Frontiers in Pharmacology
·
2021
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IF 5.811
Feng Feng,Feng Xueyan,Zhang Di,Li Qilong,Yao Li
Vascular pericytes, important mural cells that retain progenitor cell properties and protect vascular integrity in healthy tissues, are often associated with tumor development, but their functions in cancer invasion remain elusive. One prominent outcome of tumor occurrence is that the microenvironment of the lesion often stiffens, which could change resident cell behavior. Here, we found pericytes are matrix stiffness-responsive and mechanical stimuli induce pericyte-fibroblast transition (PFT). Soft PA gels that mimic the stiffness of healthy tissues retain the identity and behavior of pericytes, whereas stiff PA gels that reflect the stiffness of tumorous tissues promote PFT and the mobility and invasiveness of the cells. Matrix stiffness-induced PFT depends on the activation of YAP (Yes-associated protein), a transcription factor, which, upon receiving mechanical signals, transfers from cytoplasm to nucleus to mediate cell transcriptional activities. Our result reveals a mechanism through which vascular pericytes convert to fibroblasts and migrate away from vasculatures to help tumor development, and thus targeting matrix stiffness-induced PFT may offer a new perspective to the treatment of cancer metastasis.
研究领域:
癌症生物学
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细胞力学
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分子生物学
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肿瘤微环境
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Chengxiu Wei,Chuangang You,Liming Zhou,Huiling Liu,Shihao Zhou,Xingang Wang,Rui Guo
Excessive scar formation has severe physiological and psychological effects on patients, and tissue restoration to functioning without scar generation after wounding continues to be a significant challenge. Yes-associated protein (YAP) is a downstream effector of the Hippo pathway that interacts with the transcriptional-enhanced associate domain to regulate stem cell proliferation, tissue growth, and organ size. Blocking mechanotransduction signaling can reduce tissue fibrosis and scar formation. This study developed a biocompatible detachable hydrogel microneedle (MN) system for scarless wound healing. The photosensitizing drug bismuth nanosheets (Bi) and YAP signaling pathway inhibitor verteporfin (Vp) were integrated into the pyramidal MN array. The MN system has sufficient mechanical strength to penetrate the skin, after the separable connection degrades, the tips can be left inside the tissue for continuous active release, and the substrate can be removed safely. The study shows that inhibition of YAP signaling encouraged scar-free wound healing without fibrosis and with the regeneration of secondary skin elements (hair follicles, sebaceous glands). Therefore, MN can serve as an excellent drug delivery system and will have numerous practical benefits in scar-free wound regeneration.
研究领域:
生物材料学
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再生医学
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药理学
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产品关联
DOI
高影响因子
Journal of Materials Chemistry B
·
2026
·
IF 6.2
Hai Liu,Lulong Zhao,Weilun Pan,Songlang Liu,Hongxing Liao,Jun Hu,Liqiong Liao
The native bone matrix stiffens dynamically during development, presenting a critical mechanical cue that static biomaterials cannot effectively mimic. To address this, a photo-tunable dynamic stiffening hydrogel was developed using a dual-crosslinking strategy, combining physical crosslinking through freeze–thaw cycles and UV-triggered thiol–ene photo-click crosslinking. This photo-tunable dynamic stiffening hydrogel significantly promoted the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro and enhanced the repair of critical-sized calvarial defects in vivo. Mechanistic studies revealed that the pro-osteogenic effect is mediated through the activation of the Yes-associated protein (YAP) signaling pathway, as evidenced by its nuclear translocation. Our findings underscore the importance of temporal mechanical cues in bone regeneration and offer a novel biomimetic strategy for bone tissue engineering.
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Xinxin Lin,Xiaocong Liu,Jinglin shi,Tuohong Sun,Ting Feng,Benrui Sun,Hongbin Liang,Qiuxia Zhang,Guojun Chen,Siyu Chen,Alex Pui-Wai Lee,Shenjian Luo,Jiancheng Xiu,Xinlu Zhang
Arterial remodeling is strongly linked to cardiovascular morbidity and mortality. Adventitial inflammation is a key driver in the pathological process of arterial remodeling. However, the underlying molecular mechanism remains largely unknown. This study was conducted to elucidate the role and mechanism of peroxisome proliferator-activated receptor alpha (PPARα) in arterial remodeling. Here, by using the transverse aortic constriction (TAC) model to mimic overload pressure-induced arterial remodeling, we observed significantly decreased expression of PPARα in macrophages that infiltrated into the remodeled arterial adventitia, whereas the administration of PPARα agonist Wy14643 efficiently ameliorated such arterial changes, especially in adventitia. PPARα activation strengthened its interaction with yes-associated protein (YAP) in the cytoplasm thus decreasing the translocation of YAP into nucleus to trigger macrophage infiltration and polarization toward the classical activation phenotype. Finally, blockade of YAP signaling could also suppress pathological arterial alternations in the TAC model. Our study thus identifies PPARα as a promising therapeutic target for treating arterial remodeling.
研究领域:
心血管病学
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分子生物学
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免疫学
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信号转导
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转化医学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
·
2025
·
IF 6
Mingyue Zhong,Jun Zhao,Tingjun Fan
Human corneal endothelium (HCE) plays a vital role in preserving corneal transparency and thickness. However, a marked reduction in the cell density can result in functional decompensation, potentially leading to blindness. The scarcity of donor corneas has limited the development of clinical interventions for this condition, therefore, developing highly functional tissue-engineered HCE (TE-HCE) important. The construction of TE-HCE fundamentally relies on modulating the mechanical microenvironment of the scaffold, which is essential for promoting the optimal proliferation and metabolic activity of the seeded cells. In this study, we used polyacrylamide hydrogels with stiffnesses of 25, 50, and 100 kPa to simulate the mechanical properties of Descemet's membranes and explore the regulatory role of matrix stiffness in HCE cell metabolism and proliferation. An increased scaffold stiffness promoted the proliferation of HCE cells by enhancing the mechanical response of HCE cells, increasing the nuclear translocation of Yes-associated protein (YAP), and promoting the expression of downstream proliferation regulatory genes. Increasing the stiffness of the scaffold also enhanced the glycolysis level of HCE cells by promoting the expression of key glycolytic enzymes, thereby improving the viability and energy yield of HCE cells. Notably, the variations in scaffold stiffness could influence cell proliferation via the YAP pathway by modulating the glycolysis levels, potentially establishing the positive feedback of “metabolic response-proliferation.” This study elucidates the regulatory mechanisms by which mechanical microenvironments influence cellular functions, and provides a theoretical foundation and technical support for the development of tissue-engineered products with precise mechanical properties.
研究领域:
生物医学工程
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细胞生物学
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组织工程
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机械生物学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2023
·
IF 12.4
Jiawei Li,Chunmei Fan,Zhongyang Lv,Ziying Sun,Jie Han,Maochun Wang,Huiming Jiang,Kuoyang Sun,Guihua Tan,Hu Guo,Anlong Liu,Heng Sun,Xingquan Xu,Rui Wu,Wenjin Yan,Qing Jiang,Shiro Ikegawa,Xiao Chen,Dongquan Shi
Purpose: Chondrocytes (CHs) in cartilage undergo several detrimental events during the development of osteoarthritis (OA). However, the mechanism underlying CHs regeneration involved in pathogenesis is largely unknown. The aim of this study was to explore the underlying mechanism of regeneration of CHs involved in the pathological condition and the potential therapeutic strategies of cartilage repair. Methods and Materials: CHs were isolated from human cartilage in different OA stages and the high-resolution cellular architecture of human osteoarthritis was examined by applying single-cell RNA sequencing. The analysis of gene differential expression and gene set enrichment was utilized to reveal the relationship of cartilage regeneration and microtubule stabilization. Microtubule destabilizer (nocodazole) and microtubule stabilizer (docetaxel) treated-human primary CHs and rats cartilage defect model were used to investing the effects and downstream signaling pathway of microtubule stabilization on cartilage regeneration. Results: CHs subpopulations were identified on the basis of their gene markers and the data indicated an imbalance caused by an increase in the degeneration and disruption of CHs regeneration in OA samples. Interestingly, the CHs subpopulation namely CHI3L1 + CHs, was characterized by the cell regenerative capacity, stem cell potency and the activated microtubule (MT) process. Furthermore, the data indicated that MT stabilization was effective in promoting cartilage regeneration in rats with cartilage injury model by inhibiting YAP activity. Conclusion: These findings lead to a new understanding of CHs regeneration in the OA pathophysiology context and suggest that MT stabilization is a promising therapeutic target for OA and cartilage injury.
研究领域:
医学
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分子生物学
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再生医学
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产品关联
DOI
PubMed
高影响因子
Biofabrication
·
2026
·Vol. 18
·期 3
·035001
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IF 8.2
Duoer Xiong,Qihang Zheng,Wei Chen,Meiqi Li,You Chen,Changhua Zhang,Jie Liu
The fibrotic stroma drives tumor progression and impairs therapy, but existing models fail to capture its dual barrier and signaling roles, limiting mechanistic understanding and therapeutic development. To address this, we established a patient-derived fibrotic tumor model that recapitulates key pathophysiological features: extracellular matrix remodeling, substantial tissue stiffening (12-fold increase), and pro-malignant transcriptomic reprogramming. This model demonstrated microenvironment-mediated chemoresistance, increasing the area under the dose‐response curve by 1.3-fold and suppressing oxaliplatin-induced apoptosis. Although stiffening delayed drug penetration, barrier disruption did not restore sensitivity. Instead, stiffness inactivated the Hippo pathway, activating YAP as the key chemoprotection driver. YAP inhibition restored drug sensitivity without altering stiffness, revealing a targetable biochemical mechanism independent of the physical barrier. Using this insight, we designed a sequential regimen in which nintedanib preconditioning precedes chemotherapy, achieving near-complete tumor eradication (<5% tumor viability). This work provides a physiological model of stromal biology and a mechanism-guided strategy to overcome microenvironment-mediated chemoresistance.
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Wei Zhang,Wenting Zhu,Xiao Liu,Silong Yuan,Da Li,He Huang,Xiaoming Huang,Lei Wang,Honggang Zhang
Background The pathogenesis of sepsis-induced cardiomyopathy (SIC) remains unclear, presenting a complex challenge in both clinical practice and research. Gypenoside XLIX (Gyp-XLIX) has garnered significant attention for its anti-inflammatory, antioxidant, and various other pharmacological activities; however, its protective effect on SIC has not been thoroughly investigated. Purpose This study aims to explore the effect of Gyp-XLIX on SIC and its potential therapeutic mechanisms. Methods A sepsis mouse model was established through cecal ligation and puncture surgery and treated with Gyp-XLIX. The modeling was evaluated through sepsis model scoring, survival analysis, weight changes, wet-to-dry weight ratio, H&E staining, biochemical assays and cardiac ultrasound. The mechanism exploration was deteced using proteomics sequencing, Western blotting, qPCR, biochemical analysis, and reactive oxygen species assays. Additionally, target proteins of Gyp-XLIX were identified through LC-MS/MS proteomics analysis, molecular docking, CESTA, DARTS, SPR with SIRT1 being a primary focus. Bioinformatics and Immunoprecipitation mass spectrometry analysis, and immunohistochemistry were employed to further elucidate the downstream target of SIRT1, specifically the YAP-NLRP3 pathway. The degradation mechanisms of YAP-NLRP3 were explored using MG132, chloroquine, cycloheximide, and co-immunoprecipitation. Corresponding rescue experiments were conducted in H9C2 cells for further validation. Results Gyp-XLIX effectively mitigates SIC, reduces cardiac inflammation, and restores cardiac structural, left ventricular functional abnormalities, and oxidative stress balance. Proteomics results showed that Gyp-XLIX binded to SIRT1 and alleviates inflammation and oxidative stress. Whereas, SIRT1 is low expressed and alleviated oxidative stress and NLRP3 inflammasome activation in SIC. Mechanically, Gyp-XLIX binded to SIRT1 improved its stability and promoted the deacetylation and phosphorylation of downstream YAP, which in turn regulated YAP degradation. This process subsequently affects the ubiquitination of NLRP3, downstream of YAP, at the K27 site, leading to its degradation and, consequently, alleviating inflammation and oxidative stress during SIC. Conclusion Gyp-XLIX targets SIRT1 to block YAP-NLRP3 activation and improve SIC, suggesting that Gyp-XLIX is an effective protective agent against SIC and represents a promising therapeutic strategy.
研究领域:
心血管药理学
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分子医学
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炎症生物学
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天然产物研究
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信号转导
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8049
·
IF 13.3
Jiaorong Qu,Jianan Li,Le Wang,Yufei Li,Yinqiang Zhang,Jingtao Li,Zixuan Huo,Junsong Han,Runping Liu,Guifang Fan,Yinhao Zhang,Xiaoyong Xue,Xiaojiaoyang Li
Background and aims: Inducing the senescence of activated hepatic stellate cells (HSCs) has emerged as a promising therapeutic strategy for liver fibrosis, with potential connections to the Yes-associated protein (YAP)-controlled cGAS-STING pathway. However, the regulatory role of cytoskeletal dynamics on HSC senescence and its potential as a target for natural products have remained poorly understood. Methods: We employed preclinical in vivo and in vitro transcriptome analyses, experimental systems, Tmem173 -/- mice and liver-specific STING knockdown mice to demonstrate the anti-fibrotic effects and mechanism of ligustilide (LIG). Results: LIG selectively bound to monomeric globular actin (G-actin), thereby preventing its polymerization into polymeric filamentous actin (F-actin), which disturbed its interaction with intermediate filament component lamin A/C and initially destroyed the nuclear membrane. Moreover, the disruption of nuclear membrane caused YAP leakage from nuclear, which in turn suppressed lamin A/C and created a deleterious feedback loop that exacerbated nuclear membrane destabilization. Consequently, nuclear double stranded DNA (dsDNA) leakage caused by the above damage cascade ultimately triggered the activation of the cGAS-STING signaling pathway, promoting senescence-associated secretory phenotypes (SASPs) release and inducing HSC senescence. Moreover, the induction of HSC senescence and anti-fibrotic effects of LIG were completely abrogated in both whole-body STING knockout and liver-specific STING knockdown mice. Conclusions: By interacting with G-actin, LIG disrupted the cytoskeleton to compromise nuclear integrity with the involvement of YAP and further stimulated the cGAS-STING pathway, leading to the release of SASPs and HSC senescence, which ultimately mitigated liver fibrosis.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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生物化学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Shuai Zhan,Ningjing Zhang,Yijie Lou,Xia Ding,Zhe Chen,Yun Huang,Wanjing Ding
Acute lung injury (ALI), characterized by uncontrolled inflammatory responses, is a critical condition with limited clinical treatment options. Activation of the NLRP3 inflammasome represents a pivotal event in ALI pathogenesis. Although targeting NLRP3 (The NOD-like receptor (NLR) family member containing a pyrin domain 3) inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the pulmonary inflammation is modulated remains controversial. Here, we demonstrate that 475A, a highly selective ROCK2 (Rho-associated coiled-coil forming protein kinases 2) inhibitor, effectively attenuates pulmonary inflammation and alleviates lung injury. Mechanistically, 475A promotes NLRP3 protein ubiquitination and subsequent proteasomal degradation by disrupting YAP (Yes-associated protein)-NLRP3 protein interactions, thereby suppressing inflammatory cytokine production in macrophages. This study provides the first evidence linking ROCK2 inhibition to enhanced NLRP3 degradation in ALI treatment, paving the way for developing 475A as a therapeutic agent and establishing the ROCK2/YAP/NLRP3 axis as a novel strategy for treating NLRP3-driven inflammatory diseases.
研究领域:
免疫学
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药理学
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分子生物学
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呼吸医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PERIODONTAL RESEARCH
·
2023
·
IF 3.5
Xiaocen Zhang,Maolin Chang,Beike Wang,Xiaoyu Liu,Zhen Zhang,Guangli Han
Objective To verify the role of YAP/WNT5A/FZD4 axis in stretch-induced osteogenic differentiation of hPDLCs. Background During orthodontic tooth movement, differentiation of human periodontal ligament cells (hPDLCs) at the tension side of the periodontal ligament mediates new bone formation. WNT5A promotes osteogenesis and its regulator Yes-associated protein (YAP) is responsive to mechanical stimulation in hPDLCs. However, the mechanisms of YAP and WNT5A in alveolar bone remodeling remain unclear. Methods Cyclic stretch was applied to hPDLCs to mimic the orthodontic stretching force. Osteogenic differentiation was determined by alkaline phosphatase (ALP) activity, Alizarin Red staining, qRT-PCR and western blotting. To detect activation of YAP and expression of WNT5A and its receptor Frizzled-4 (FZD4), western blotting, immunofluorescence, qRT-PCR and ELISA were performed. Verteporfin, Lats-IN-1, small interfering RNAs and recombinant protein were used to explore the relationship of YAP, WNT5A and FZD4, and the effect of their relationship on stretch-induced osteogenesis of hPDLCs. Results WNT5A, FZD4 and nuclear localization of YAP were upregulated by cyclic stretch. YAP positively regulated WNT5A and FZD4 expression and osteogenic differentiation of hPDLCs under cyclic stretch by YAP inhibition or activation assay. Knockdown of WNT5A and FZD4 attenuated YAP-induced and stretch-induced osteogenic differentiation. Recombinant WNT5A rescued the suppressed osteogenic differentiation by YAP inhibitor in hPDLCs, whereas knockdown of FZD4 weakened the effect of WNT5A and amplified the suppression. Conclusions WNT5A/FZD4 could be positively regulated by YAP and the YAP/WNT5A/FZD4 axis mediated osteogenic differentiation of hPDLCs under cyclic stretch. This study provided further insight into the biological mechanism of orthodontic tooth movement.
研究领域:
牙科学
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细胞生物学
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正畸学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Medical Sciences
·
2020
·
IF 2.523
Hao Hu,Liang Xu,Shao-Ju Luo,Ting Xiang,Yan Chen,Zhi-rui Cao,Yu-jian Zhang,Zhuomao Mo,Yongdan Wang,Dong-fang Meng,Ling Yu,Li-zhu Lin,Shi-Jun Zhang
Retinal dehydrogenase 5 (RDH5) is an important enzyme in the visual cycle. Several studies have reported that the RDH family may play crucial roles in tumor prognosis. However, the role of RDH5 in tumor prognosis is still unclear. We examined the mRNA level of RDH5 by using q-PCR in hepatocellular carcinoma (HCC) and adjacent non-cancerous tissues. The proliferation rate of HCC cells was detected by MTS assay, and the invasive ability was examined by transwell and scratch wound assays. The YAP protein localization and expression were visualized by immunofluorescence in two different cell lines. CpG islands in the promoter region were predicted by using the methprimer database. Clinical characteristics of a patient cohort data came from The Cancer Genome Atlas database. RDH5 was significantly downregulated in hepatocellular carcinoma tissues, and low RDH5 expression was associated with metastasis and poor patient prognosis. Functional assays revealed that the RDH5 promoter is methylated in HCC cell lines. Moreover, overexpressing RDH5 can suppress metastasis by reversing the epithelial-mesenchymal transition (EMT) process, and RDH5 also inhibits cell proliferation in HCC cell lines. Furthermore, suppressing RDH5 can activate the Hippo/YAP signaling pathway and promote the nuclear translocation of YAP. Clinical data demonstrated that RDH5 is an independent prognostic factor in HCC. In our study, we provided the first evidence that RDH5 plays a crucial role in suppressing proliferation and metastasis, and the RDH5 promoter is methylated in hepatocellular carcinoma. And as an important regulator, RDH5 can suppress the Hippo/YAP signaling pathway. Taken together, it revealed that RDH5 might be a potential therapeutic target in HCC patients.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
·
基因组学
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DOI
PubMed
高影响因子
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