Journal of Translational Medicine
·
2019
·Vol. 17
·期 1
·1-12
·
IF 4.098
Liu Dandan,Lv Hang,Liu Qi,Sun Yanli,Hou Shenglong,Zhang Lu,Yang Mengyue,Han Baihe,wang Gang,Wang Xuedong,Du Wenjuan,Nie Honggang,Zhang Ruoxi,Huang Xingtao,Hou Jingbo,Yu Bo
Background Atherosclerosis preferentially develops in regions of disturbed flow (DF). Emerging evidence indicates that yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway, sense different blood flow patterns and regulate atherosclerotic lesions. We previously found that methotrexate (MTX) reduces in-stent neoatherosclerosis, decreases the plaque burden, and has an effect on local fluid shear stress. Here, we investigated the atheroprotective effect of MTX under DF and the mechanisms underlying these properties. Methods Human umbilical vein endothelial cells (HUVECs) were subjected to biomechanical stretch using a parallel-plate flow system and treated with or without MTX at therapeutically relevant concentrations. Additionally, an extravascular device was used to induce DF in the left common carotid artery of C57BL/6 mice, followed by treatment with MTX or 0.9% saline. The artery was then assessed histopathologically after 4 weeks on a Western diet. Results We observed that MTX significantly inhibited DF-induced endothelial YAP/TAZ activation. Furthermore, it markedly decreased pro-inflammatory factor secretion and monocyte adhesion in HUVECs but had no effect on apoptosis. Mechanistically, AMPKa1 depletion attenuated these effects of MTX. Accordingly, MTX decreased DF-induced plaque formation, which was accompanied by YAP/TAZ downregulation in vivo. Conclusions Taken together, we conclude that MTX exerts protective effects via the AMP-dependent kinase (AMPK)-YAP/TAZ pathway. These results provide a basis for the prevention and treatment of atherosclerosis via the inhibition of YAP/TAZ.
研究领域:
心血管疾病
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2025
·
IF 3.7
Yi-Jun Qi,Ye-Lin Jiao,Pan Chen,Qiao-Qing Zhu,Ran Guo,Dang-Rou Wu,Yu-Bo Du,Wan-Ying Li,Yue-Yue Cheng,Xiao-Shuang Wu,Meng-Xiang Li,Wei Li,Shegan Gao
Porphyromonas gingivalis ( P. gingivalis ), a keystone pathogen in adult periodontitis, is linked to an increased risk of many cancers. Although autophagy stimulated by P. gingivalis in ESCC has been reported, the molecular mechanisms and functional roles of autophagy in P. gingivalis -related ESCC progression are still unclear. P. gingivalis infection promoted the malignant progression of ESCC through autophagy, as demonstrated in both in vitro and in vivo studies. Once P. gingivalis invaded cancer cells, it induced the dephosphorylation and nuclear accumulation of YAP/TAZ, which are the effectors of Hippo pathway. In a TEAD-dependent manner, YAP/TAZ activated the miR-21-5p/RASA1/ERK signaling pathway to enhance autophagy-mediated tumor-promoting roles in the proliferation, migration, and invasion of ESCC. Additionally, P. gingivalis infection was correlated with higher levels of miR-21-5p, YAP/TAZ, and LC3, all of which were associated with shorter overall survival of patients with ESCC. Taken together, our findings reveal that the YAP/TAZ-miR-21-5p-ERK axis plays a crucial role in the P. gingivalis -infected subtype of ESCC, suggesting P. gingivalis and the autophagy pathway as promising therapeutic targets for ESCC treatment.
研究领域:
肿瘤学
·
微生物学
·
分子生物学
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口腔医学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL AND MOLECULAR MEDICINE
·
2023
·Vol. 55
·期 1
·183-195
·
IF 12.8
Wu Zhuhua,Zhu Li,Nie Xinran,Wei Li,Qi Yong
Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disease characterized by pulmonary vascular remodeling. Excessive growth and migration of pulmonary artery smooth muscle cells (PASMCs) are believed to be major contributors to pulmonary vascular remodeling. Ubiquitin-specific protease 15 (USP15) is a vital deubiquitinase that has been shown to be critically involved in many pathologies. However, the effect of USP15 on PH has not yet been explored. In this study, the upregulation of USP15 was identified in the lungs of PH patients, mice with SU5416/hypoxia (SuHx)-induced PH and rats with monocrotaline (MCT)-induced PH. Moreover, adeno-associated virus-mediated functional loss of USP15 markedly alleviated PH exacerbation in SuHx-induced mice and MCT-induced rats. In addition, the abnormal upregulation and nuclear translocation of YAP1/TAZ was validated after PH modeling. Human pulmonary artery smooth muscle cells (hPASMCs) were exposed to hypoxia to mimic PH in vitro, and USP15 knockdown significantly inhibited cell proliferation, migration, and YAP1/TAZ signaling in hypoxic hPASMCs. Rescue assays further suggested that USP15 promoted hPASMC proliferation and migration in a YAP1/TAZ-dependent manner. Coimmunoprecipitation assays indicated that USP15 could interact with YAP1, while TAZ bound to USP15 after hypoxia treatment. We further determined that USP15 stabilized YAP1 by inhibiting the K48-linked ubiquitination of YAP1. In summary, our findings reveal the regulatory role of USP15 in PH progression and provide novel insights into the pathogenesis of PH.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2017
·
IF 2.759
QiuShi Wei,MinCong He,MeiHui Chen,ZhenQiu Chen,Fan Yang,HaiBin Wang,Jin Zhang,Wei He
Icariin, the major ingredient of Herba Epimedii, promotes the osteogenic differentiation of rat bone marrow stromal cells (rBMSCs) and exerts protective effects against bone loss and increases bone regeneration, but the underlying signaling pathway by which icariin affects osteogenic differentiation remain unclear. Transcriptional coactivator with PDZ-binding motif (TAZ) is a transcriptional modulator of the Hippo signaling pathway, which plays an important role in the osteogenic differentiation of BMSCs by activating Runx2 gene during the terminal osteogenic differentiation. In this study, we found that 0.1 μM icariin markedly promoted the proliferation, calcium depositions, and osteogenic genes expression of rBMSCs. Icariin (0.1 μM) upregulated TAZ, Runx2, β-catenin, Osteopotin, and Dlx5 expression mainly at the early stage of osteogenic differentiation, and increased osteocalcin expression at the late stage. Our result further demonstrated that knockdown TAZ expression by lentivirus-mediated TAZ shRNA inhibited the icariin-induced osteogenic differentiation. Moreover, ICI 182780 (the estrogen receptor alpha inhibitor) or DKK1 (the Wnt/β-catenin pathway inhibitor), inhibited the icariin-induced increase in TAZ expression. Furthermore, icariin stimulated the activation of TAZ as evidenced by increased total TAZ protein and nuclear translocation, but these effects of icariin were blocked by ICI 182780 or DKK1. Taken together, our results demonstrate that icariin promotes the osteogenic differentiation of rBMSCs by increasing TAZ expression, and that the increased TAZ expression induced by icariin is mostly mediated by the ERα and Wnt/β-catenin pathway.
研究领域:
药理学
·
细胞生物学
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分子生物学
·
骨再生
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Xuyan Wei,Sicong Ren,Mucong Li,Yihan Wang,Jiameng Zhang,Shaobo Zhai,Lijun Liu,Hanchi Wang,Yanmin Zhou
The treatment of complicated infected skin wounds faces many challenges. The presence of stubborn bacterial biofilms is one of the key reasons why such wounds are difficult to heal, because the bacteria in the biofilms can resist multiple antimicrobial agents and delay the healing process by inhibiting the immune response. In order to effectively manage complicated infected wounds, we are developing a hydrogel dressing (CGOD-FNP) with multiple functions. These FNP-based phenolic network hydrogels can activate the PTT effect through near-infrared light (NIR) irradiation and inhibit iron ion metabolism to achieve dual mechanism antibacterial, thereby effectively removing bacterial biofilms. In addition, in the inflammatory response stage, the hydrogel exerts an immunomodulatory function by activating the Hippo-YAP/TAZ signaling pathway, effectively regulating the immune microenvironment of the wound, and finally showing excellent adhesion, antibacterial, immunomodulatory, and tissue healing promotion in a mouse skin infection model. Therefore, CGOD-FNP will become a promising therapeutic strategy for the clinical treatment of complicated infection injuries.
研究领域:
生物材料
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伤口愈合
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抗菌治疗
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免疫调节
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组织工程
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纳米医学
✓ 已验证
产品关联
DOI
高影响因子
Stem Cell Research & Therapy
·
2020
·Vol. 11
·期 1
·1-15
·
IF 5.116
Shen Ying-Shan,Chen Xiao-Jun,Wuri Sha-Na,Yang Fan,Pang Feng-Xiang,Xu Liang-Liang,He Wei,Wei Qiu-Shi
Objectives Polydatin (PD), extracted from Polygonum cuspidatum , has shown potential therapeutic applications due to its antiosteoporotic and anti-inflammatory activities. Our previous study suggested that PD promotes the osteogenesis of human bone marrow stromal cells (hBMSCs) via the BMP2-Wnt/β-catenin pathway. The aim of our present study was to further explore the role of PD-mediated regulation of Tafazzin (TAZ), a transcriptional coactivator with a PDZ-binding motif, in osteogenesis. Materials and methods hBMSCs were isolated and treated with PD at various concentrations. Alizarin red staining and RT-qPCR were performed to identify calcium complex deposition in hBMSCs as well as the expression of specific osteoblast-related markers, respectively, in each group. Next, TAZ-silenced hBMSCs were generated by lentivirus-produced TAZ shRNA. After treatment with PD, the osteogenic abilities of the TAZ-silenced and control hBMSCs were estimated by ALP activity assay, and expression of the TAZ protein was detected by Western blot analysis and immunofluorescence staining. In vitro, an ovariectomized (OVX) mouse model was established and used to evaluate the effect of PD on bone destruction by micro-CT, immunohistochemistry, and ELISA. Results In vitro, 30 μM PD significantly improved the proliferation and calcium deposition of hBMSCs and markedly stimulated the expression of the mRNAs RUNX2 , Osteopontin , DLX5 , β-catenin , TAZ , and Osteocalcin ( OCN ). Osteogenic differentiation induced by PD was blocked by lentivirus-mediated TAZ shRNA. Furthermore, Noggin (a regulator of bone morphogenic protein 2 (BMP2)) and DKK1 (an inhibitor of the Wnt/β-catenin pathway) were found to inhibit the increase in TAZ expression induced by PD. In vivo, PD prevented estrogen deficiency-induced bone loss in the OVX mouse model. Conclusion Taken together, our findings suggest that PD improved the osteogenic differentiation of hBMSCs and maintained the bone matrix in the OVX mouse model through the activation of TAZ, a potential target gene of the BMP2-Wnt/β-catenin pathway.
研究领域:
药理学
·
干细胞生物学
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骨骼生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Scientific Reports
·
2016
·
IF 5.228
Zhe Chen,Qing Luo,Chuanchuan Lin,Dongdong Kuang,Guanbin Song
Microgravity induces observed bone loss in space flight, and reduced osteogenesis of bone mesenchymal stem cells (BMSCs) partly contributes to this phenomenon. Abnormal regulation or functioning of the actin cytoskeleton induced by microgravity may cause the inhibited osteogenesis of BMSCs, but the underlying mechanism remains obscure. In this study, we demonstrated that actin cytoskeletal changes regulate nuclear aggregation of the transcriptional coactivator with PDZ-binding motif (TAZ), which is indispensable for osteogenesis of bone mesenchymal stem cells (BMSCs). Moreover, we utilized a clinostat to model simulated microgravity (SMG) and demonstrated that SMG obviously depolymerized F-actin and hindered TAZ nuclear translocation. Interestingly, stabilizing the actin cytoskeleton induced by Jasplakinolide (Jasp) significantly rescued TAZ nuclear translocation and recovered the osteogenic differentiation of BMSCs in SMG, independently of large tumor suppressor 1(LATS1, an upstream kinase of TAZ). Furthermore, lysophosphatidic acid (LPA) also significantly recovered the osteogenic differentiation of BMSCs in SMG through the F-actin-TAZ pathway. Taken together, we propose that the depolymerized actin cytoskeleton inhibits osteogenic differentiation of BMSCs through impeding nuclear aggregation of TAZ, which provides a novel connection between F-actin cytoskeleton and osteogenesis of BMSCs and has important implications in bone loss caused by microgravity.
研究领域:
生物医学工程
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细胞生物学
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干细胞研究
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空间生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNOLOGIC RESEARCH
·
2024
·
IF 3.3
Su Xiaoran,Wang Xinliu,Zhang Xin,Sun Yajie,Jia Yugai
Massive evidence shows that intestinal tryptophan metabolites affected by intestinal flora can modulate the progression of rheumatoid arthritis (RA). However, the effects and mechanisms of intestinal tryptophan metabolites on RA are not yet detailed. Herein, we investigated the protective effects of intestinal tryptophan metabolites on RA and its detailed mechanisms. In this study, the collagen-induced arthritis (CIA) rat model was established. Based on metabolomics analysis, the contents of β-indole-3-acetic acid (IAA), indolylpropionic acid, and indole-3-β-acrylic acid in the sera of CIA rats were significantly less compared with those of the normal rats. Under the condition of Treg or Th17 cell differentiation, IAA significantly promoted the differentiation and activation of Treg cells instead of Th17 cells. Intestinal tryptophan metabolites are well-known endogenic ligands of aryl hydrocarbon receptor (AhR). Not surprisingly, IAA increased the level of Foxp3 through activating the AhR pathway. Interestingly, IAA had little impact on the level of Foxp3 mRNA, but reducing the ubiquitination and degradation of Foxp3. Mechanically, IAA reduced the expression of the transcriptional coactivator TAZ, which was almost completely reversed by either AhR antagonist CH223191 or siRNA. In vitro, IAA decreased the combination of TAZ and the histone acetyltransferase Tip60, while it increased the combination of Tip60 and Foxp3. In CIA rats, oral administration of IAA increased the number of Treg cells and relieved the inflammation. A combined use with CH223191 almost abolished the effect of IAA. Taken together, IAA attenuated CIA by promoting the differentiation of Treg cells through reducing the ubiquitination of Foxp3 via the AhR-TAZ-Tip60 pathway.
研究领域:
免疫学
·
风湿病学
·
代谢组学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Zhou Yan,Yang Yifan,Wang Yuehan,Cheang Wai San
YAP/TAZ and SMAD1/5 signaling modulate atherosclerosis. These involvements in diabetes-associated endothelial dysfunction remain unexplored, thereby being investigated from different endothelial cells and a total of 102 mice in the current study. Male C57BL/6 mice were fed a high-fat diet (45% kcal% fat, 15 weeks) and orally administered with endoplasmic reticulum (ER) stress alleviator 4-phenylbutyric acid (100 mg·kg –1 ·d –1 ) and jatrorrhizine (50 mg·kg –1 ·d –1 ) for 5 weeks. Endothelial cells were cultured with high glucose, ER stress inducer tunicamycin, ER stress alleviators, YAP inhibitor simvastatin, or jatrorrhizine. The mouse aorta was divided into the aortic arch and thoracic aorta regions to investigate the regional difference. Treatment with PBA and jatrorrhizine ameliorated endothelium-dependent relaxations as well as inhibited ER stress, YAP/TAZ-SMAD1/5 signaling and oxidative stress in aortas. Phosphorylation of YAP/TAZ was highly expressed in the thoracic aorta but low in the aortic arch. On the other hand, phosphorylation of SMAD1/5 was upregulated in the inner curvature of the aortic arch but downregulated in the thoracic aorta. In HUVECs, ER stress alleviators significantly inhibited YAP/TAZ-SMAD1/5 signaling and increased NO bioavailability, but the YAP inhibitor did not suppress ER stress. Inhibition of YAP/TAZ downregulated SMAD1/5 signaling under high glucose stimulation, followed by the Akt/eNOS pathway. YAP/TAZ directly interacts with SMAD1/5, and their binding is significantly enhanced under high-glucose conditions. A natural compound, jatrorrhizine, was identified to inhibit YAP/TAZ-SMAD1/5 signaling and protect vascular function in diabetes. To conclude, ER stress activates YAP/TAZ and SMAD1/5 signaling, resulting in endothelial dysfunction in diabetes. Inhibition of YAP/TAZ-SMAD1/5, such as by ER stress alleviators and natural product jatrorrhizine, ameliorates endothelial dysfunction associated with diabetes. These findings support the cross-talk between ER stress and YAP/TAZ-SMAD1/5 as well as their potential as therapeutic targets.
✓ 已验证
DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2022
·Vol. 23
·期 1
·1-16
·
IF 7.162
Liu Haitao,Zhang Sha,Liu Yi,Ma Jing,Chen Wei,Yin Tao,Li Tongbin,Liang Bin,Tao Ling
Background Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance and artery pressure. Vascular remodeling is associated with the excessive cell proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). In this paper, the effects of heat shock protein-110 (HSP110) on PH were investigated.Methods The C57BL/6 mice and human PASMCs (HPASMCs) were respectively exposed to hypoxia to establish and simulate PH model in vivo and cell experiment in vitro. To HSP110 knockdown, the hypoxia mice and HPASMCs were infected with adeno-associated virus or adenovirus carring the shRNAs (short hairpin RNAs) for HSP110 (shHSP110). For HSP110 and yes-associated protein (YAP) overexpression, HPASMCs were infected with adenovirus vector carring the cDNA of HSP110 or YAP. The effects of HSP110 on PH development in mice and cell proliferation, migration and autophagy of PASMCs under hypoxia were assessed. Moreover, the regulatory mechanisms among HSP110, YAP and TEA domain transcription factor 4 (TEAD4) were investigated.Results We demonstrated that expression of HSP110 was significantly increased in the pulmonary arteries of mice and HPASMCs under hypoxia. Moreover, knockdown of HSP110 alleviated hypoxia-induced right ventricle systolic pressure, vascular wall thickening, right ventricular hypertrophy, autophagy and proliferation of PASMCs in mice. In addition, knockdown of HSP110 inhibited the increases of proliferation, migration and autophagy of HPASMCs that induced by hypoxia in vitro. Mechanistically, HSP110 knockdown inhibited YAP and transcriptional co-activator with PDZ-binding motif (TAZ) activity and TEAD4 nuclear expression under hypoxia. However, overexpression of HSP110 exhibited the opposite results in HPASMCs. Additionally, overexpression of YAP partially restored the effects of shHSP110 on HPASMCs. The interaction of HSP110 and YAP was verified. Moreover, TEAD4 could promote the transcriptional activity of HSP110 by binding to the HSP110 promoter under hypoxia.Conclusion sOur findings suggest that HSP110 might contribute to the development of PH by regulating the proliferation, migration and autophagy of PASMCs through YAP/TAZ-TEAD4 pathway, which may help to understand deeper the pathogenic mechanism in PH development.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2026
·Vol. 462
·期 2
·115168
·
IF 3.5
Yanxia Wang,Yanyan Sun,Peng Shen,Wen Zhang,Wenxuan Pan,Xinchen Zhang,Zhaoxia Xu,Xiumei Guan,Yiying Sun,Min Cheng
MIE-induced WSS exerts a protective effect on vascular endothelial dysfunction. • YAP/TAZ mediate the amelioration of endothelial dysfunction by MIE-induced WSS. • AMPK regulates MIE-induced WSS-mediated protection via inhibiting YAP/TAZ activation. Background Arterial endothelial dysfunction is a critical early pathological change in cardiovascular diseases. Exercise-induced wall shear stress (WSS) exerts protective effects on impaired arterial endothelial function, while the underlying mechanism remains unclear. YAP/TAZ are core mechanotransduction molecules. This study aims to investigate whether YAP/TAZ mediate the ameliorative effect of moderate intensity exercise (MIE)-induced WSS on endothelial dysfunction via AMPK regulation. Methods Lipopolysaccharide (LPS)-injured HUVECs were exposed to MIE-induced WSS using a multicomponent parallel-plate flow chamber system. SiRNA-mediated knockdown of AMPK and YAP was performed to verify the regulatory signaling pathway. In vivo , high-fat diet ApoE −/− mice received MIE intervention to assess the impacts of MIE on endothelial function and YAP expression. Results LPS induced YAP/TAZ activation and endothelial dysfunction, whereas MIE-induced WSS inhibited YAP/TAZ activation and reversed endothelial dysfunction in LPS-treated cells. YAP knockdown strengthened the ameliorative effect of MIE-induced WSS on endothelial dysfunction. Furthermore, AMPK knockdown promoted YAP activation and attenuated the beneficial impact of MIE-induced WSS on endothelial dysfunction. Consistently, MIE intervention reversed high-fat diet-induced impairment of common carotid arterial endothelial function, concurrent with YAP downregulation in vivo . These results indicate that MIE-induced WSS ameliorates endothelial dysfunction via activating AMPK, which in turn inhibits YAP/TAZ. Conclusions This study provides novel insights into the molecular mechanism by which MIE-induced WSS alleviates endothelial dysfunction, and provides a theoretical foundation for the clinical application of MIE as a rehabilitation strategy to improve impaired arterial endothelial function.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2023
·
IF 9.9
Kaiyue Song,Lingling Du,Guoli Yue,Tao Li,Haohong Li,Shoutian Zheng,Zhirong Chen,Huidong Zheng
The study about simultaneously enhancing the resistive switching level and ambient-air-stability of perovskite-based memorizers will promote its commercialization. Here, a new 3D perovskite (TAZ-H)PbBr 3 (TAZ-H + = protonated thiazole) has been fabricated as FTO/(TAZ-H)PbBr 3 /Ag device, which only exhibits binary memory performance with the high tolerant temperature of 170 °C. After encapsulating by polyvinylpyrrolidone (PVP), the (TAZ-H)PbBr 3 @PVP composite-based device can demonstrate ternary resistive switching behavior with considerable ON2/ON1/OFF ratio (10 5.9 : 10 3.9 :1) and high ternary yield (68 %). Specially, this device presents good ambient-air stability at RH 80 % and thermal tolerance of 100 °C. The binary resistive switching mechanism can be ascribed to the halogen ion migration induced by bromine defects in the (PbBr 3 ) n n – framework. But the ternary resistive switching phenomenon in the (TAZ-H)PbBr 3 @PVP-based device could be depicted as the carrier transport from filled traps of PVP to (PbBr 3 ) n n – framework (ON1 state) and then carriers flowing in the re-arranged (TAZ-H) n n + chain in 3D channels (ON2 state). The PVP treatment can not only modify the grain boundary defects, but also facilitate the transport of injected carriers to the perovskite films via Pb-O coordinated bonds and inhibition of order-disorder transformation. This facial strategy for implementing ternary perovskite-based memorizers with good ambient-air-stability is quite meaningful for high-density memory in harsh environments.
研究领域:
材料科学
·
电子工程
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）