Advanced Science
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2025
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IF 14.1
Jiafei Chen,Xiaoxu Guan,Lina Chen,Bingzhu Zheng,Feiyu Li,Chao Fang,Yike Fu,Xiang Li,Huiming Wang,Yi Zhou
Advanced periodontitis initiates with Porphyromonas gingivalis ( P. gingivalis ) infection, which subsequently triggers chronic inflammation, immune imbalance, and ultimately causes alveolar bone resorption. Traditional periodontal treatment focuses on the elimination of triggering factors, but tend to ignore the improvement of the inflammatory microenvironment and the remodeling of the osteogenic mineralization space. Herein, zinc-aluminum layered double hydroxide nanosheets (LDHs) loaded with icariin (ICA) are encapsulated into a gallic acid (GA)-modified hydroxybutyl chitosan hydrogel (GA-HBC), giving rise to a customized hydrogel system named GA-HBC-LIC, which can sequentially actualize antibacterial, anti-inflammatory, and remineralization functions. A neutral chemical-humoral space is created for osteogenesis via means of sequential regulation by the smart hydrogel. Concomitantly, appropriate mechanical properties and degradation performance of the hydrogel provide a desirable physical space for remineralization. In the spatiotemporal modulation of the hydrogel, zinc finger E-box-binding homeobox 1 (ZEB1) target of released zinc ions (Zn 2+ ) action promotes macrophage polarization from M1 to M2 phenotype, thereby remodeling the immune microenvironment and releasing cytokines conducive to tissue regeneration. In sum, this study highlights the critical role of sequential inflammation regulation and the maintenance of osteogenic space in the regeneration of periodontal tissues, offering new insights for the clinical management of periodontitis.
研究领域:
口腔医学
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材料科学
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免疫学
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DOI
PubMed
高影响因子
Cancers
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2024
·Vol. 16
·期 19
·3269
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IF 4.5
Xinyue Zhao,Zhihui Han,Ruiying Liu,Zehao Li,Ling Mei,Yue Jin
Simple SummaryEpithelial-to-mesenchymal transition (EMT) plays a critical role in cancer progression, contributing to the invasive and migratory abilities of tumor cells. In this study, we show that FBXO11 promotes the degradation of ZEB1, a key EMT regulator, via ubiquitination. Loss of FBXO11 increases ZEB1 levels, enhancing the invasiveness of lung cancer cells, while its overexpression reduces ZEB1 and suppresses invasion. Importantly, higher FBXO11 expression is associated with better prognosis in non-small cell lung cancer (NSCLC), highlighting its potential role as a therapeutic target for controlling EMT and cancer metastasis.AbstractEpithelial-to-mesenchymal transition (EMT) affects the invasion and migration of cancer cells. Here, we show that FBXO11 recognizes and promotes ubiquitin-mediated degradation of ZEB1. There is a strong association between FBXO11 and ZEB1 in non-small cell lung cancer (NSLC) in a clinical database. FBXO11 interacts with ZEB1, a core inducer of EMT. FBXO11 leads to increased ubiquitination and proteasomal degradation of ZEB1. Depletion of endogenous FBXO11 causes ZEB1 protein accumulation and EMT in A549 and H1299 cells, while overexpression of FBXO11 reduces ZEB1 protein abundance and cellular invasiveness. Importantly, the depletion of ZEB1 suppresses the increased migration and invasion of A549 and H1299 cells promoted by the depletion of FBXO11. The same results are shown in xenograft tumors. High FBXO11 expression is associated with a favorable prognosis in NSLC. Collectively, our study demonstrates that FBXO11 modulates EMT by mediating the stability of ZEB1 in lung cancer cells.
研究领域:
癌症生物学
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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
Frontiers in Pharmacology
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2022
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IF 5.988
Chen Bo,Li Xiaoli,Wu Lihong,Zhou Duanfang,Song Yi,Zhang Limei,Wu Qiuya,He Qichen,Wang Gang,Liu Xu,Hu Hui,Zhou Weiying
High invasiveness is a biological and clinical characteristic of glioblastoma and predicts poor prognosis of patients. Quercetin, a natural flavonoid compound, exhibits anticancer activity. However, we have a limited understanding of the possible underlying mechanism of quercetin in glioblastoma. In this study, we investigated the anticancer effect of quercetin in human glioblastoma cells. Our results showed that quercetin markedly suppressed the viability of glioblastoma cells in vitro and in vivo, and significantly inhibited glioblastoma cell migration and invasion. Moreover, quercetin reversed EMT-like mesenchymal phenotype and reduced the expression levels of EMT-related markers. Furthermore, we found that quercetin suppressed GSK-3β/β-catenin/ZEB1 signaling in glioblastoma. Taken together, our results demonstrate that quercetin inhibited migration and invasion of human glioma cells by suppressing GSK3β/β-catenin/ZEB1 signaling. Our study provides evidence that quercetin is a promising therapeutic natural compound to treat glioblastoma.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Jiajin Xu,Zeyi Zhang,Hongtao Hu,Yaqin Yang,Chenghong Xiao,Luyi Xi,Jiahui Lu,Shasha Tian,Huajun Zhao
Peiminine, the primary biologically active compound from Fritillaria thunbergii Miq., has demonstrated significant pharmacological activities. Doxorubicin is one of the most potent chemotherapeutic agents for breast cancer (BC). This study was designed to investigate the efficacy and underlying mechanisms of Peiminine combined with Doxorubicin in treating BC. Our results demonstrated that the combination of Peiminine and 1 mg/kg Doxorubicin exhibited more significant suppression of tumor growth compared with the monotherapy in MDA-MB-231 xenograft nude mice model, which is comparable to the effect of 3 mg/kg Doxorubicin in vivo. Notably, the 3 mg/kg Doxorubicin monotherapy resulted in organ toxicity, specifically in the liver and heart, whereas no toxicity was observed in the combination group. In vitro , this combined treatment exhibited a synergistic reduction on the viability of BC cells. Peiminine enhanced the cell cycle arrest and DNA damage induced by Doxorubicin. Furthermore, the combination treatment effectively blocked DNA repair by inhibiting the MAPKs signaling pathways. And ZEB1 knockdown attenuated the combined effect of Peiminine and Doxorubicin on cell viability and DNA damage. In conclusion, our study found that the combination of Peiminine and Doxorubicin showed synergistic inhibitory effects on BC both in vivo and in vitro through enhancing Doxorubicin-induced DNA damage. These findings support that their combination is a novel and promising therapeutic strategy for treating BC .
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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癌症治疗
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DOI
PubMed
高影响因子
Nature Communications
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2025
·Vol. 16
·期 1
·1-22
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IF 15.7
Cao Lixia,Sun Wei,Chen Xiao,Liu Lei,Zhao Shaorong,Liu Jingjing,Ou Yang,Guo Min,Qi Chunchun,Li Zhaoxian,Shi Jie,Liu Yuxin,Shuai Qiuying,Zuo Siyu,Hu Huayu,Yu Tianwen,Wang Yanjing,Feng Mengdan,Lv Jianying,Wang Hang,Sun Peiqing,Zhang Jin,Wang Longlong,Shi Yi,Yang Shuang
Upon penetrating the basement membrane, breast cancer cells directly interact with their surrounding adipose tissue, which forms a unique tumor-associated adipose microenvironment (TAME). However, the underlying mechanism of lipid metabolic remodeling in the TAME remains elusive. Herein, we report a Zeb1-orchestrated bidirectional communication between breast cancer cells and their adjacent cancer-associated adipocytes (CAAs). At the molecular level, breast cancer cells, through the secretion of adrenomedullin (AM), induce downregulation of Zeb1 expression to activate the Atgl/Hsl/Scd-dependent lipolysis in CAAs, resulting in the release of palmitoleic acid (POA) into the TAME. In turn, the increased POA in breast cancer competes with arachidonic acid (ARA) for the phospholipid synthesis, leaving more ARA is utilized for PDG 2 production to trigger the malignant progression of breast cancer and AM production. Importantly, disruption of Zeb1-dependent lipolytic activity and/or membrane phospholipid remodeling within the TAME dramatically diminishes the aggressiveness of breast cancer in vitro and in vivo.
研究领域:
生物化学与分子生物学
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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
Dose-Response
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2021
·Vol. 19
·期 1
·15593258211001255-15593258211001255
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IF 2.658
Chen-Xia Wen,Hai-Li Tian,E Chen,Jin-Fang Liu,Xiao-Xing Liu
Objective Our group aimed to investigate the expression pattern of miRNA-873-5p in cervical cancer (CC) patients and its association with CC progression. Methods Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied for the examination of the expressions of miRNA-873-5p in both CC specimens and cell lines. The clinical significance of miRNA-873-5p was statistically analyzed. MTT, colony formation, Transwell and flow cytometry assays were used to detect cell proliferation, metastasis, and apoptosis changes of Hela and Siha cell line. Luciferase reporter assays and Western blots were utilized to identify the target genes of miRNA-873-5p. Western blot and RT-PCR were used to judge the dysregulation of Notch signaling. Results Our results indicated that miRNA-873-5p expression was distinctly reduced in CC patients. Low miRNA-873-5p expressions were distinctly correlated with positively distant metastasis, The International Federation of Gynecology and Obstetrics (FIGO) stage and poor prognosis of CC patients. A functional assay using miRNA-873-5p mimics indicated that overexpression of miRNA-873-5p distinctly suppressed CC cells proliferation and metastasis, and promoted apoptosis. Bioinformatic assays revealed that miRNA-873-5p may target the 3'-UTR of ZEB1 and lead to the suppression of its translation, which was verified by the use of luciferase assays. Finally, overexpression of miRNA-873-5p suppressed the expressions of Jag1, Maml2 and Hey1. Conclusion Taken together, we firstly provided evidence that miRNA-873-5p expression was a poor favorable factor for CC patients, and the use of miRNA-873-5p may represent a and potential biomarker and promising therapeutic approach for CC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2023
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IF 7.2
Yuan Zhu,Wei-feng Yin,Pei Yu,Chao Zhang,Ming-hui Sun,Ling-yi Kong,Lei Yang
Distal metastases from breast cancer, especially bone metastases, are extremely common in the late stages of the disease and are associated with a poor prognosis. EMT is a biomarker of the early process of bone metastasis, and MMP-9 and MMP-13 are important osteoclastic activators. Previously, we found that meso-Hannokinol (HA) could significantly inhibit EMT and MMP-9 and MMP-13 expressions in breast cancer cells. On this basis, we further explored the role of HA in breast cancer bone metastasis. In vivo, we established a breast cancer bone metastasis model by intracardially injecting breast cancer cells. Intraperitoneal injections of HA significantly reduced breast cancer cell metastasis to the leg bone in mice and osteolytic lesions caused by breast cancer. In vitro, HA inhibited the migration and invasion of breast cancer cells and suppressed the expressions of EMT, MMP-9, MMP-13, and other osteoclastic activators. HA inhibited EMT and MMP-9 by activating the ROS/JNK pathway as demonstrated by siJNK and SP600125 inhibition of JNK phosphorylation and NAC scavenging of ROS accumulation. Moreover, HA promoted bone formation and inhibited bone resorption in vitro. In conclusion, our findings suggest that HA may be an excellent candidate for treating breast cancer bone metastasis.
研究领域:
肿瘤学
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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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产品关联
DOI
PubMed
高影响因子
Journal of Oncology
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2022
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IF 4.501
Junying Xu,Xuejing Yang,Jiadong Pan,Honghong Fan,Jie Mei,Dong Hua
Objective. To investigate the regulatory effect of ZEB1 on PD-L1 expression and the pharmacodynamic effects of Biochanin A on the malignant biological behaviors of colorectal cancer (CRC). Methods. The correlation between epithelial-mesenchymal transition (EMT) score and features of the tumor microenvironment (TME) was investigated using the Cancer Genome Atlas (TCGA) dataset. The correlation between ZEB1 and PD-L1 expression was validated using immunohistochemistry (IHC) staining, and the regulatory effect of ZEB1 on PD-L1 expression was explored by in vitro assays. Moreover, the pharmacodynamic effects of Biochanin A on ZEB1 and PD-L1 expression, as well as malignant biological behaviors of CRC cells, were evaluated by in vitro and in vivo assays. Results. EMT score was positively correlated with a majority of immunostimulators, immune checkpoints, activities of antitumor immunity cycles, and infiltration levels of most immune cells in the TCGA dataset. In addition, ZEB1 was correlated with and positively regulated PD-L1 expression in CRC. Besides, Biochanin A, an inhibitor for the ZEB1/PD-L1 axis, notably inhibited ZEB1-mediated aggressiveness and PD-L1 expression of CRC cells. Moreover, Biochanin A also exerted a tumor-inhibitory role in vivo in the CRC mouse model. Conclusion. Overall, we found that ZEB1 is a main regulator of PD-L1 expression in CRC. In addition, we also identified Biochanin A as a novel inhibitor for the ZEB1/PD-L1 axis, which could inhibit tumor progression and immune escape.
研究领域:
肿瘤学
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分子生物学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2022
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IF 6.656
Hong Lu,Zhengyu Wu,Yijun Wang,Di Zhao,Biyun Zhang,Mei Hong
Background Triple-negative breast carcinomas (TNBCs) are a breast carcinoma with the most aggressive form, which is demonstrated as enhanced invasion and recurrence. Britannin is extracted mainly from the traditional Chinese herb Inula japonica Thunb, and few studies have focused on its effect on TNBC. Moreover, there is still no report concerning the role of Britannin in degrading the transcripts of Zinc finger E-box-binding homeobox 1 (ZEB1) proteins. Purpose To explore the potential effect of Britannin on invasion and stemness of TNBCs and its underlying mechanism. Methods Cellular activity was measured using MTT, and cell cycle was measured using flow cytometry (FCM). The effect of Britannin on the migrating and invading abilities of MDA-MB-231 and 4T1 cells were measured using the wound healing and transwell assays. The sizes and number of breast carcinoma cells were measured by tumor formation assay and in vitro limiting-dilution assay. CD44 expression in tumor spheroids was tested by immunofluorescence assay . Nextly, the expressions of epithelial-mesenchymal transition (EMT) markers and ZEB1 protein expressional level were detected by western blot . ZEB1 mRNA expressional level was analyzed using RT-qPCR. Drug affinity-responsive target stability (DARTS) method was used to detect the binding activity between Britannin and ZEB1. Co-immunoprecipitation (Co-IP) analysis was applied to test the ubiquitination of ZEB1. The mouse models for experimental lung metastasis of 4T1 cells were established to detect the anti-metastasis effect of Britannin in vivo , and the expressional levels of EMT markers in lung metastases were detected by immunohistochemistry . Results Britannin could inhibit cell growth and G2/M arrest in TNBC cells. Britannin could inhibit the migrating and invading ability without inducing severe apoptosis of MDA-MB-231 and 4T1 cells. Meanwhile, Britannin reduced the size and number of spheroids formed in these two cells, and decreased the expressional level of stem cells biomarker CD44 in tumor spheroids. Mechanism research showed that Britannin specifically bound to ZEB1 and induced its ubiquitination in MDA-MB-231 cells. Afterwards, Britannin disturbed protein stability and promoted ZEB1 protein degradation. Importantly, Britannin could not inhibit cell invasion and spheroid formation after ZEB1 expression was knocked down. Finally, Britannin inhibition of 4T1 cell metastasis was confirmed through establishing mouse models for the experimental lung metastasis. It was proved that both Britannin and paclitaxel could decrease the lung metastases, and Britannin could also down-regulate the protein expressional levels of ZEB1, MMP9 and CD44. Conclusion This study reveals that Britannin suppresses the invasion and metastasis of TNBC cells through degrading ZEB1, which suggests that Britannin can be used to prevent tumor metastasis and recurrence via degrading ZEB1proteins.
研究领域:
肿瘤学
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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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产品关联
DOI
PubMed
高影响因子
Reproductive Biology
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2023
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IF 2.1
Ganping Lai,Dan Bu,Maolin Chen,Hongfang Liu,Lei Dong
The present study aimed to identify the role of circPLOD2 in endometriosis and its underlying mechanisms. We determined circPLOD2 and miR-216a-5p expression in ectopic endometrial (EC) and eutopic endometrial (EU) samples as well as in endometrial samples from uterine fibroids of ectopic patients (EN) and embryonic stem cells (ESCs) using qRT-PCR. The association between circPLOD2 and miR-216a-5p or miR-216a-5p and zinc finger E-box binding homeobox 1 (ZEB1) expression was analyzed using Starbase, TargetScan, and dual-luciferase reporter gene assays. Cell viability , apoptosis , and migration and invasion were assessed using MTT, flow cytometry, and transwell assays, respectively. In addition, qRT-PCR and western blotting was used to measure circPLOD2, miR-216a-5p, E-cadherin, N-cadherin, and ZEB1 expression. circPLOD2 was upregulated and miR-216a-5p was downregulated in EC samples compared with that in EU samples. Similar trends were observed in ESCs. circPLOD2 interacted and negatively regulated miR-216a-5p expression in EC-ESCs. circPLOD2-siRNA significantly inhibited EC-ESC growth; promoted cellular apoptosis; and inhibited EC-ESC migration, invasion, and epithelial–mesenchymal transition; these effects could be reversed following miR-216a-5p inhibitor transfection. miR-216a-5p directly targeted and negatively regulated ZEB1 expression in EC-ESCs. In conclusion, circPLOD2 promotes the proliferation, migration, and invasion of EC-ESCs and inhibits their apoptosis by targeting miR-216a-5p. These findings indicate potential therapeutic targets for endometriosis.
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF CANCER
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2025
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IF 6.8
Chen Xiao,Cao Lixia,Feng Mengdan,Shuai Qiuying,Guo Min,Li Zhaoxian,Qi Chunchun,Shi Jie,Liu Yuxin,Zuo Siyu,Yu Tianwen,Hu Huayu,Wang Yanjing,Xue Yao,Sun Peiqing,Shi Yi,Wang Hang,Liu Lei,Yang Shuang
Background Breast cancer cells that break through the basement membrane interact directly with neighboring adipocytes. Therefore, adipocytes adjacent to the invasive front of tumour undergo lipolysis and transform into cancer-associated adipocytes (CAAs), which is vital for the malignant progression of breast cancer. However, tumor-derived factors that trigger this process are still to be determined. Methods Transcriptome sequencing was used to identify the downstream transcription factor of adrenomedullin (AM). Tet-On system was used to construct the 3T3-L1 cell line with inducible overexpression of Zeb1. Adipocyte-specific knock-in Zeb1 transgenic mice ( Zeb1 adiTG ) were used to construct an allograft tumor model. Results Breast cancer cell-derived AM downregulated the transcriptional expression of Zeb1 by triggering the cAMP/PKA/Creb1 pathway, thereby exerting lipolytic effects in CAAs. On the contrary, adipose tissue-specific upregulation of Zeb1 significantly attenuated AM-induced lipolytic phenotypes. Of note, we used the Zeb1 adiTG mice to construct allograft tumor models. The results confirmed that breast cancer cell-derived AM conferred tumorigenicity in vivo, which effect was predominantly dependent on the aberrant expression of adipocyte-specific Zeb1. Conclusions These findings collectively suggested that breast cancer cell-derived AM promotes lipid metabolic reprogramming through a Zeb1-dependent manner in CAAs, which displays significant clinical implications and may provide promising therapeutic approaches for targeting the breast cancer-associated adipose microenvironment.
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DOI
PubMed
高影响因子
Research
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2023
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IF 11
Zhenyu Zhao,Huitong Ruan,Aopan Chen,Wei Xiong,Mingzhu Zhang,Ming Cai,Wenguo Cui
Genetic engineering technology can achieve specific gene therapy for a variety of diseases, but the current strategy still has some flaws, such as a complex system, single treatment, and large implantation trauma. Herein, the genetic engineering injectable hydrogels were constructed by ultrasonic technology for the first time to realize in vivo ultrasound-triggered in situ cross-linking and cell gene transfection, and finally complete in situ gene therapy to promote bone reconstruction. First, ultrasound-triggered calcium release was used to activate transglutaminase and catalyze the transamidation between fibrinogen. Simultaneously, liposome loaded with Zinc-finger E-box-binding homeobox 1 (ZEB1) gene plasmid (Lip-ZEB1) was combined to construct an ultrasound-triggered in situ cross-linked hydrogels that can deliver Lip-ZEB1. Second, ultrasound-triggered injectable hydrogel introduced ZEB1 gene plasmid into endothelial cell genome through Lip-ZEB1 sustained release, and then acted on the ZEB1/Notch signal pathway of cells, promoting angiogenesis and local bone reconstruction of osteoporosis through genetic engineering. Overall, this strategy provides an advanced gene delivery system through genetic engineered ultrasound-triggered injectable hydrogels.
研究领域:
生物医学工程
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基因治疗
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材料科学
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组织工程
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DOI
高影响因子
危险品化学品经营许可证（带存储）