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
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脑血管疾病
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免疫学
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分子生物学
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细胞代谢
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再生医学
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DOI
PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Zhao Fangfang,Yang Sen,He Ting,Yang Lijuan,Mo Ting,Kang Juying,Cao Hui,Sun Xiangping,Yu Yang
Yes-associated protein 1 ( YAP1 ), a core effector of the Hippo signaling pathway, has garnered increasing attention for its role in ferroptosis signaling in breast cancer. This study investigates the antitumor properties of Lycium barbarum polysaccharides (LBPs) and develops LBPs-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LBPs NPs), further exploring the mechanisms of free LBPs and LBPs NPs in normal and malignant breast cells. Results demonstrated that YAP1 overexpression drives malignant transformation in normal mammary cells, including aberrant proliferation, apoptosis resistance, cytoskeletal remodeling, and enhanced invasiveness, alongside mitochondrial hyperfunction and altered energy metabolism. However, LBPs effectively suppressed these malignant phenotypes and counteracted the associated mitochondrial and metabolic enhancements by inhibiting YAP1 upregulation. In breast cancer cells, YAP1 overexpression similarly promoted proliferation, invasion, cytoskeletal reorganization, and apoptosis resistance, accompanied by enhanced mitochondrial dysfunction and energy, and acquired ferroptosis resistance. Both LBPs and LBPs NPs significantly inhibited cell proliferation, invasion, and cytoskeletal reorganization, disrupted energy metabolism, and ultimately induced ferroptosis via downregulation of YAP1 expression. Notably, both free LBPs and LBPs NPs effectively suppressed YAP1 expression, with LBPs NPs exhibiting significantly superior efficacy compared to free LBPs. This enhancement is attributed to improved drug delivery efficiency facilitated by the PLGA-based nanocarrier system. Mechanistically, LBPs NPs target the Hippo-YAP1 signaling axis, leading to altered phosphorylation status of YAP1 (p-YAP1), and synergistically induce changes in energy metabolism and ferroptosis to inhibit breast cancer metastasis. These findings provide a proof-of-concept at the in vitro level and a potential nanoparticle-based formulation platform for the treatment of breast cancer.
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DOI
PubMed
高影响因子
REPRODUCTIVE TOXICOLOGY
·
2018
·
IF 2.58
Liaoliao Hu,Tingting Peng,Jian Huang,Tie Su,Ruichen Luo,Yuehui Zheng,Zhisheng Zhong,Peiling Yu,Kun Nie,Liping Zheng
As a plasticizer widely used in society, tri-ortho-cresyl phosphate (TOCP) is reported to inhibit spermatogenesis and growth of spermatogonial stem cells. However, its effects on female reproductive system are virtually unknown. The present study investigated the effects of TOCP on ovarian follicle development by using mouse model of chronic TOCP exposure, and examined the expression of the core components of the Hippo pathway, which had been proven to be crucial for ovarian follicle development. Furthermore, through up-regulation of Hippo-yes-associated protein 1 ( Yap1 ) in ovaries, the potential protective effects of Yap1 over-expression on TOCP-induced ovarian dysfunction were observed. The results showed that TOCP impaired ovarian function in a dose-dependent manner, and the expression of the Hippo pathway changed significantly in TOCP-exposed ovaries. Further, YAP1 over-expression partially reversed the TOCP-induced ovarian impairment. Collectively, these data indicate that the Hippo pathway is involved in the mechanism by which TOCP elicits ovarian function impairment.
研究领域:
毒理学
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生殖生物学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2026
·Vol. 22
·期 5
·2302
·
IF 11.7
Jiaoshun Chen,Gengqiao Wang,Haoxiang Zhang,Qingyi Hu,Jun Zhao,Qiang Shen,Qingke Duan,Tao Yin
Pancreatic cancer is a highly aggressive malignancy characterized by a progressively stiffened extracellular matrix, which promotes mechanical memory acquisition in cancer cells and facilitates malignant progression and metastasis. Despite its clinical significance, the mechanisms underlying matrix stiffening and mechanical memory formation remain poorly defined. This study demonstrates that a high-stiffness microenvironment induces mechanical memory in pancreatic tumor cells, which in further aggravates stromal remodeling and adversely affects prognosis. Under mechanically stiff conditions, pancreatic cancer cells exhibit pronounced enrichment of RNA modification-related and metabolic pathways, along with significantly increased m6A levels. Mechanistically, METTL14 enhances YAP1 expression through YTHDF3-mediated m6A-dependent translational regulation, while YAP1 in turn transcriptionally upregulates METTL14 via TEAD1, establishing a positive feedback loop that sustains mechanical memory. This METTL14-YAP1 axis activates CD166-EGFR-LOXL2 signaling, leading to enhanced collagen cross-linking and deposition, increased stromal stiffness, and maintenance of tumor stemness. These results identify the METTL14-YAP1 feedback loop as a core regulator of mechanical memory in pancreatic ductal adenocarcinoma, which drives stromal dysfunction and tumor progression through CD166-LOXL2 axis, and suggest targeting this loop as a potential therapeutic strategy to disrupt mechanical memory and ameliorate stiffness-induced remodeling.
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高影响因子
JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY
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2026
·
IF 4
Zhewen Deng,Mengyuan Zhang,Senqiang Zhu,Yunlong Zhang,Haitao Liao,Jiaqi Li,Peiyu Yan,Qi Zhang,Rui Liu,Bo Ma
Osteosarcoma (OS), a highly aggressive bone cancer with a dismal prognosis in the metastatic setting, urgently demands novel therapeutic modalities. While phototherapy offers a promising, minimally invasive strategy, its clinical efficacy is often hampered by the poor aqueous solubility of photosensitizers and the development of multidrug resistance. In response, we constructed the dual-modal nanoplatform BDP-NPs by leveraging a multifunctional F127/TPGS mixed micelle to encapsulate a cationic BODIPY photosensitizer, thereby creating a system engineered for enhanced tumor accumulation and to overcome multidrug resistance. Benefiting from their uniform size, colloidal stability, and hypoxia-responsive properties, the BDP-NPs demonstrate potent reactive oxygen species generation and high photothermal conversion efficiency under 525 nm laser irradiation. This dual-modal action induces severe mitochondrial dysfunction, thereby triggering apoptosis in both 3D tumor spheroids and tumor tissues. The synergistic phototherapy elicited profound mitochondrial-targeted cytotoxicity, inhibited clonogenic survival, and significantly suppressed tumor growth in human osteosarcoma models, all while maintaining a favorable biosafety profile. Mechanistic analyses revealed that this synergistic phototherapy plays a pivotal role in suppressing the YAP1/β-catenin axis, thereby reversing the epithelial-mesenchymal transition (EMT) program and consequently inhibiting OS cell proliferation, migration and invasion. This study not only establishes BDP-NPs as a potent and biocompatible nanotherapeutic for OS but also presents a groundbreaking phototherapeutic strategy to disrupt the YAP1/β-catenin axis-a key signaling network driving tumorigenesis and malignant progression. This approach provides a robust conceptual foundation for devising next-generation phototherapeutics that precisely target oncogenic signaling in aggressive cancers.
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DOI
PubMed
高影响因子
Cell Reports
·
2022
·
IF 9.995
Ruipeng Zhuge,Chao Wang,Jie Wang,Shuyu Yu,Liming Liao,Xiaofeng Zheng
Summary YAP1 functions in lineage differentiation of pluripotent embryonic stem cells (ESCs); however, the detailed mechanisms underlying the regulation of YAP1 activity during ESC differentiation remain elusive. Here, we report that hCINAP serves as a negative regulator of YAP1 during ESC fate decisions. The expression of mCINAP, the murine homolog of hCINAP, is downregulated during the differentiation process of murine ESC (mESC) ectoderm lineage, leading to liquid-liquid phase separation (LLPS) of NEDD4 and activation of YAP1. Mechanistically, hCINAP interacts with and prevents NEDD4 from forming cytoplasmic condensates that compartmentalize YAP1 and its kinase NLK, facilitating YAP1 phosphorylation at Ser128 and promoting YAP1 activation. mCINAP depletion leads to the formation of NEDD4 condensates and YAP1 activation, which impedes endoderm differentiation of mESCs. Our study shows that hCINAP is a vital regulator of YAP1 activity and is essential for stem cell fate decisions, which provides mechanistic insight into early embryogenesis.
研究领域:
干细胞生物学
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细胞信号传导
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发育生物学
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DOI
PubMed
高影响因子
Journal of Oncology
·
2022
·
IF 4.501
Peng Zhang,Luhao Liu,Weiting Zhang,Jiali Fang,Guanghui Li,Lei Zhang,Jiali Li,Xuanying Deng,Junjie Ma,Kun Li,Zheng Chen
To explore the function and mechanism of lncRNA HOXA-AS2 in cancer-associated fibroblasts (CAFs)-derived exosomes in gallbladder cancer metastasis, and provide new research targets for the treatment of gallbladder cancer. At the same time, in order to clarify the early predictive value of lncRNA HOXA-AS2 for gallbladder cancer metastasis, and to provide a theoretical basis for clinical individualized treatment of gallbladder cancer. Methods. In our previous work, we used TCGA database analysis to find that lncRNA HOXA-AS2 was highly expressed in gallbladder cancer tissues compared with normal tissues. In this study, the expression levels of HOXA-AS2 in gallbladder cancer cell lines and control cells were first verified by QPCR and Western blot methods. Then, lentiviral tools were used to construct knockdown vectors (RNAi#1, RNAi#2) and negative control vectors targeting two different sites of HOXA-AS2, and the vectors were transfected into NOZ and OCUG-1 cells, respectively. Real-time PCR was used to detect knockdown efficiency. Then, the effects of silencing HOXA-AS2 on the proliferation, cell viability, cell migration, and invasion ability of gallbladder cancer cells were detected by MTT, plate cloning assay, Transwell migration chamber assay, and Transwell invasion chamber assay. Finally, the interaction between HOXA-AS2 and miR-6867 and the 3UTR of YAP1 protein was detected by luciferase reporter gene. The results showed that the expression level of HOXA-AS2 in gallbladder cancer cell lines was higher than that in control cells. The expression of HOXA-AS2 in gallbladder carcinoma tissues was significantly higher than that in adjacent tissues (). After successful knockout of HOXA-AS2 by lentiviral transfection, the expression of HOXA-AS2 in gallbladder cancer cell lines was significantly decreased. Through cell proliferation and plate clone detection, it was found that silencing HOXA-AS2 inhibited cell proliferation and invasion. Through software prediction and fluorescein reporter gene detection, it was found that HOXA-AS2 has a binding site with miR-6867, and the two are negatively correlated, that is, the expression of miR-6867 is enhanced after the expression of HOXA-AS2 is downregulated. And the 3UTR of YAP1 protein in the Hippo signaling pathway binds to miR-6867. Therefore, HOXA-AS2 may affect the expression of YAP1 protein by regulating miR-6867, thereby inhibiting the Hippo signaling pathway and promoting the proliferation and metastasis of gallbladder cancer cells. HOXA-AS2 is abnormally expressed in gallbladder cancer cells. HOXA-AS2 may promote the migration and invasion of gallbladder cancer cells by regulating the Hippo signaling pathway through miR-6867. HOXA-AS2 may serve as a potential diagnostic and therapeutic target for gallbladder cancer in clinic.
研究领域:
分子生物学
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肿瘤学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2023
·
IF 8.8
Tingting Yang,Jiayu Yuan,Yuting Peng,Jiale Pang,Zhen Qiu,Shangxiu Chen,Yuhan Huang,Zhenzhou Jiang,Yilin Fan,Junjie Liu,Tao Wang,Xueyan Zhou,Sitong Qian,Jinfang Song,Yi Xu,Qian Lu,Xiaoxing Yin
The occurrence of benign prostate hyperplasia (BPH) was related to disrupted sex steroid hormones, and metformin (Met) had a clinical response to sex steroid hormone-related gynaecological disease. However, whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear. Here, our clinical study showed that along with prostatic epithelial cell (PEC) proliferation, sex steroid hormones were dysregulated in the serum and prostate of BPH patients. As the major contributor to dysregulated sex steroid hormones, elevated DHT had a significant positive relationship with the clinical characteristics of BPH patients. Activation of AMPK by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor (AR)-mediated YAP1-TEAD4 heterodimers. Met’s anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells. Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.
研究领域:
泌尿学
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内分泌学
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药理学
·
细胞生物学
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2026
·
IF 4.7
Xiliang Cong,Xijie Zhang,Hang Yang,Qianwen Zhao,Yang Gao,Zhiqiang Jiang,Jiankai Lv,Haonan Guo,Sen Li
Cancer-associated fibroblasts (CAFs) are key regulators of tumor progression within the gastric cancer microenvironment. Chloride Intracellular Channel-2 (CLIC-2), a member of the CLIC protein family, has been implicated in tumor biology. However, its role in CAFs remains unclear. In this study, we found that CLIC-2 expression was significantly reduced in gastric CAFs and that low CLIC-2 levels were associated with poor patient prognosis. Loss-of-function experiments demonstrated that CLIC-2 deficiency promoted CAF-like activation of non-cancer fibroblasts (NFs), whereas CLIC-2 overexpression attenuated the activated phenotype of CAFs. Conditioned medium from CLIC-2-knockdown fibroblasts enhanced the viability, migratory, and invasion of gastric cancer cells, while conditioned medium from CLIC-2-overexpressing CAFs suppressed these malignant phenotypes. In vivo , co-injection of MKN-45 cells with CLIC-2-deficient fibroblasts promoted tumor growth and liver metastasis, whereas CLIC-2 overexpression in CAFs exerted tumor-suppressive effects. Proteomic analysis of CAF-derived exosomes identified Solute Carrier Family 35 Member B2 (SLC35B2) as a candidate downstream component associated with CLIC-2-regulated exosomal alterations. Exosomes derived from CLIC-2-overexpressing CAFs exhibited reduced SLC35B2 levels and inhibited malignant behaviors in gastric cancer cells. Mechanistically, SLC35B2 promoted YAP1 activation, as evidenced by enhanced nuclear accumulation of YAP1 and upregulation of its target genes CYR61 and CTGF. YAP1 silencing attenuated SLC35B2-induced malignant phenotypes, while SLC35B2 overexpression partially reversed the tumor-suppressive effects mediated by CLIC-2-overexpressing CAF-derived exosomes. Collectively, these findings suggest that CLIC-2 suppresses CAF-driven gastric cancer progression, at least partly through SLC35B2-associated regulation of YAP1 signaling, highlighting a potential stromal regulatory mechanism in gastric cancer.
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高影响因子
MOLECULAR BIOTECHNOLOGY
·
2022
·Vol. 65
·期 4
·612-623
·
IF 2.86
Han Ning,Zhang Lihong,Guo Mi,Yu Li
Advanced proliferative diabetic retinopathy (PDR) characterized by aberrant retinal angiogenesis is a leading cause of retinal detachment and blindness. Krüppel-like factor 9 (KLF9), a member of the zinc-finger family of transcription factors, participates in the development of diabetic nephropathy and the promotion of angiogenesis of human umbilical vein endothelial cells. Therefore, we speculate that KLF9 may exert a crucial role in PDR. The current study revealed that KLF9 was highly expressed in the high glucose (HG)-treated human retinal microvascular endothelial cells (HRMECs) and the retinas of oxygen-induced retinopathy (OIR) rats. Knockdown of KLF9 inhibited the proliferation, migratory capability, invasiveness and tube formation of HG-treated HRMECs. Besides, knockdown of KLF9 decreased the expression of yes-associated protein 1 (YAP1) in HG-treated HRMECs. Dual-luciferase reporter assays confirmed that KLF9 transcriptionally upregulated YAP1 expression. Overexpression of YAP1 reversed the KLF9 silencing-induced repression of HRMEC proliferation and tube formation. Further in vivo evidence demonstrated that knockdown of KLF9 reduced the expression of Ki67, CD31 and vascular endothelial growth factor A (VEGFA) in the retinas of OIR rats. Collectively, KLF9 silencing might mitigate the progression of PDR by inhibiting angiogenesis via blocking YAP1 transcription.
研究领域:
糖尿病
·
视网膜
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分子生物学
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细胞生物学
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转录因子
·
血管生成
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DOI
PubMed
高影响因子
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