated by FFAs stimulation, GMFG might function as a novel negative regulator through participating in the PI3K/Akt signaling pathway, suggesting that macrophage-specific modulation of GMFG may be beneficial in the treatment of FFAs induced inflammation. Disclosures: No relevant conflicts of interest to declare.

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