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Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke 被引量:2
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作者 Xiu-De Qin Tai-Qin Yang +6 位作者 Jing-Hui Zeng Hao-Bin Cai Shao-Hua Qi Jian-Jun Jiang Ying Cheng Long-Sheng Xu Fan Bu 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第8期1743-1749,共7页
Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB le... Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB leakage.Selective inhibition of mitogen-activated protein kinase,the negative regulatory substrate of mitogen-activated protein kinase phosphatase(MKP)-1,improves tight junction protein function in ECs,and genetic deletion of MKP-1 aggravates ischemic brain injury.However,whether the latter affects BBB integrity,and the cell type-specific mechanism underlying this process,remain unclear.In this study,we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke.We found that overexpression of MKP-1 in ECs reduced infarct volume,reduced the level of inflammatory factors interleukin-1β,interleukin-6,and chemokine C-C motif ligand-2,inhibited vascular injury,and promoted the recovery of sensorimotor and memory/cognitive function.Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase(ERK)1/2 and the downregulation of occludin expression.Finally,to investigate the mechanism by which MKP-1 exerted these functions in ECs,we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose,and pharmacologically inhibited the activity of MKP-1 and ERK1/2.Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death,cell monolayer leakage,and downregulation of occludin expression,and that inhibiting ERK1/2 can reverse these effects.In addition,co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2.These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2,thereby protecting the integrity of BBB,alleviating brain injury,and improving post-stroke prognosis. 展开更多
关键词 blood-brain barrier brain injury cerebral ischemia endothelial cells extracellular signal-regulated kinase 1/2 functional recovery mitogenactivated protein kinase phosphatase 1 OCCLUDIN oxygen and glucose deprivation transient middle cerebral artery occlusion
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Signaling pathway of insulin-like growth factor-Ⅱ as a target of molecular therapy for hepatoblastoma 被引量:2
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作者 Minoru Tomizawa Hiromitsu Saisho 《World Journal of Gastroenterology》 SCIE CAS CSCD 2006年第40期6531-6535,共5页
AIM: To address the possibility that insulin-like growth factor (IGF)-Ⅱ is a growth factor and its signaling pathway so as to develop a molecular therapy for hepatoblastoma. METHODS: Huh-6 and HepG2, human hepato... AIM: To address the possibility that insulin-like growth factor (IGF)-Ⅱ is a growth factor and its signaling pathway so as to develop a molecular therapy for hepatoblastoma. METHODS: Huh-6 and HepG2, human hepatoblastoma cell lines, were used. IGF-Ⅱ was added to the medium deprived of serum. Western blot analysis was performed to clarify the expression of IGF-Ⅰ receptor (IGF-IR). Inhibitors of IGF-IR (piclopodophyllin, PPP), phosphatidyl-inositol (PI) 3-kinase (LY294002 and Wortmannin), or mitogen-activated protein (MAP) kinase (PD98059) were added to unveil the signaling pathway of IGF-Ⅱ. Cells were analyzed morphologically with hematoxylin-eosin staining to reveal the mechanism of suppression of cell proliferation. RESULTS: IGF-Ⅱ stimulated cells proliferated to 2.7 (269% ± 76%) (mean ± SD) (Huh-6) and 2.1 (211% ± 85%) times (HepG2). IGF-IR was expressed in Huh-6 and HepG2. PPP suppressed the cell number to 44% ± 11% (Huh-6) and 39% ± 5% (HepG2). LY294002 and Wortmannin suppressed the cell number to 30% ± 5% (Huh-6), 44% ± 0.4% (HepG2), 49% ± 1.0% (Huh-6) and 46% ± 1.1% (HepG2), respectively. PD98059 suppressed the cell number to 33% ± 11% for HepG2 but not for Huh-6. When cell proliferation was prohibited, many Huh-6 and HepG2 cells were dead with pyknotic or fragmented nuclei, suggesting apoptosis. CONCLUSION: IGF- Ⅱ was shown to be a growth factor of hepatoblastoma via IGF-Ⅰ receptor and PI3 kinase which were good candidates for target of molecular therapy. 展开更多
关键词 3- (4 5-dimethylthiazol-2-yl)-5- (3-carbo xymethoxyphenyl)-2- (4-sulfophenyl) -2H-tetrazolium inner salt assay Phosphatidyl-inositol-3-kinase mitogenactivated protein kinase HEPATOBLASTOMA Molecular therapy
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Overexpression of Arabidopsis thaliana cysteine2/histidine2-type transcription factor 6 gene enhances plant resistance to a bacterial pathogen
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作者 Wei Tang Anna Y.Tang 《Journal of Forestry Research》 SCIE CAS CSCD 2021年第1期249-262,共14页
Transcription factors can be used to engineer plants for enhanced productivity.However,the mechanism(s)by which the C2H2-type zinc fi nger transcription factor enhances pathogen resistance in cells is not fully unders... Transcription factors can be used to engineer plants for enhanced productivity.However,the mechanism(s)by which the C2H2-type zinc fi nger transcription factor enhances pathogen resistance in cells is not fully understood.Here,Agrobacterium tumefaciens carrying the gene for Arabidopsis thaliana cysteine2/histidine2-type transcription factor 6(ZAT6)was used to engineer rice(Oryza sativa L.),cotton(Gossypium hirsutum L.),and slash pine(Pinus elliottii Engelm.)to generate transgenic cell lines.Transgenic cells were then inoculated with the pathogenic bacterium Pseudomonas syringae.Compared to the control,cell viability of transgenic cells increased 39–47%and growth rate increased 9–15%by 7 days after inoculation in rice,cotton and slash pine.Acid phosphatase activity and alkaline phosphatase activity and transcript levels of Ca 2+-dependent protein kinase genes OsCPK1,OsCPK2,OsCPK6,and OsCPK8 and mitogen-activated protein kinase genes OsMAPK1,OsMAPK2,OsMAPK3,and OsMAPK8 increased signifi cantly in transgenic rice cells by 3 day after inoculation,and extracellular pH had decreased by 10–14%by 96 min after inoculation in transgenic rice,cotton and slash pine cells.These results suggest that ZAT6 enhances P.syringae resistance in plant cells by modulating transcription of CPK and MAPK and oxidase activity. 展开更多
关键词 Ca^2+-dependent protein kinase mitogenactivated protein kinase OXIDASE PATHOGEN PINUS
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Peptide RL-QN15 promotes wound healing of diabetic foot ulcers through p38 mitogen-activated protein kinase and smad3/miR-4482-3p/vascular endothelial growth factor B axis
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作者 Dandan Sun Kun Guo +15 位作者 Naixin Liu Yilin Li Yuansheng Li Yan Hu Shanshan Li Zhe Fu Yinglei Wang Yutong Wu Yingxuan Zhang Jiayi Li Chao Li Zhuo Wang Zijian Kang Jun Sun Ying Wang Xinwang Yang 《Burns & Trauma》 SCIE 2023年第1期694-708,共15页
Background:Wound management of diabetic foot ulcers(DFUs)is a complex and challenging task,and existing strategies fail to meet clinical needs.Therefore,it is important to develop novel drug candidates and discover ne... Background:Wound management of diabetic foot ulcers(DFUs)is a complex and challenging task,and existing strategies fail to meet clinical needs.Therefore,it is important to develop novel drug candidates and discover new therapeutic targets.However,reports on peptides as molecular probes for resolving issues related to DFUs remain rare.This study utilized peptide RL-QN15 as an exogenous molecular probe to investigate the underlying mechanism of endogenous non-coding RNA in DFU wound healing.The aim was to generate novel insights for the clinical management of DFUs and identify potential drug targets.Methods:We investigated the wound-healing efficiency of peptide RL-QN15 under diabetic con-ditions using in vitro and in vivo experimental models.RNA sequencing,in vitro transfection,quantitative real-time polymerase chain reaction,western blotting,dual luciferase reporter gene detection,in vitro cell scratches,and cell proliferation and migration assays were performed to explore the potential mechanism underlying the promoting effects of RL-QN15 on DFU repair.Results:Peptide RL-QN15 enhanced the migration and proliferation of human immortalized keratinocytes(HaCaT cells)in a high-glucose environment and accelerated wound healing in a DFU rat model.Based on results from RNA sequencing,we defined a new microRNA(miR-4482-3p)related to the promotion of wound healing.The bioactivity of miR-4482-3p was verified by inhibiting and overexpressing miR-4482-3p.Inhibition of miR-4482-3p enhanced the migration and proliferation ability of HaCaT cells as well as the expression of vascular endothelial growth factor B(VEGFB).RLQN15 also promoted the migration and proliferation ability of HaCaT cells,and VEGFB expression was mediated via inhibition of miR-4482-3p expression by the p38 mitogen-activated protein kinase(p38MAPK)and smad3 signaling pathways.Conclusions:RL-QN15 is an effective molecule for the treatment of DFUs,with the underlying mechanism related to the inhibition of miR-4482-3p expression via the p38MAPK and smad3 signaling pathways,ultimately promoting re-epithelialization,angiogenesis and wound healing.This study provides a theoretical basis for the clinical application of RL-QN15 as a molecular probe in promoting DFU wound healing. 展开更多
关键词 RL-QN15 Diabetic foot ulcer Wound healing miR-4482-3p Vascular endothelial growth factor B PEPTIDE mitogenactivated protein kinase
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Mitogen-activated protein kinase cascades in plant signaling 被引量:21
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作者 Mengmeng Zhang Shuqun Zhang 《Journal of Integrative Plant Biology》 SCIE CAS CSCD 2022年第2期301-341,共41页
Mitogen-activated protein kinase(MAPK)cascades are key signaling modules downstream of receptors/sensors that perceive either endogenously produced stimuli such as peptide ligands and damage-associated molecular patte... Mitogen-activated protein kinase(MAPK)cascades are key signaling modules downstream of receptors/sensors that perceive either endogenously produced stimuli such as peptide ligands and damage-associated molecular patterns(DAMPs)or exogenously originated stimuli such as pathogen/microbe-associated molecular patterns(P/MAMPs),pathogen-derived effectors,and environmental factors.In this review,we provide a historic view of plant MAPK research and summarize recent advances in the establishment of MAPK cascades as essential components in plant immunity,response to environmental stresses,and normal growth and development.Each tier of the MAPK cascades is encoded by a small gene family,and multi ple members can function redundantly in an MAPK cascade.Yet,they carry out a diverse array of biological functions in plants.How the signaling specificity is achieved has become an interesting topic of MAPK research.Future investigations into the molecular mechanism(s)underlying the regulation of MAPK activation including the activation kinetics and magnitude in response to a stimulus,the spatiotemporal expression patterns of all the components in the signaling pathway,and functional characterization of novel MAPK substrates are central to our understanding of MAPK functions and signaling specificity in plants. 展开更多
关键词 abiotic stress ligand-receptor interaction mitogenactivated protein kinase MAPK substrate plant growth and development plant hormone plant immunity receptor-like protein kinase signal transduction
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