EXPERIMENTAL AND MOLECULAR PATHOLOGY
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2020
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IF 2.28
Chunyan Tian,Fengli Gao,Xing Li,Zhuying Li
Asthma is a chronic inflammatory airway disease. Icariside II has been reported to exert anti-inflammatory effect in multiple human diseases . The present study aimed to investigate the effects and mechanisms of Icariside II on airway inflammation and remodeling in asthma. We established an asthma mouse model with ovalbumin (OVA) immunization. Histological analysis using H&E, PAS and Masson staining showed that administration of Icariside II attenuated OVA-induced airway inflammation and remodeling. Icariside II reduced the numbers of total white blood cells and eosinophils in bronchoalveolar lavage fluid (BALF). The levels of interleukin (IL)-4, IL-5, IL-13 and transforming growth factor (TGF)-β1 in peripheral blood and the expression of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), eotaxin-1, CC-chemokine receptor-3 (CCR-3), Toll-like receptor (TLR)-2 and TLR-4 were significantly down-regulated in lung tissues of OVA-induced mouse model. These results suggested that Icariside II inhibited eosinophil activation and thus decreased eosinophils-induced airway inflammation and remodeling in asthma. Moreover, Icariside II suppressed TGF-β1-induced cell proliferation , migration, and CTGF expression in airway smooth muscle cells (ASMCs). In both OVA-induced mouse model of asthma and TGF-β1-induced ASMCs, Icariside II decreased IκBα degradation, nuclear translocation of NF-κB p65 and STAT3 phophorylation, indicating an inactivation of NF-κB and STAT3 in the presence of Icariside II. Therefore, we demonstrate that Icariside II attenuates eosinophils-induced airway inflammation and remodeling in asthmatic mice and inhibits TGF-β1-induced cell proliferation and migration in ASMCs via suppressing NF-κB and STAT3 signalings.
研究领域:
免疫学
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药理学
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呼吸医学
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Pharmaceuticals
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2022
·Vol. 16
·期 1
·9
·
IF 5.215
Chunyu Wu,Chenping Sun,Xianghui Han,Yiyi Ye,Yuenong Qin,Sheng Liu
Sanyin formula (SYF) is used as a complementary treatment for triple-negative breast cancer (TNBC). The purpose of this study was to identify the potential functional components and clarify the underlying molecular mechanisms of SYF in TNBC. High-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) was used to identify the main components of SYF extracts. Network pharmacology and bioinformatic analyses were carried out to identify potential candidate targets of SYF in TNBC. Cell proliferation was determined with a Celigo imaging cytometer. Wound-healing and Transwell assays were adopted to evaluate cell migration. A Transwell cell-invasion assay was performed with Matrigel-coated membranes. In vivo bioluminescence imaging (BLI) and pathological analyses illustrated the effect of SYF on cancer cell metastasis in tumour-bearing mice. The inhibitory mechanism of SYF was investigated via quantitative PCR (qPCR) and Western blotting. We found that 3,4-dihydroxyphenyllactic acid, kaempferol, p-coumaric acid, and vanillic acid may be the active components of SYF. Molecular docking confirmed that kaempferol, p-coumaric acid, vanillic acid, and 3,4-dihydroxyphenyllactic acid bound stably to proteins such as AKR1C3, MMPs, and STAT3. SYF extract suppressed TNBC cell proliferation, migration, invasion, and metastasis by inhibiting JAK/STAT3 signalling and then regulating downstream genes, such as MMP-2/MMP-9. SYF regulates the expression of genes involved in cell proliferation, migration, and invasion by regulating the JAK/STAT3 signalling pathway and finally inhibits tumour cell metastasis in TNBC. The present study clarifies the mechanism by which SYF inhibits TNBC metastasis and lays an experimental foundation for the continued clinical development of SYF targeting the JAK/STAT3 pathway.Keywords:Sanyin formula (SYF);triple-negative breast cancer (TNBC);signal transducer and activator of transcription 3 (STAT3) pathway;cancer cell metastasis;network pharmacology
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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BRITISH JOURNAL OF CANCER
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2026
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IF 7.8
Zhao Kun,Zhang Jian,Wang Ran,Wang Bin,Ye Dongfan,Huang XiaoOu,Qiu Lingxiao,Duan Yi,Xu Zhi
Background EGFR-tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with non-small cell lung cancer (NSCLC); however, drug resistance limits their long-term efficacy. The role of STAT3 signaling in EGFR-TKI resistance is not completely understood. Methods Using immunohistochemistry, we assessed changes in STAT3 phosphorylation levels in NSCLC before and after EGFR-TKIs treatment. Through gene editing and transcriptome sequencing experiments, we investigated the mechanism by which STAT3 signaling mediates drug resistance. We conducted cell proliferation and nude mice tumorigenesis experiments to verify whether STAT3 inhibitors enhanced the anti-tumor effect of EGFR-TKIs on NSCLC. Results We found that inhibition of the MAPK pathway by EGFR-TKIs triggers the rapid activation of STAT3 in NSCLC. RNA-seq analysis and cellular experiments confirmed that STAT3 regulates the expression of stemness markers, which contribute to drug resistance. Cancer stemness maintenance depends on telomerase. We found that STAT3 also mediates NSCLC resistance by regulating telomerase expression. Finally, we demonstrated in both cellular and animal models that icaritin, an anti-hepatocellular carcinoma agent, significantly potentiates the anti-tumor efficacy of EGFR-TKIs against NSCLC by inhibiting STAT3 activation. Conclusions The combination of EGFR-TKIs and STAT3 inhibitors has the potential to be a better therapeutic strategy for EGFR-mutant NSCLC than EGFR-TKI monotherapy. The alternative text for this image may have been generated using AI.
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NEUROSCIENCE LETTERS
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2026
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IF 2.2
Qiang Zhang,Yilin Wang
Background Rheumatoid arthritis (RA) discomfort is linked to spinal cord microglia activation. Manual acupuncture (MA, twirling manipulation) reduces RA pain. MA’s ability to relieve RA discomfort was examined in this study. Methods After receiving complete Freund’s adjuvant (CFA), RA rats received acupuncture (with or without twisting manipulation). Paw withdrawal latency (PWL), nociceptive threshold, and hematoxylin and eosin (H&E) staining assessed arthritis severity. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate the levels of inflammatory factors (IL-1β, TNF-α and IL-6) in the spinal dorsal horn. Immunofluorescence was used to assess the expression of p-p38 and Iba-1 in the ipsilateral hippocampus and ipsilateral (right) dorsal root ganglia (DRG). Western blot was used to evaluate the expression of proteins linked to the nuclear factor kappa-B (NF-κB) /signal transducer and activator of transcription 3 (STAT3) pathway. Results MA treatment enhanced PWL, inhibited the expression of spinal dorsal horn inflammatory factor and the activation of ipsilateral DRG or ipsilateral hippocampal microglia, also down-regulated NF-κB/STAT3 pathway proteins. The effect of MA on RA symptoms was better than acupuncture alone. Conclusions Our findings demonstrate that MA significantly ameliorates pain in CFA-induced RA rats. The novelty of this study lies in identifying that this analgesic effect is achieved through the inhibition of the NF-κB/STAT3 signaling pathway, leading to a marked reduction in spinal microglia activation
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ONCOGENE
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2026
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IF 9.1
Liu Pengpeng,Wang Huizhen,Yu Kexun,Ma Mengdi,Yang Xiongwei,Wang Yuexiang,Li Yongxiang
Lymphangiogenesis drives gastric cancer lymph node (GC LN) metastasis via neuro-immune-cancer interactions in the tumor microenvironment. However, the underlying mechanisms remain incompletely understood. Here, we demonstrate that chronic stress (CS) in GC patients correlates with poorer short-term prognosis, perineural/lymphovascular invasion, and advanced LN staging. Mechanistically, CS-induced neutrophil extracellular traps (NETs) are key mediators of LN metastasis. Inhibiting NETs suppressed popliteal LN metastasis and lymphangiogenesis. In vitro and in vivo experiments revealed that CS upregulated acetylcholine (ACh) and choline acetyltransferase (ChAT) levels, with ACh directly inducing NETs formation in a dose-dependently. Exogenous ACh increased LN metastasis (volume), whereas gastric vagotomy attenuated CS-mediated orthotopic tumor growth. Functional assays confirmed that ACh-driven NETs enhanced GC cell malignant behaviors, accelerated adhesive suspension state transformation via extracellular matrix remodeling, and activated a feedforward ACh-NGF axis. This triggered PKC-γ/STAT3-S100A8/A9-ROS cascade, mediating NETs formation and upregulating VEGFA/C. Protein analysis showed CD300ld overexpression in CS + GC tissues, independent of ACh signaling. Notably, combined targeting of the NGF/TrkA and CD300ld exerted synergistic anti-LN metastatic and lymphangiogenic effects. Collectively, this study elucidates a CS-driven mechanism regulating NETs to promote GC LN metastasis and identifies NGF/TrkA and CD300ld as therapeutic targets for GC LN metastasis.
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Cell Communication and Signaling
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2025
·Vol. 23
·期 1
·1-21
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IF 8.9
Jia Yifan,He Muchen,Wang Fan,Zhan Yaqing,Deng Qiwen,Shen Jiantong,Wang Xiwen,Ran Qi,Huang Wenqi,Ling Yihong,Wen Shihong
Background & Aims Dysfunction of the intestinal epithelial barrier (IEB) and gut vascular barrier (GVB) contributes to the development of intestinal ischemia/reperfusion (IR) injury. Tryptophan (TRP), an essential amino acid, plays a crucial role in maintaining intestinal homeostasis, yet its regulatory effects on the GVB following IR remain unexplored. We aimed to better define the role of TRP in intestinal IR in vivo and in vitro. Methods Mice underwent intestinal ischemia/reperfusion (IR) and were fed control, TRP-recommended (TRP-r), or TRP-sufficient (TRP-s) diets. Fecal metagenomic sequencing analyzed microbial composition, and targeted metabolomics quantified tryptophan and its metabolites in intestinal and serum samples. ILA’s effects on barrier integrity were assessed via tight junction protein expression and FITC-dextran permeability assays. RNA sequencing of intestinal endothelial cells elucidated mechanisms by which ILA modulated GVB function. The STAT3-claudin 2 relationship was validated in vitro by ChIP-qPCR. Results TRP supplementation significantly reshaped the gut microbiota, mitigated tissue damage and enhanced the integrity of both the IEB and GVB. Indole-3-lactic acid (ILA), a key tryptophan metabolite, was identified as an important factor in preserving GVB function. Mechanistically, our results show that the aryl hydrocarbon receptor (AhR)/Nrf2/signal transducer and activator of transcription 3 (STAT3) pathway is essential for ILA-mediated improvement of GVB integrity and downregulation of the pore-forming protein claudin 2. Conclusions Our findings highlight the dual role of ILA in reinforcing both IEB and GVB functions and shed light on the molecular mechanisms underlying ILA’s GVB-protective effects. This study implicates that ILA or other AhR-activating metabolites may serve as promising pharmacological agents for alleviating IR-induced intestinal damage. Graphical
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Yu Yang,Hongda Liu,Junling Ren,Lin Liu,Hui Sun,Li Wang,Guangli Yan,Ying Han,Xijun Wang
Ethnopharmacological relevance Danggui Buxue Decoction (DBD) is a classic traditional Chinese medicine formula that has shown significant efficacy in treating blood deficiency syndrome (BDS), though its mechanisms of action remain unclear. Aim of the study To identify the absorbed bioactive components of DBD and elucidate its molecular mechanisms in BDS by integrating metabolomics and bioinformatics. Materials and methods Using a benzene induced BDS mouse model, we analyzed serum-absorbed components of DBD via UPLC-Q/TOF-MS. A multi-omics approach combining metabolomics, molecular docking, and dynamics simulations was utilized to identify therapeutic targets and bioactive components, followed by experimental validation using pharmacological assays, Western blot, and cellular thermal shift assay (CETSA). Results In the BDS mouse model, DBD primarily corrected nicotinate and nicotinamide metabolism and improved hematopoietic function. Furthermore, it significantly decreased the levels of inflammatory cytokines that activate the STAT3 signaling pathway, including interleukin-6 (IL-6), interleukin-17 (IL-17), and transforming growth factor-β (TGF-β). It also suppressed the expression of p-JAK2/JAK2 and p-STAT3/STAT3. Under the effective status of DBD, we identified eleven prototype components and three metabolites derived from DBD, among which astragaloside IV was a high-affinity binder to STAT3, with molecular dynamics simulations and CETSA confirming its binding stability. Conclusion Our integrated approach suggests that DBD may alleviate BDS by normalizing metabolic imbalance and suppressing the IL-6/JAK2/STAT3 signaling pathway. A role for astragaloside IV as a potent bioactive compound of DBD with high-affinity binder to STAT3 is supported by molecular dynamics simulations and CETSA experiments. These findings provide a mechanistic foundation for DBD's therapeutic effects in treating BDS.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2021
·
IF 4.432
Guanghui Xu,Huiqi Wan,Litao Yi,Wei Chen,Youhua Luo,Yiqi Huang,Xiaojuan Liu
Accumulating evidence showed that berberine possessed the anti-inflammatory action in various diseases caused by inflammation. However, it was still unclear whether both inhalation and injection with berberine produced pulmonary protective role in acute respiratory distress syndrome (ARDS). This study was aimed to evaluate the effects of both administration routes including inhalation and injection with berberine in ARDS induced by lipopolysaccharide (LPS) inhalation. Histopathological examination and weight of lung were evaluated. Phosphorylation of NF-κB, JAK2 and STAT3 were measured to assess the activity of inflammation related signaling pathways. Proinflammatory cytokines including interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) and serum were also detected. The results showed that LPS caused the lung injury, while both administration routes with berberine attenuated the injury and improved the pulmonary morphology. In addition, the primary TLR4/NF-κB and secondary JAK2/STAT3 signaling pathways which were activated by LPS in lung were totally inhibited by berberine administration. Moreover, proinflammatory cytokines in both BALF and serum were decreased by berberine. Considering that molecular docking simulation indicated that berberine could bind with TLR4, the present suggested that the inhibition of the inflammation related TLR4/NF-κB and JAK2/STAT3 signaling pathways might be involved in the pulmonary protective effect of berberine in LPS-induced ARDS.
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PHARMACEUTICAL BIOLOGY
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2021
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IF 3.503
Rubin Cheng,Yilan Huang,Yun Fang,Qirui Wang,Meixiu Yan,Yuqing Ge
Context A portion of patients with chronic myeloid leukaemia (CML) develop resistance to the Bcr-Abl tyrosine kinase inhibitors (TKIs), limiting the clinical applications. Previous results have demonstrated the synergistic effects between cryptotanshinone (CPT) and imatinib on apoptosis of CML cells in vitro.Objective To determine the antileukemia effects of CPT and TKIs on the resistant CML cells, and further investigate the effect of combined treatment of CPT and imatinib on tumour growth and apoptosis in the xenograft model and clarify its regulatory mechanisms.Materials and methods The combination effects of CPT and second-generation TKIs were evaluated in resistant CML cells K562-R. CPT and imatinib were orally administered once daily for 21 days on K562-R xenografts in nude mice (6 per group). Tumour proliferation and apoptosis were examined by Ki-67, PCNA and TUNEL staining. The expression levels of apoptotic markers and activities of STAT3 and eIF4E pathways were determined via immunohistochemistry staining and western blotting analysis.Results CPT significantly enhanced the antiproliferative effects of TKIs, via triggering cleavages of caspase proteins, and inhibiting activities of STAT3 and eIF4E pathways. The administration of CPT and imatinib dramatically inhibited the tumour growth of xenografts and achieved a suppression of 60.2%, which is 2.6-fold higher than that of single imatinib group. Furthermore, CPT and imatinib increased the apoptotic rates and markedly decreased the phosphorylation levels of STAT3 and eIF4E.Conclusions Our results demonstrated that CPT could significantly enhance the antileukemia efficacy of TKIs, suggesting the therapeutic potential of CPT to overcome CML resistance.
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Food Bioscience
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2023
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IF 5.2
Qiaoli Wu,Bing Liu,Rongxian Yu,Xiaoling Sun,Ziyan Wang,Jun Zhou,Chenyang Lu,Jing Zhang,Jiaojiao Han,Xiurong Su
Osteoarthritis (OA) is a chronic disease associated with bone and muscle degeneration that causes great disturbances to daily lives. Skipjack tuna elastin peptides (STEP) is a kind of small molecule mixed peptides extracted from skipjack tuna bulbus cordis that have multiple active functions, including anti-inflammatory activity. However, it is ambiguous whether STEP reduce OA inflammation. Zebrafish served as a model in the present research for verifying the anti-inflammatory efficacy of STEP. Then, the composition of STEP was figured out by LC-MS/MS analysis, and the potential anti-inflammatory peptides were screened by molecular docking and microscale thermophoresis (MST). Finally, in vitro experiments were conducted on the potential peptides. According to the in vivo findings, STEP protected the cartilage tissues of zebrafish and regulated the expression of inflammatory factors and the JAK2/STAT3 signaling pathway . The in vitro results showed that the potential peptides (LGVGSPPGK, GFDPSR and PGAPGGGFDI) positively regulated the inflammatory responses and the JAK2/STAT3 signaling pathway and were effective in inhibiting extracellular matrix (ECM) degeneration and chondrocyte apoptosis. As a consequence, STEP possess anti-inflammatory and chondroprotective effects and could be a functional product for the alleviation of OA.
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Cell Death Discovery
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2023
·Vol. 9
·期 1
·1-10
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IF 7
Wang Xianzhe,Shi Wei,Wang Xumei,Lu Jin-Jian,He Ping,Zhang Hongjie,Chen Xiuping
Though palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor has been approved for treating breast cancer, two major clinical challenges remain: (i) Triple-negative breast cancer (TNBC) appears to be more resistant to palbociclib, and (ii) Palbociclib-induced senescence-associated secretory phenotype (SASP) has a pro-tumorigenic function. Here we report that combining palbociclib with the STAT3 inhibitor nifuroxazide uncouples SASP production from senescence-associated cell cycle exit. Moreover, we identified nifuroxazide as a CDK2 inhibitor that synergistically promotes palbociclib-induced growth arrest and senescence in TNBC cells. In vitro, the combination of nifuroxazide with palbociclib further inhibited the TNBC cell proliferation and enhanced palbociclib-induced cell cycle arrest and senescence. The modulation of palbociclib-induced SASP by nifuroxazide was associated with the reduction of phosphorylated-STAT3. Nifuroxazide also blocks SASP-dependent cancer cell migration. Furthermore, thermal shift assay and molecular docking of nifuroxazide with STAT3 and CDK2 revealed that it binds to their active sites and acts as a potent dual inhibitor. In vivo, the combination of nifuroxazide with palbociclib suppressed 4T1 tumor growth and lung metastasis. Our data suggest that nifuroxazide enhances the anticancer effects of palbociclib in TNBC by uncoupling SASP production from senescence-associated cell cycle exit and inhibiting CDK2 to promote tumor senescence.
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Food & Function
·
2023
·Vol. 14
·期 10
·4807-4823
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IF 6.1
Suwen Liu,Wenhong Jiang,Chang Liu,Shuo Guo,Hao Wang,Xuedong Chang
Chinese chestnut shell is a by-product of chestnut food processing and is rich in polyphenols. This study sought to investigate the effect of chestnut shell polyphenol extract (CSP) on weight loss and lipid reduction in a 12-week high-fat diet (HFD)-induced murine obesity model. CSP (300 mg per kg body weight) was administered intragastrically daily. AG490, a JAK2 protein tyrosine kinase inhibitor, was also intraperitoneally injected. The results showed that an HFD induced leptin resistance (LR). Compared to corresponding values in the HFD group, CSP treatment improved blood lipid levels, weight, and leptin levels in obese mice (p < 0.01). Additionally, CSP treatment enhanced enzyme activity by improving total antioxidant capacity, attenuating oxidative stress, and reducing fat droplet accumulation and inflammation in the liver, epididymal, and retroperitoneal adipose tissue. CSP also activated the LEPR-JAK2/STAT3-PTP1B-SOCS-3 signal transduction pathway in hypothalamus tissue and improved LR while regulating the expression of proteins related to lipid metabolism (PPARγ, FAS, and LPL) in white adipose tissue in the retroperitoneal cavity. However, the amelioration of lipid metabolism by CSP was dependent on JAK2. Molecular docking simulation further demonstrated the strong binding affinity of procyanidin C1 (−10.3983297 kcal mol−1) and procyanidin B1 (−9.12686729 kcal mol−1) to the crystal structure of JAK2. These results suggest that CSP may be used to reduce HFD-induced obesity with potential application as a functional food additive.
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