iScience
·
2025
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IF 4.1
Weiyu Wu,Ren Zhang,Geer Chen,Ziyu Chen,Zicong Lin,Yin Chen,Jiaqi Li,Weilin Liao,Junyi Wang,Xiaoxuan Wang,Junhao Huang,Lijuan Ma,Haijie Yu
Natural compounds are valuable templates for anticancer drug development. Through high-throughput screening of 1,880 natural compounds and structure-activity analysis, we identified sappanchalcone (SC) as a potent agent that induces intracellular calcium elevation and causes G2/M phase arrest in H1975, H1299, and A549 cells. Transcriptomic and protein-protein interaction network analyses revealed multi-target effects of SC, involving oxidative stress, cell cycle dysregulation, and ion homeostasis perturbation. Mechanistically, SC induced ROS accumulation, upregulated the DNA damage, and enhanced the expression of p21 and GADD45α, thereby suppressing the CDK1/Cyclin B1 complex. SC also activated ER stress pathways by phosphorylating IRE1α and PERK. Notably, SC downregulated the mechanosensitive ion channel PIEZO1, and its inhibitor ruthenium red (RR) significantly reversed SC-induced proliferation inhibition and G2/M arrest. This study delineates an antitumor mechanism of SC mediated via a calcium–ER stress–cell cycle axis with translational potential for NSCLC therapy.
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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天然产物化学
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细胞信号传导
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DOI
PubMed
高影响因子
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
·
2025
·
IF 5.3
Mingzhi Luo,Xiangrong Zhang,Jia Guo,Rong Gu,Youyuan Qin,Kai Ni,Lei Liu,Yan Pan,Jingjing Li,Honglei Shi,Linhong Deng
Bronchodilators that relax airway smooth muscle cells (ASMCs) are essential for treating constrictive airway diseases such as asthma. However, the existing bronchodilators are often unable to control symptoms of severe asthmatic patients, leaving a pressing need to search for alternatives. Recent studies indicate that the transmembrane mechanosensitive channel, Piezo1 may provide a novel target for bronchodilation as it mediates ASMCs relaxation via calcium signaling and activation of large-conductance calcium-activated potassium channels (BKCa), and Piezo1 specific agonist Yoda1 has been shown to reduce cell stiffness and traction force in cultured ASMCs after 24 h incubation. Thus in this study, we further explored the potential of Yoda1 for inducing rapid ASMCs relaxation and bronchodilation. We treated either cultured ASMCs or allergen-induced mouse models of asthma with Yoda1 at various doses, and then assessed the resulting variations in cell stiffness, traction force, and molecular signaling of cultured ASMCs, as well as in airway resistance of the mouse models. We found that exposure to Yoda1 rapidly decreased cell stiffness, traction force in association with induced calcium signaling and BKCa activation in cultured ASMCs, and reduced airway resistance in methacholine-challenged mice in a dose-dependent manner. These results indicate that chemical activation of Piezo1 with specific agonist Yoda1 was indeed capable of inducing bronchodilation by relaxing ASMCs, and thus provide insights into development of Piezo1 agonist-based novel bronchodilators for treating constrictive airway disorders such as asthma.
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PubMed
高影响因子
BIOCHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 3.9
Yi Zhou,Yawen Chen,Yuanyuan Zhao,Qiaohui Lu,Shihao Li,Wen-song Tan,Yan Zhou
Hydrostatic pressure (HP) is one of the important mechanical stimuli to maintain the structure and function of bone tissue. Under non-physiological conditions, abnormal increases or decreases in HP can lead to loss of bone tissue function. Although HP has been proven to affect osteogenic differentiation, the rules and mechanisms of its regulatory effect are still unclear. In this study, the HP showed a marginal effect on promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The regulation of osteogenic differentiation by HP is closely related to the Piezo1 ion channel. On the one hand, the activity of mTOR is inhibited by HP through the CaMKK2/AMPKα/mTOR signaling axis, thereby promoting the osteogenic differentiation. On the other hand, the cell morphology is also regulated by HP and tends to be round, which is not conducive to osteogenesis. The two regulatory modes jointly control the ultimate osteogenic differentiation ability of BMSCs in a complex way. This study provides new insights into the mechanism by which HP regulates osteogenic differentiation, suggesting the need to consider the role of signaling cascades and physical changes simultaneously.
研究领域:
生物力学
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干细胞生物学
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骨组织工程
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DOI
高影响因子
Advanced Healthcare Materials
·
2023
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IF 10
Jinghong Yang,Kaiting Yuan,Tingting Zhang,Shiqi Zhou,Weichang Li,Zetao Chen,Yan Wang
Guided bone regeneration membranes are widely used to prevent fibroblast penetration and facilitate bone defect repair by osteoblasts. However, the current clinically available collagen membranes lack bone induction and angiogenic capacities, exhibiting limited bone regeneration. The mechanically sensitive channel, Piezo1, which is activated by Yoda1, has been reported to play crucial roles in osteogenesis and angiogenesis. Nevertheless, the application of Yoda1 alone is unsustainable to maintain this activity. Therefore, this study fabricates a Yoda1-loading bilayer membrane using electrospinning technology. Its inner layer in contact with the bone defect is composed of vertically aligned fibers, which regulate the proliferation and differentiation of cells, release Yoda1, and promote bone regeneration. Its outer layer in contact with the soft tissue is dense with oriented fibers by UV cross-linking, mainly preventing fibroblast infiltration and inhibiting the immune response. Furthermore, the loaded Yoda1 affects osteogenesis and angiogenesis via the Piezo1 / RhoA /Rho-associated coiled-coil-containing protein kinase 1/Yes1-associated transcriptional regulator signaling pathway. The results reveal that the Yoda1 bilayer membrane is efficient and versatile in accelerating bone regeneration, suggesting its potential as a novel therapeutic agent for various clinical issues.
研究领域:
生物医学工程
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组织工程
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骨科
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药理学
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DOI
PubMed
高影响因子
Materials Today Bio
·
2026
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IF 10.2
Xiaoling Jia,Lin Zhao,Juncheng Bai,Lu Wen,Qianyu Meng,Haikun Wang,Junqi Men,Hui Shao,Yingying Guo,Xinlan Chen,Xing Chen,Lin-Hua Jiang,Yubo Fan,Huawei Liu
Matrix stiffening profoundly influences cancer cell functions and cancer progression, and the mechanosensitive Piezo1 channel is implicated in these processes. Different from what is observed in most solid tumors, the Piezo1 channel in lung cancer is down-regulated and negatively regulates cancer cell migration, but the underlying mechanism is still unclear. Herein, we investigated the role of Piezo1 channel in matrix stiffness regulation of lung cancer cell migration and the mechanisms in A549 cells growing on polyacrylamide (PA) hydrogels with different stiffness. Compared with soft substrate, stiff substrate promoted cell migration, down-regulated Piezo1 expression, favored filopodia formation, as well as restraining the rise in intracellular calcium concentration ([Ca 2+ ] i ). Additionally, blockade or knockdown of Piezo1 channel promoted, whereas its activation suppressed, cell migration and filopodia formation. Furthermore, reducing the [Ca 2+ ] i promoted cell migration and filopodia formation. Finally, stiff substrate induced cofilin phosphorylation, which was enhanced by inhibiting the Piezo1 channel or reducing the [Ca 2+ ] i and, conversely, suppressed by activating the Piezo1 channel. Collectively, our study has revealed that stiff matrix down-regulates the Piezo1 channel expression and thereby restrains the rise in the [Ca 2+ ] i to facilitate cofilin phosphorylation and filopodia formation, leading to an increase in lung cancer cell migration. These findings broaden our understanding of the molecular mechanism by which the Piezo1 channel functions in lung cancer differently from in other cancers.
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PubMed
高影响因子
LIFE SCIENCES
·
2023
·
IF 6.1
Shaoya Rong,Luyun Zhang,Jianxin Wang,Hui Dong
Aims Although endothelial Piezo1 channel is known to induce NO-mediated vasorelaxation of conduit vessels, it remains largely unknown if it can induce endothelial-dependent hyperpolarization (EDH)-mediated vasorelaxation of resistance vessels. Therefore, the present study aims to investigate Piezo1/EDH-mediated vasorelaxation in health and its involvement in ulcerative colitis (UC) and sepsis , two intractable and deadly inflammatory diseases . Main methods The tension of the second-order branch of mouse mesenteric artery was measured via the Danish DMT600M microvascular measurement system. The changes in cytoplasmic calcium ([Ca 2+ ] cyt ) signaling in vascular endothelial cells were detected by fluorescent calcium assay, and the membrane potential changes were monitored by patch clamp . Experimental murine models of UC and sepsis were induced by dextran sulfate sodium (DSS) and lipopolysaccharides (LPS), respectively. Key findings A selective activator of Piezo1 channel, Yoda1, dose-dependently induced vasorelaxation of the second-order branch of mouse mesenteric artery in an endothelium-dependent manner. The endothelial Piezo1 channel mediated the vasorelaxation through EDH mechanism by a functional coupling of Piezo1 and TRPV4 channels . Their function and coupling were verified by [Ca 2+ ] cyt imaging and patch clamp study in single endothelial cells . Moreover, while ACh-induced vasorelaxation played a major role in health, it was significantly impaired in the pathogenesis of UC and sepsis; however, Piezo1/EDH-mediated vasorelaxation remained intact. Finally, Piezo1/EDH-mediated vasorelaxation recovered ACh-induced vasorelaxation impaired in UC and sepsis. Significance Piezo1/TRPV4/EDH-mediated vasorelaxation rescues the impaired ACh-induced vasorelaxation to likely recover hemoperfusion to organs, leading to organ protection against UC and sepsis. Our study not only suggests that endothelial Piezo1, TRPV4 and K Ca channels are the potential therapeutic targets, but also implies that Piezo1 activators may benefit to prevent/treat UC and sepsis.
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DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-13
·
IF 15.7
Jin Kai-Qi,Sun Tian-Cai,Zhou Zi-Xing,Li Jing-Du,Zhao Yi,Fan Wen-Ting,Yan Jing,Huang Guo-You,Huang Wei-Hua,Liu Yan-Ling
Mechanical cues are critical regulators of cell fate and behavior through the orchestrated and continual conversion of physical forces into biochemical responses. However, due to the poor compatibility between mechanical and biochemical techniques, existing methods are often limited in characterizing the occurring biochemical signals during mechanical stimulation. Herein, this work presents a magneto-responsive nanomesh (MRnM) biosensor capable of mechanically stimulating cells in vitro and tissues in vivo and simultaneously detecting the triggered biomolecules. Under external magnetic fields, the sensor exhibits excellent magnetic responsiveness with remote, controllable and tailored deformation, while maintaining prominent and stable electrochemical sensing performance. As a proof of concept, this MRnM sensor achieves the magnetically-actuated deformation of osteoblasts and real-time monitoring of the ensuing nitric oxide release, revealing the role of Piezo1 channels in nitric oxide synthase signaling pathways. Furthermore, we demonstrate the capability of MRnM sensor for in vivo applications. Ultimately, the developed MRnM biosensor holds great potential for mechanical stimulation and real-time monitoring of various biological systems, ranging from living cells to soft tissues and in vivo organs.
研究领域:
生物传感器
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力学生物学
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电化学
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纳米技术
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生物医学工程
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细胞信号传导
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
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IF 6.7
Jiawen Yu,Kunying Chen,Yujing Zhang,Xujie Wang,Yangchun Shen,Yu Deng,Xingtao Zhou
Abstract Modulating intestinal macrophage polarization is critical for maintaining intestinal barrier integrity. Our previous study demonstrated that glucomannan from Aloe vera gel (AGP) improved the intestinal barrier, yet its direct impact on intestinal macrophages remained undefined. Here, we demonstrated that AGP reduced M1 macrophage infiltration in colonic tissue. Integrated serum untargeted metabolomics identified lactic acid as a key AGP-induced metabolite, with 16S rRNA sequencing pointing to the gut microbiota as its potential source. Mechanistically, lactic acid suppressed M1 polarization by inhibiting the mechanosensitive cation channel Piezo1, thereby attenuating calcium influx, concurrently dampening STAT3 activation and ROS production─core drivers of M1 commitment. Critically, these effects were abrogated by a Piezo1 agonist, confirming the centrality of the lactic acid–Piezo1–Ca2+ axis. Collectively, our study defines a novel immunometabolic pathway wherein AGP fortifies the intestinal barrier through microbiota-derived lactic acid, which restrains macrophage M1 polarization via the lactic acid–Piezo1–calcium axis.
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高影响因子
Materials Today Advances
·
2022
·
IF 9.918
Siyong Gao,Yuxin Tang,Wei Sun,Zhixin Liu,Tianyu Zhao,Xiang Li,Tianlu Wang,Guiqing Liao,Tao Xu,Guangsen Zheng,Yujie Liang
Schwann cells (SCs)-based nerve guidance conduits (NGCs) is a promising strategy for repairing long-gap peripheral nerve injury (PNI). But the number of SCs is limited as terminally differentiated cells. Matrix stiffness is able to direct cell fate of stem cells. And nerve-special stiffness (NSS) may contribute to stem cells converting into SCs. However, the potential mechanisms remain uncertain. The present study aimed to elucidate whether the given NSS was able to promote mesenchymal stem cells (MSCs) trans -differentiating into Schwann cell-like cells (SCLCs), facilitating cell-based NGCs repairing PNI. Gelatin methacryloylate (GelMA) hydrogels with different stiffness were manufactured, and their roles in the trans -differentiation of MSCs into SCLCs were investigated in vitro study. The most favorable stiffness (0.9–2.9 kPa) for trans -differentiation and neurotrophic factors expression was confirmed by western blot and immunofluorescence assays. The reason might lie in softer stiffness stretched cell morphology, leading to up-regulation of PIEZO1 and then activating YAP nuclear translocation. As for in vivo study, multi-channel NGCs containing SCLCs were fabricated with extrusion-based bioprinting and then filled a 5 mm gap in sciatic nerve defect of SD rats. It turned out that GelMA-made NGCs with stiffness of 2.9 kPa achieved promising neurogenerative capacity, not only promoting recovering sensory and motor functions, but also improving myelinated nerve fiber regeneration. Our findings demonstrated that 0.9–2.9 kPa might be the desired mechanical strength inducing trans -differentiation into SCLCs via PIEZO1/YAP axis, and the 3D-printed GelMA NGCs combined with SCLCs could be a potential candidate for long-gap peripheral nerve injury.
研究领域:
生物医学工程
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组织工程
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神经科学
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干细胞生物学
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高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 12
·期 3
·2201925
·
IF 11.092
Xianpeng Huang,Di Chen,Chengzhen Liang,Kesi Shi,Xiaopeng Zhou,Yuang Zhang,Yi Li,Jiangjie Chen,Kaishun Xia,Jiawei Shu,Biao Yang,Jingkai Wang,Haibin Xu,Chao Yu,Feng Cheng,Shaoke Wang,Yongxiang Zhang,Chenggui Wang,Liwei Ying,Hao Li,Meiling Han,Fangcai Li,Yiqing Tao,Qian Zhao,Qixin Chen
Mechanical stimulation is an effective approach for controlling stem cell differentiation in tissue engineering. However, its realization in in vivo tissue repair remains challenging since this type of stimulation can hardly be applied to injectable seeding systems. Here, it is presented that swelling of injectable microgels can be transformed to in situ mechanical stimulation via stretching the cells adhered on their surface. Poly(acrylamide- co -acrylic acid) microgels with the upper critical solution temperature property are fabricated using inverse emulsion polymerization and further coated with polydopamine to increase cell adhesion. Adipose-derived mesenchymal stem cells (ADSCs) adhered on the microgels can be omnidirectionally stretched along with the responsive swelling of the microgels, which upregulate TRPV4 and Piezo1 channel proteins and enhance nucleus pulposus (NP)-like differentiation of ADSCs. In vivo experiments reveal that the disc height and extracellular matrix content of NP are promoted after the implantation with the microgels. The findings indicate that swelling-induced mechanical stimulation has great potential for regulating stem cell differentiation during intervertebral disc repair.
研究领域:
组织工程
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干细胞生物学
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生物医学工程
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骨科
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PubMed
高影响因子
CELL
·
2024
·
IF 45.5
Jinjia Zhang,Junhong Li,Yongqiang Hou,Yao Lin,Hao Zhao,Yiran Shi,Kaiyun Chen,Cheng Nian,Jiayu Tang,Lei Pan,Yunzhi Xing,Huan Gao,Bingying Yang,Zengfang Song,Yao Cheng,Yue Liu,Min Sun,Yueyue Linghu,Jiaxin Li,Haitao Huang,Zhangjian Lai,Zhien Zhou,Zifeng Li,Xiufeng Sun,Qinghua Chen,Dongxue Su,Wengang Li,Zhihai Peng,Pingguo Liu,Wei Chen,Hongling Huang,Yixin Chen,Bailong Xiao,Lilin Ye,Lanfen Chen,Dawang Zhou
Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8 + T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8 + T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8 + T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8 + T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8 + T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8 + T cell exhaustion and could be targeted to potentiate cancer immunotherapy.
研究领域:
免疫学
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癌症生物学
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细胞生物学
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转录调控
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DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
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IF 26.8
Longwei Li,Zheng Li,Muxin Yue,Yangshi Shao,Jing Wang,Yutong Song,Zhong Lin Wang,Yongsheng Zhou,Xiong Pu
Articular cartilage regeneration has long been a formidable challenge because of its avascular and aneural nature. Traditional approaches, using exogenous electrical stimulation or electroactive materials, often fail to align with the endogenous iontronic bioelectricity of natural cartilage. Herein, an implantable mechano-iontronic hydrogel (MI-hydrogel) is biomimetically designed to enhance cartilage repair. This MI-hydrogel generates iontronic electricity under deformation, closely mimicking the characteristics and mechanisms of natural cartilage. It is demonstrated that the MI-hydrogel synergistically integrates iontronic electricity and mechanical stimulation during physical activity, activating the ion channel protein Piezo1. This activation promotes the chondrogenic differentiation of stem cells in vitro and facilitates cartilage repair in vivo. Additionally, these coupled effects are shown to reprogram the metabolic microenvironment, enhancing glutamine metabolism and accelerating the cartilage regeneration process. This study not only underscores the potential of the MI-hydrogel as a novel therapeutic platform but also introduces a new mechanism for tissue regeneration, paving the way for innovative approaches in regenerative medicine.
研究领域:
组织工程
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再生医学
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生物材料
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软骨生物学
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分子生物力学
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代谢重编程
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）