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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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
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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
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产品关联
DOI
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.
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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.
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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.
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PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2024
·
IF 5.4
Xinyue Xu,Youwei Wang,Changhao Han,Jingsong Lin,Qingan Shen,Youyi Lan,Linjing Long,Xudong Tan,Jiankai Liu,Siyi Liu,Lanxinhui Luo,Mingqi Lv,Yuchan Zhang,Guixue Wang,Guangchao Zang
Without intervention, the natural wound healing process can often result in scarring, which can have detrimental effects on both the physical and mental well-being of patients. Therefore, it is crucial to develop biomaterials that can promote healing without scarring. Regulating the Yes-associated protein-1/PDZ-binding motif (YAP/TAZ) signaling pathway is possible to reduce excessive fibrosis of fibroblasts and proliferation of vascular endothelial cells, ultimately impacting scar formation. Arsenic trioxide (ATO), an ancient drug with medicinal and toxic properties, has shown promise in regulating this pathway. An ATO-loaded hydrogel dressing (ATO@CS/SA) was created to facilitate scarless wound healing, utilizing chitosan (CS) and sodium alginate (SA) to prevent direct contact of ATO with the wound tissue and minimize potential side effects. In vitro studies demonstrated that low concentrations of ATO did not impact cell viability and even promoted proliferation and migration. Co-culturing the hydrogel with fibroblasts and vascular endothelial cells led to decreased expression levels of YAP and TAZ. Animal studies over a 90-day period revealed significant inhibition of scar formation with this system. Histological experiments further confirmed that the decreased expression of YAP and TAZ was responsible for this outcome. In conclusion, when administered at the appropriate dose, ATO can be repurposed from a traditional poison to a therapeutic agent, effectively suppressing excessive cell fibrosis and blood vessel proliferation and offering a novel approach to scar-free treatment.
研究领域:
生物医学工程
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药学
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组织工程
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再生医学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 40
·9314-9324
·
IF 5.344
Maowen Chen,Yan Hu,Yanhua Hou,Menghuan Li,Maohua Chen,Lu Tan,Caiyun Mu,Bailong Tao,Zhong Luo,Kaiyong Cai
The high surface elastic modulus of the titanium (Ti) implant is one of the critical factors causing poor osteointegration between the implant surface and surrounding bone tissue. To address this challenge, spherical silica nanoparticles (SSNs) and spherical titania nanoparticles (STNs) with different sizes were synthesized and embedded into Ti surfaces via a micro-arc oxidation (MAO) technique. There were no significant changes in the surface roughness and protein adsorption behaviors before and after the embedding of spherical silica nanoparticles and titania nanoparticles into the Ti implant. However, the surface elastic modulus of Ti-SSNs decreased from 93 GPa to 6.7 GPa, while there was still no change in surface elastic modulus between Ti and Ti-STN groups. In vitro experiments showed that Ti-SSNs, especially Ti-SSN3, significantly stimulated the expression level and nuclear localization of the transcription factor YAP. YAP/TAZ could further inhibit the phosphorylation of AKT and mTOR proteins in MSCs, leading to higher LC3-II protein expression and osteogenic differentiation of MSCs. Ti-SSNs also showed a higher level of autophagosome formation, ALP activity and mineralization capability compared to the other groups. Our results showed that the surface elasticity modulus of an implant plays an important role in the regulation of MSC behaviors. Therefore, designing an implant with an optimal elastic modulus at the surface might have great clinical potential in the bone repair field.
研究领域:
生物材料
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组织工程
·
干细胞生物学
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生物力学
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骨科研究
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Xiaomeng Li,Shuaibing Liu,Shanshan Han,Qingqing Sun,Jianmin Yang,Yuhang Zhang,Yongchao Jiang,Xiaofeng Wang,Qian Li,Jianglin Wang
Biomechanical stimuli derived from the extracellular matrix (ECM) extremely tune stem cell fate through three-dimensional (3D) and spatiotemporal changes in vivo. The matrix stiffness as a crucial factor during bone tissue development is dynamic stiffening. However, most in vitro models to study the osteogenesis of mesenchymal stem cells (MSCs) are static or stiffening in a 2D environment. Here, we create a dynamic and controllable stiffening 3D biomimetic model to regulate the osteoblastic differentiation of MSCs with a dual-functional gelatin macromer that can generate a double-network hydrogel by sequential enzymatic and light-triggered crosslinking reactions. Our findings showed that these dynamic hydrogels allowed cells to spread and volume expansion prior to secondary crosslinking and to sense high stiffness after stiffening. The MSCs in the dynamic hydrogels, especially the hydrogel stiffened at the late period, presented the significantly elevated osteogenic ECM secretion, gene expression, and YAP/TAZ nuclear localization. In vivo evaluation of animal experiments further indicated that the enhancement of dynamic stiffening on osteogenesis of MSCs substantially promoted bone remodeling. Consequently, this work reveals that the 3D dynamic stiffening microenvironment as a critical biophysical cue not only mediates the stem cell fate in vitro, but also augments bone restoration in vivo. This article is protected by copyright. All rights reserved
研究领域:
生物材料
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组织工程
·
再生医学
·
细胞生物学
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生物力学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Ziang Li,Jincheng Tang,Liang Zhou,Jiannan Mao,Wei Wang,Ziyan Huang,Lichen Zhang,Jie Wu,Xinzhao Jiang,Zhouye Ding,Kun Xi,Feng Cai,Yong Gu,Liang Chen
The extracellular matrix (ECM) stores signaling molecules and facilitates mechanical and biochemical signaling in cells. However, the influence of biomimetic “rejuvenation” ECM structures on aging- and degeneration-related cellular activities and tissue repair is not well understood. We combined physical extrusion and precise “on–off” alternating cross-linking methods to create anisotropic biomaterial microgels (MicroRod and MicroSphere) and explored how they regulate the cell activities of the nucleus pulposus (NP) and their potential antidegenerative effects on intervertebral discs. NP cells exhibited aligned growth along the surface of the MicroRod, enhanced proliferation, and reduced apoptosis. This suggests an adaptive cellular response involving adhesion and mechanosensing, which causes cytoskeletal extension via environmental cues. NP cells maintain nuclear membrane integrity through the YAP/TAZ pathway, which activates the cGAS-STING pathway to rectify the aging mechanisms. In vivo, MicroRod carries NP cells and reduces inflammatory factor and protease secretion in degenerated intervertebral discs, inhibiting degeneration and promoting NP tissue regeneration. Our findings highlight the role of mechanical stress in maintaining cellular activity and antiaging effects in harsh environments, providing a foundation for further research and development of antidegenerative biomaterials.
研究领域:
生物材料
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组织工程
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力学生物学
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细胞衰老
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退行性疾病
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DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-17
·
IF 39.3
Liu Yi,Ji Yanhong,Jiang Ruiyi,Fang Chao,Shi Gang,Cheng Lin,Zuo Yinan,Ye Yixin,Su Xiaolan,Li Junshu,Wang Huiling,Wang Yuan,Lin Yi,Dai Lei,Zhang Shuang,Deng Hongxin
Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population. Given the increased incidence of cancer and the population ageing trend globally, it is very important to explore how ageing impairs tissue wound healing and spontaneous cancer. In a murine model of DSS-induced acute colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly decreases intestinal wound healing and simultaneous CAC initiation, although ageing does not affect the incidence of AOM-induced, sporadic non-inflammatory CRC. Mechanistically, reduced fibroblasts were observed in the colitis microenvironment of ageing mice. Through conditional lineage tracing, an important source of fibroblasts potentially derived from intestinal smooth muscle cells (ISMCs) was identified orchestrating intestinal wound healing and CAC initiation in young mice. However, the number of transformed fibroblasts from ISMCs significantly decreased in ageing mice, accompanied by decreased intestinal wound healing and decreased CAC initiation. ISMCs-fibroblasts transformation in young mice and reduction of this transformation in ageing mice were also confirmed by ex-vivo intestinal muscular layer culture experiments. We further found that activation of YAP/TAZ in ISMCs is required for the transformation of ISMCs into fibroblasts. Meanwhile, the reduction of YAP/TAZ activation in ISMCs during intestinal wound healing was observed in ageing mice. Conditional knockdown of YAP/TAZ in ISMCs of young mice results in reduced fibroblasts in the colitis microenvironment, decreased intestinal wound healing and decreased CAC initiation, similar to the phenotype of ageing mice. In addition, the data from intestine samples derived from inflammatory bowel disease (IBD) patients show that activation of YAP/TAZ also occurs in ISMCs from these patients. Collectively, our work reveals an important role of the ageing stromal microenvironment in intestinal wound healing and CAC initiation. Furthermore, our work also identified a potential source of fibroblasts involved in colitis and CAC.
研究领域:
胃肠病学
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肿瘤学
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老年医学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）