FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Yan Zhang,Yuanyuan Ren,Zhen Wang,Xi Zhang,Xiaofang Li,Yi Yu,Lu Qian,Yuyan Xiong
A high-fat diet and obesity significantly increase the risk of gastric cancer (GC), with persistent obesity contributing to a notable rise in GC incidence. However, the underlying molecular mechanisms remain largely unclear. In this study, we identified exosomal SLC1A5 (Exo-SLC1A5) as a novel senescence-associated secretory phenotype (SASP) factor that promotes GC malignancy. Exosomal SLC1A5 drives GC progression by suppressing ferroptosis in a GPX4-dependent manner. Mechanistically, in the context of obesity, senescent endothelial cells release exosomal SLC1A5, which engages EGFR on GC cells, triggering SRC phosphorylation at Tyr416 and subsequent YAP1 activation at Tyr357. This leads to YAP1 interaction with MYO1B to enhance the nuclear translocation of YAP1, and subsequent upregulation of GPX4, resulting in ferroptosis suppression and accelerated GC progression. In vivo, depletion of exosomal SLC1A5 from PA-induced senescent ECs attenuated GC tumor growth and metastasis in a xenograft mouse model. These findings reveal a novel mechanism by which exosomal SLC1A5 promotes GC progression through the EGFR/SRC/YAP1/GPX4 signaling axis. Targeting the Exo-SLC1A5/EGFR/SRC/YAP1/GPX4 axis may provide a therapeutic strategy for GC.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 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
·
分子生物学
·
细胞生物学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
·
2022
·
IF 1.798
Ning HAN,Ying SU,Mi GUO,Li YU
Diabetic retinopathy (DR) is the prevalent microvascular complication of diabetes mellitus (DM), and it may lead to permanent blindness. The previous publication has indicated that both inflammatory response and oxidative stress are critical factors involved in DR progression, however, the accurate regulatory mechanism remains to be revealed. Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), a member of the protein tyrosine phosphatase family, was reported to play a role in diabetic nephropathy, whereas its function in DR was unknown and required further exploration. The level of phosphorylated, not the total, SHP2 increased in the retinas of rats with streptozotocin injection-induced DM. Further, the intravitreal injection of SHP2 shRNA lentivirus alleviated retinal pathological changes, and inhibited inflammatory response and oxidative stress, which were accompanied with Yes-associated protein 1 (YAP1) deactivation in DR rats. Additional co-immunoprecipitation results confirmed the interaction of SHP2 and YAP1. Collectively, our data preliminarily show that DR amelioration-induced by SHP2 inhibition in rats may attribute to the deactivation of YAP1 pathway.
研究领域:
眼科学
·
分子生物学
·
糖尿病研究
·
细胞信号传导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Minfeng Zhou,Huifang Niu,Guoquan Huang,Minquan Zhou,Dandan Cui,Huarong Li,Han Wen,Hongxing Zhang,Fengxia Liang,Rui Chen
Suppressing tumor metastasis is a crucial strategy for improving survival rates in patients with colorectal cancer (CRC), with cancer stem cells (CSCs) being the primary drivers of metastasis. Current therapeutic approaches targeting CSCs are limited, and their molecular mechanisms remain unclear. To address this challenge, a biomimetic nanoparticle delivery system, CMD-BHQ3-PTL/DOX@RBCM is developed, to deliver the stem cell regulator, piceatannol (PTL). This system used carboxymethyl dextran (CMD) and Black Hole Quencher 3 (BHQ3) to encapsulate PTL and the cytotoxic drug doxorubicin (DOX) within a red blood cell membrane (RBCm), enhancing stability and biocompatibility while allowing gradual drug release under hypoxic conditions. The effects of PTL are investigated on CSCs using molecular biology experiments, plasmid construction, and high-throughput sequencing and elucidated the molecular mechanisms underlying this biomimetic nanoparticle delivery system. The therapeutic efficacy of PTL is validated at the tissue level using subcutaneous and metastatic tumor models in human and murine systems. The results demonstrated that CMD-BHQ3-PTL/DOX@RBCM effectively addressed the challenges of specificity and biocompatibility in vivo, significantly inhibiting CSC-related tumor metastasis. This inhibitory effect is closely associated with the Hippo/YAP1/SOX9 pathway. This study highlights the effectiveness of the pH-responsive biomimetic nanoparticle system CMD-BHQ3-PTL/DOX@RBCm in delivering PTL to tumor sites, with SOX9 and its upstream Hippo/YAP1 pathway playing a critical role in the underlying mechanism.
研究领域:
肿瘤学
·
分子生物学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2022
·
IF 5.307
Tingting Ma,Huanli Cheng,Tongxi Li,Yifan Chen,Tianying Cai,Junjie Bai,Ziming Wu,Xianming Xia,Tiancheng Liang,Yichao Du,Wenguang Fu
Background Although liver fibrosis is a key pathologic process in many liver diseases, therapeutic approaches for inhibiting liver fibrosis are still very limited. N-Acetyl- l -tryptophan ( l -NAT) has a hepatoprotective effect via inhibiting the destruction of liver cells, enhancing cell viability and reducing the inflammation. However, the effect of l -NAT on liver fibrosis is not determined. Purpose The present study investigated the effect of l -NAT on liver fibrosis and explored it potential molecular mechanism. Methods To address this concern, this study was carried out via fibrotic mice model induced by CCl 4 and many approaches such as various histological staining methods, western blot assay, etc. Result l -NAT decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in fibrotic mice model induced by carbon tetrachloride (CCl 4 ). Histological staining showed that l -NAT ameliorated liver injury and fibrosis, and reduced the expression of α-smooth muscle actin (α-SMA) and Collagen I protein. l -NAT also attenuated apoptosis by down-regulating the level of pro-apoptotic protein Bax and up-regulating that of anti-apoptotic protein Bcl-2. Moreover, l -NAT inhibited the expressions of TGF-β1/SMAD and matrix metalloproteinase 9 (MMP9) proteins, and reversed the expression of YAP1 protein in CCl 4 -induced liver fibrosis. Conclusion These results clearly demonstrated that l -NAT attenuated CCl 4 -induced liver fibrosis in mice, and this protective mechanism might relate to TGF-β1/SMAD and Hippo/YAP1 signaling pathway. Thus, this study provided data basis for the prevention and treatment of liver fibrosis.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Xuepeng Wang,Chunchun Zou,Changju Hou,Zhenyu Bian,Wu Jiang,Maoqiang Li,Liulong Zhu
Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have emerged as promising tools for promoting bone regeneration. This study investigates the functions of EVs derived from bone marrow-derived MSCs (BMSCs) in osteoporosis (OP) and the molecular mechanism. EVs were isolated from primary BMSCs in mice. A mouse model with OP was induced by ovariectomy. Treatment with EVs restored bone mass and strength, attenuated trabecular bone loss and cartilage damage, and increased osteogenesis while suppressing osteoclastogenesis in ovariectomized mice. In vitro , the EVs treatment improved the osteogenic differentiation of MC-3T3 while inhibiting osteoclastic differentiation of RAW264.7 cells. Microarray analysis revealed a significant upregulation of ubiquitin specific peptidase 7 (USP7) expression in mouse bone tissues following EV treatment. USP7 was found to interact with Yes1 associated transcriptional regulator (YAP1) and stabilize YAP1 protein through deubiquitination modification. YAP1-related genes were enriched in the Wnt/β-catenin signaling, and overexpression of YAP1 promoted the nuclear translocation of β-catenin. Functional experiments underscored the critical role of maintaining USP7, YAP1, and β-catenin levels in the pro-osteogenic and anti-osteoclastogenic properties of the BMSC-EVs. In conclusion, this study demonstrates that USP7, delivered by BMSC-derived EVs, stabilizes YAP1 protein, thereby ameliorating bone formation in OP through the Wnt/β-catenin activation.
研究领域:
干细胞生物学
·
骨生物学
·
分子生物学
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2025
·
IF 7.5
Ying Feng,Jiamei Yue,Si Fan,Jiayan Wu
Background EMS (Endometriosis) is characterized by the presence of functional endometrial tissue outside the uterus and is one of the most common gynecological disorders. SOX18 (SYR-related high-mobility group box 18) is a transcription factor whose expression is higher in ectopic endometrial tissues than in eutopic endometrial tissues. However, its role in EMS has not been confirmed. Methods Here, immunohistochemistry (IHC) staining was used to analyze the expression pattern of SOX18 in EMS. Next, the effects of SOX18 on cell viability, migration and invasion were investigated. Dual-luciferase reporter assay, chromatin-immunoprecipitation (ch-IP) and DNA pull-down were employed to verify SOX18 binding to the OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) promoter. In addition, co-immunoprecipitation (co-IP) was used to analyze the binding of OTUB1 to YAP1 (Yes-associated protein 1). Allograft mouse model of EMS was established to explore the role of SOX18 in vivo. Results In vitro results demonstrated that upregulation of SOX18 promoted the proliferation, migration and invasion of Ishikawa cells and induced the EMT process, while knockdown of SOX18 showed the opposite effect. In vivo results also confirmed that SOX18 overexpression led to the deterioration of EMS, as reflected by significant pathological changes in mice. Mechanistically, our data proved that SOX18 directly bound to the OTUB1 promoter region and activated its transcription. Further investigation demonstrated that OTUB1 deubiquitinated YAP1 and enhanced its protein stability. Rescue experiments suggested that SOX18 modulated YAP1 expression through upregulating OTUB1, indicating the role of SOX18-OTUB1-YAP1 axis in EMS. Conclusions These discoveries underscore that SOX18 contributes to the pathogenesis of EMS through promoting OTUB1 transcription and activating Hippo/YAP1 signaling pathway, which may provide a new therapeutic target for EMS. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-025-06677-y.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Thoracic Cancer
·
2024
·
IF 2.3
Xiaoxu Lan,Xiao Wang,Liying Shao,Jiayue An,Simin Rong,Xiancong Yang,Hongfang Sun,Yan Liang,Ranran Wang,Shuyang Xie,Youjie Li
Background Existing studies have shown that transferrin receptor (TfR) is highly expressed on the surface of lung cancer cells, and nanoparticles (NPs) have been widely used as delivery vehicles. The aim of this study was to investigate the effect of the targeted delivery of Fe 3 O 4 NPs modified with transferrin (Tf) compared with photothermal treatment for lung cancer. Methods The morphology and properties of Fe3O4 NPs modified with Tf were tested by internal morphological characterization experiments including transmission electron microscopy, particle size meter infrared spectrometer and other experiments. The delivery of materials was investigated by cell proliferation and apoptosis experiments, and western blot experiment was used to detect yes-associated protein 1(YAP1) protein expression changes after delivering miR-15a-5p. In addition, animal models were constructed to further explore the targeting properties of the material. Results The results demonstrated that the nanomaterial has good stability and targeting properties. Meanwhile, we also discovered that the miR-15a-5p carried by NPs can inhibit cell growth after its entry to the lung cancer cells. The effect became more evident when the nanomaterials were assisted with laser therapy, as verified by in vivo and in vitro experiments. In terms of the related mechanism, miR-15a-5p inhibited YAP1 expression, which affected cell proliferation and apoptosis. Conclusion In this study, Fe3O4 NPs modified with Tf delivered miR-15a-5p in combination with photothermal therapy for lung cancer. In future research, the targeted delivery of Tf and the photothermal synergy of nanomaterials will provide a theoretical basis for cancer treatment.
研究领域:
癌症研究
·
纳米技术
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
·
2026
·Vol. 24
·期 1
·89-99
·
IF 4.9
Wei Li,Guangming Li,Yi Wang,Yuxin Zhou
The activation of pancreatic stellate cells (PSCs) and the secretion of inflammatory factors play critical roles in the development of pancreatic fibrosis. While gambogic acid (GA), a flavonoid with anti-tumor properties, has been studied, its role in this process remains unclear. This study demonstrated that GA promoted YAP1 degradation and reduced its nuclear localization, thereby inhibiting PSC activation and the progression of pancreatic fibrosis. GA inhibited PSC proliferation, decreased α -smooth muscle actin ( α -SMA) expression, and reduced lipid droplets in LTC14 and primary mouse PSCs (mPSCs). Additionally, GA suppressed the expression of inflammatory factors [nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), nuclear factor erythroid 2-related factor 2 (NRF2), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and nuclear factor κ B (NF- κ B)] in PSCs and counteracted the transforming growth factor (TGF)-β-induced increase in these proteins. GA also reduced collagen Ι and tissue inhibitor of metalloproteinase-1 (TΙMP1) expression, thereby attenuating fibrosis. Mechanistically, GA decreased YAP1 expression and nuclear translocation and reversed TGF-β-induced YAP1 upregulation. YAP1 overexpression abrogated GA’s inhibitory effects on PSC activation and inflammation. Furthermore, GA activated the Hippo pathway, increased phosphorylated (p)-LATS1 and p-YAP levels, and promoted ubiquitin-mediated YAP1 degradation. In vivo studies confirmed that GA inhibited dibutyltin dichloride (DBTC)-induced pancreatic fibrosis via suppressing YAP1 and NF- κ B in BALB/c mice. In conclusion, GA activates the Hippo pathway and promotes YAP1 translocation to the cytoplasm, leading to its degradation and subsequent inhibition of PSC activation and fibrosis. These findings highlight the critical role of ubiquitin-mediated YAP1 degradation in regulating PSC activity and offer novel insights into the therapeutic potential of GA for treating pancreatic fibrosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Qing Zhao,Qin-Xiao Hu,Jian-Ping Li,Han-Bo Su,Zhen-Yan Li,Jun He,Qi You,Yi-Li Yang,Huan-Tian Zhang,Ke-Wei Zhao
Wound healing is a multistage process, related to complex cellular and molecular interactions that manipulate the cell behaviors to promote regeneration and repair of skin. Interestingly, plant-derived extracellular vesicles-like particles (EVs) show great potential as preparations for skin diseases. In this study, extracellular vesicle-like particles derived from Morinda Officinalis (MOEVLPs) were isolated and effectively promoted the proliferation, migration, and tube formation of endothelial cells in vitro. Mechanistically, MOEVLPs significantly activated the MAPK/YAP1 signaling pathway, confirmed by proteomics analysis and immunofluorescence staining, with an increase in YAP1 expression level in a full-thickness skin wound model. Subsequently, MOEVLPs were further integrated into a hydrogel carrier, enabling them to affect wound microenvironments and accelerate wound healing at the molecular level. The functional hydrogel exhibited a prolonged release of MOEVLPs, promoting angiogenesis and wound healing in vivo, which provided a promising strategy for clinical applications in advanced skin healthcare.
研究领域:
药理学
·
分子生物学
·
皮肤科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2026
·
IF 5.3
Fenqian Yuan,Jingkang Yong,Xueming Liu,Yifeng Wang,Dan Zhao
Background Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy in which epithelial–mesenchymal transition (EMT) contributes to tumor progression. Piezo1 and Galectin-1 have each been implicated in cancer progression, but their functional relationship in HNSCC remains incompletely understood. We investigated Piezo1-associated mechanosensitive signaling and its potential relationship with Galectin-1 in HNSCC. Methods Public transcriptomic and proteomic analyses were integrated with validation using 16 paired oral squamous cell carcinoma (OSCC) tumor and adjacent non-tumor specimens. Functional studies were performed in HNSCC cell lines using genetic and pharmacological modulation of PIEZO1/Piezo1 and Galectin-1-associated signaling. Two independent SCC-9 xenograft studies were conducted in separate cohorts (n = 6 per group): one comparing vehicle, Yoda1, and GsMTx4, and the other comparing vehicle, GsMTx4, OTX008, and their combination. Results Piezo1 was consistently upregulated in HNSCC datasets, OSCC tissues, and HNSCC cell lines, whereas its association with survival was modest and not uniformly reproduced across analytical platforms. Piezo1 activation was associated with increased Ca 2+ -associated signaling, nuclear YAP1 accumulation, and EMT-related phenotypes, whereas PIEZO1 silencing and pharmacological inhibition of mechanosensitive channel activity attenuated these effects. Galectin-1 emerged as a Piezo1-responsive candidate effector associated with YAP1 signaling and EMT-related phenotypes. OTX008 treatment reduced proliferation, wound closure, invasion, and EMT-related marker changes. In xenografts, combined GsMTx4 and OTX008 treatment produced greater reductions in tumor growth, Ki67 positivity, endpoint CD31 fluorescence intensity, and EMT-associated marker changes than either monotherapy at the tested doses. Conclusion These findings support an important contribution of Piezo1-associated mechanosensitive signaling to EMT-related phenotypes and tumor progression in HNSCC and support Galectin-1 as a functionally relevant, Piezo1-responsive candidate effector associated with YAP1 signaling. The greater antitumor effects observed with combined GsMTx4 and OTX008 treatment support further investigation of co-targeting mechanosensitive channel activity and Galectin-1 in HNSCC.
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Yanan Li,Yanmei Qiu,Yunlei Yang,Yanhao Wei,Haokun Peng,Longhai Zeng,Pengcheng Li,Rentang Bi,Bo Hu
The role of microglia in blood–brain barrier (BBB) leakage and neovascularization after ischemic stroke remains unclear. Here, a post-stroke perivascular niche of microglia characterized by low expression of M2 markers and elevated glycolysis, oxidative phosphorylation (OXPHOS), and phagocytic activity is identified, which is termed stroke-activated vascular-associated microglia (stroke-VAM). It is found that Fkbp5 acts as a central regulator driving BBB disruption and impaired neovascularization through stroke-VAM. Single-nucleus RNA sequencing (snRNA-seq) analysis of Cx3cr1 Cre Fkbp5 flox/flox ( Fkbp5 cKO) mice in the ipsilateral hemisphere reveals enhanced interactions between stroke-VAM and endothelial cells, influencing signaling pathways that maintain BBB integrity and promote neovascularization. After ischemic injury, microglia in Fkbp5 cKO mice exhibits higher M2 marker expression and reduces glycolysis, OXPHOS, and phagocytosis, resulting in decreased BBB leakage and enhanced angiogenesis. Mechanistically, unbiased snRNA-seq analysis shows that the Hippo signaling pathway is altered in Fkbp5 cKO stroke-VAM. Fkbp5 inhibits Yap1 phosphorylation, facilitating its nuclear translocation. These findings provide new insights into how the perivascular microglial niche contributes to both the degradation and regeneration of cerebral vasculature, offering potential therapeutic avenues for acute ischemic stroke.
研究领域:
神经科学
·
脑血管疾病
·
免疫学
·
分子生物学
·
细胞代谢
·
再生医学
✓ 已验证
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）