JOURNAL OF MOLECULAR HISTOLOGY
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2025
·Vol. 56
·期 3
·1-15
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IF 2.2
Bai Jing,Yang Yujuan
The Hippo/YAP signaling pathway is closely related to the occurrence and development of cardiovascular diseases. However, it’s still unclear whether this pathway plays a certain role in hypertension. In this study, aortic morphology and function in spontaneously hypertensive rats (SHR) were comprehensively evaluated using Wistar-Kyoto rats (WKY) as controls. Results indicated that the aorta of SHRs have distinct changes in pathological structure. Furthermore, the proliferative activity of vascular smooth muscle cells (VSMCs) was enhanced, with vascular fibrosis being aggravated. Immunohistochemical analysis revealed that SHRs exhibited high expression of Yes-Associated Protein (YAP). Western Blot analysis showed that cytoplasmic YAP and TAZ expression decreased in hypertensive rats, indicating that YAP/TAZ nuclear transfer increased and Hippo/YAP signaling pathway had been activated. The cell function experiments of VSMCs extracted from rat aorta showed that the cell viability and proliferation ability of VSMCs in SHRs were enhanced, the expression of Fibronectin and collagen I was increased, and vascular fibrosis was aggravated. siRNA-YAP (si-YAP) can reverse the above phenomenon in VSMCs. Knockdown of YAP can inhibit Foxm1 expression. As an inhibitor of large tumor suppressor kinases LAST1/2, GA-107 can inhibit the phosphorylation level of YAP, increase blood pressure, aggravate aortic pathomorphological changes, promote VSMCs proliferation and vascular fibrosis, and thus aggravate hypertension symptoms in SHRs. However, these effects of GA-107 can be antagonized by inhibiting Foxm1 with thiosulfathiazole (Thio). Conclusively, Hippo/YAP signaling pathway promotes vascular remodeling through the regulation of Foxm1 and causes hypertension.
研究领域:
心血管疾病
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分子生物学
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病理学
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PubMed
高影响因子
Journal of the American Heart Association
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2022
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IF 6.106
Xiaofei Luo,Chengcheng Hang,Ziming Zhang,Kaixing Le,Yuhan Ying,Ying Lv,Lingling Yan,Yajie Huang,Lixia Ye,Xuefeng Xu,Ying Zhong,Lizhong Du
BackgroundIntrauterine growth restriction (IUGR) is closely related to systemic or pulmonary hypertension (PH) in adulthood. Aberrant crosstalk between pulmonary vascular endothelial cells (PVECs) and pulmonary arterial smooth muscle cells (PASMCs) that is mediated by exosomes plays an essential role in the progression of PH. FoxM1 (Forkhead box M1) is a key transcription factor that governs many important biological processes.Methods and ResultsIUGR‐induced PH rat models were established. Transwell plates were used to coculture PVECs and PASMCs. Exosomes were isolated from PVEC‐derived medium, and a microRNA (miRNA) screening was proceeded to identify effects of IUGR on small RNAs enclosed within exosomes. Dual‐Luciferase assay was performed to validate the predicted binding sites of miRNAs on FoxM1 3’ untranslated region. FoxM1 inhibitor thiostrepton was used in IUGR‐induced PH rats. In this study, we found that FoxM1 expression was remarkably increased in IUGR‐induced PH, and PASMCs were regulated by PVECs through FoxM1 signaling in a non‐contact way. An miRNA screening showed that miR‐214‐3p, miR‐326‐3p, and miR‐125b‐2‐3p were downregulated in PVEC‐derived exosomes of the IUGR group, which were associated with overexpression of FoxM1 and more significant proliferation and migration of PASMCs. Dual‐Luciferase assay demonstrated that the 3 miRNAs directly targeted FoxM1 3’ untranslated region. FoxM1 inhibition blocked the PVECs‐PASMCs crosstalk and reversed the abnormal functions of PASMCs. In vivo, treatment with thiostrepton significantly reduced the severity of PH.ConclusionsTransmission of exosomal miRNAs from PVECs regulated the functions of PASMCs via FoxM1 signaling, and FoxM1 may serve as a potential therapeutic target in IUGR‐induced PH.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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转化医学
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PubMed
高影响因子
PHYTOMEDICINE
·
2024
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IF 6.7
Yang-yang Lu,Yuan-yuan Fang,Sha-sha Wang,Jing Guo,Jia-lin Song,Liang Zhu,Zhong-kun Lin,Rui Wang,Si-yi Zhang,Wen-sheng Qiu,Wei-wei Qi
Background Gastric cancer is among the common solid tumors. Chemotherapy resistance is the most common issue in gastric cancer treatment. Inhibiting intracellular autophagy may be a feasible method for overcoming chemotherapy resistance. Cepharanthine (CEP), a natural small molecule extracted from the stephania cephalantha Hayata plant, has been demonstrated to significantly inhibit cancer growth and can regulate autophagy. Although CEP can significantly inhibit cancer growth, it remains unclear whether CEP can regulate autophagy in gastric cancer. This study aimed to investigate whether CEP can enhance the sensitivity of gastric cancer to chemotherapy and elucidate its molecular mechanism. Methods Three gastric cancer cell lines (AGS, SGC7901, and MFC) and one normal gastric mucosal epithelial cell line (GES-1) were used for in vitro experiments. The characterization of autophagy in gastric cancer cells included the detection of autophagy markers and autophagy flux through immunofluorescence staining and Western blotting, as well as the assessment of lysosomal function using fluorescence staining (LysoTracker Red DND-99, Acridine Orange staining) and Western blotting. The cytotoxicity of CEP, autophagy inhibitors (chloroquine [CQ] and 3-methyladenine [3MA]), and chemotherapy drugs (doxorubicin [DOX] and cisplatin [CIS]) was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell colony formation, and fluorescence staining techniques (H2DCFDA, Dihydroethidium, and JC-1 staining). The interaction between CEP and autophagy inhibitors was tested in a 615 mice model, and changes in the gut microbiota were determined through accurate 16S absolute quantification sequencing. The signaling pathway and autophagy regulatory target TRIB3-FOXO3-FOXM1 were confirmed through molecular docking, RNA sequencing, bioinformatic analysis, transfection techniques, and Western blotting. Results CEP blocked autophagic flux in gastric cancer cells without affecting lysosomal function. As a novel autophagy inhibitor, CEP could combine with conventional autophagy inhibitors (CQ and 3MA) to block intracellular autophagy, thereby inhibiting gastric cancer growth. During this process, changes in the gut microbiota were observed, including low-level changes in Odoribacterium, Erysipelatoclostridium , and ParaPrevotella and high-level changes in Ileibacterium, Enterorhabdus , and Bifidobacterium . Additionally, CEP synergistically inhibited the growth of gastric cancer when combined with chemotherapy drugs. Mechanistically, the TRIB3-FOXO3-FOXM1 signaling axis was found to be involved in the inhibition of gastric cancer by CEP combined with autophagy inhibitors and chemotherapy drugs, thereby mediating cell apoptosis. Conclusion This study links the TRIB3-FOXO3-FOXM1 axis with chemotherapy efficacy. Our findings demonstrated that CEP inhibits autophagy by modulating the FOXO3-FOXM1 axis. When combined with chemotherapy drugs (DOX and CIS), CEP, as an autophagy inhibitor, can limit TRIB3 protein expression, thereby regulating the FOXO3-FOXM1 axis and enhancing its ability to prevent gastric cancer growth. These findings may contribute to improving the prognosis of patients with gastric cancer. Furthermore, these results enrich the fundamental understanding of how autophagy inhibition can enhance clinical cancer treatment efficacy and provide insights into the potential mechanisms by which CEP functions as an anti-tumor drug, thereby exploring its value for clinical application.
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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微生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
LiYao Ma,Xin Yin,Yan Zhang,Yidan Ma,Yanqing Geng,Xinyi Mu,Rufei Gao,Xuemei Chen,Junlin He
Cetylpyridinium chloride (CPC), a widely used surfactant, functions as an antimicrobial agent in pharmaceuticals and personal care products (PPCPs). However, its effect on the female reproductive system remains largely unknown. Herein, female mice were gavaged with 0.01, 0.1, or 1 mg CPC/kg body weight (bw)/d during adolescence. Results showed reduced body and ovarian weights, decreased primordial follicle numbers, and increased atretic follicles. Additionally, CPC disrupted serum hormone levels, reduced cell viability and proliferation, and increased apoptosis in granulosa cells. Transcriptomic analysis of primary granulosa cells revealed altered genes in homologous recombination (HR) repair pathway, including the downregulation of FOXM1 and the MRN complex. Further validation demonstrated decreased expression of HR repair components and increased DNA damage in both in vivo and in vitro . Mechanistically, CPC inhibited the FOXM1/CREBBP interaction and inhibited HR repair gene transcription, including MRE11 and NBS1 . Finally, FOXM1 overexpression partially reversed the detrimental effects of CPC on HR repair and cell proliferation. These results indicate that CPC-induced ovarian dysfunction during adolescence is mediated through FOXM1/CREBBP complex inhibition and homologous recombination repair impairment, potentially increasing the risk for the development of diminished ovarian reserve (DOR) and providing new experimental evidence to assess the reproductive toxicity effects of CPC.
研究领域:
生殖生物学
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毒理学
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分子生物学
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PubMed
高影响因子
LUNG
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2022
·Vol. 200
·期 5
·619-631
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IF 3.777
Zhai Cui,Zhang Nana,Wang Jian,Cao Meng,Luan Jing,Liu Huan,zhang Qianqian,Zhu Yanting,Xue Yuxin,Li Shaojun
Purpose It has been shown that activation of autophagy promotes the development of pulmonary arterial hypertension (PAH). Meanwhile, forkhead box M1 (FOXM1) has been found to induce autophagy in several types of cancer. However, it is still unclear whether FOXM1 mediates autophagy activation in PAH, and detailed mechanisms responsible for these processes are indefinite. Method PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) to rats. The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), percentage of medial wall thickness (%MT), α-smooth muscle actin (α-SMA) staining, and Ki67 staining were performed to evaluate the development of PAH. The protein levels of FOXM1, phospho-focal adhesion kinase (p-FAK), FAK, and LC3B were determined by immunoblotting or immunohistochemistry. Results FOXM1 protein level and FAK activity were significantly increased in MCT-induced PAH rats, this was accompanied with the activation of autophagy. Pharmacological inhibition of FOXM1 or FAK suppressed MCT-induced autophagy activation, decreased RVSP, RVHI and %MT in MCT-induced PAH rats, and inhibited the proliferation of pulmonary arterial smooth muscle cells and pulmonary vessel muscularization in MCT-induced PAH rats. Conclusion FOXM1 promotes the development of PAH by inducing FAK phosphorylation and subsequent activation of autophagy in MCT-treated rats.
研究领域:
心血管疾病
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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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DOI
PubMed
高影响因子
Cell Death & Disease
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2026
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IF 12.2
Ruan Banzhan,Wang Bingshu,Zhang Xiaodian,Liu Fujin,Wan Zhenling,Chen Yan,Wu Julan,Luo Chun,Lu Wenyan,Lu Yanda,Zheng Shaojiang
Pancreatic cancer is a highly lethal disease characterized by rapid onset, aggressive progression, and limited treatment options. The involvement of FoxM1 in the TGF-β/Smad signaling pathway has been linked to pancreatic cancer progression; however, the mechanisms behind the cooperative regulation of TGF-β signaling by FoxM1 and Smad4 remain poorly understood. In this study, we utilized molecular cytology techniques, animal models, and human pancreatic cancer tissues to investigate the role of FoxM1 in Smad4 stabilization and its regulation of TGF-β signaling. Our findings reveal that FoxM1 inhibits ubiquitin-proteasome-mediated degradation of Smad4, resulting in its stabilization. Once translocated into the nucleus, Smad4 binds to the FoxM1 promoter region, inducing FoxM1 expression and forming a positive feedback loop. Furthermore, we observed significantly higher expression of this feedback loop in pancreatic cancer tissues compared to adjacent normal tissues, with markedly elevated levels in poorly differentiated tissues compared to well-differentiated ones. Therefore, the loop aberrantly activates the TGF-β pathway, driving pancreatic cancer progression. These findings uncover a novel mechanism of TGF-β pathway activation and provide potential new targets for the prevention and treatment of pancreatic cancer. This study elucidates that FoxM1 functions to impede the ubiquitin proteasome-mediated degradation of Smad4, consequently stabilizing it. Following nuclear translocation, Smad4 binds to the FoxM1 promoter region, initiating FoxM1 expression and establishing a positive feedback loop. This loop plays a pivotal role in promoting pancreatic cancer development and migration by aberrantly activating the TGF-β pathway.
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高影响因子
INTERNATIONAL ENDODONTIC JOURNAL
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2026
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IF 6.4
Wenmin Wang,Jing Wang,Shuang Wu,Jie Wang,Zehan Li,Yadong Luo,Jintao Wu,Ming Yan,Na Li,Jinhua Yu
Aim Regenerative endodontics focuses on the restoration of the pulp-dentine complex by promoting odontogenic differentiation of stem cells of the apical papilla (SCAPs). Although SSUH2 has been implicated in developmental processes and dentine dysplasia type I (DD-I), the specific role of SSUH2 in regulating SCAPs differentiation remains unclear. In this study, we identified SSUH2 as a novel biomarker for SCAPs odontogenic differentiation and revealed its critical regulatory mechanism. Methodology Immunohistochemical staining of mouse mandibular first molar sections and immunofluorescence staining of human dental pulp tissues were performed to investigate the expression characteristics of SSUH2 during root development. SCAPs were treated with siRNA-mediated knockdown or lentivirus-mediated overexpression of SSUH2, followed by assessment of proliferation and odontogenic differentiation. Subcutaneous implantation of hydrogel-scaffold-root fragments loaded with SSUH2-overexpressing SCAPs in nude mice was performed to evaluate in vivo odontogenic capacity. Mechanistically, transcriptome sequencing and bioinformatic analysis identified downstream signalling pathways. Co-immunoprecipitation, nuclear-cytoplasmic fractionation, and immunofluorescence confirmed the direct interaction between SSUH2 and FOXM1, promoting FOXM1 nuclear translocation and subsequent transcriptional upregulation of PDK1. Moreover, transmission electron microscopy, mitochondrial membrane potential assays and ROS detection collectively demonstrated that SSUH2 regulates mitochondrial function in SCAPs via the FOXM1/PDK1 axis. Results During the development of the first molar in the mouse's lower jaw, SSUH2 is enriched in the root tip papilla region and it is also enriched in the root tip papilla region of humans. SSUH2 positively regulated the odontogenic differentiation of SCAPs in vitro. In vivo transplantation models showed that SSUH2 overexpression enhanced the odontogenic differentiation capacity of SCAPs and promoted dentine-pulp-like structure formation. Transcriptomic and functional analyses indicated that SSUH2 maintained mitochondrial function. SSUH2 directly interacted with FOXM1, promoted its nuclear translocation, and upregulated PDK1 expression. FOXM1 silencing abrogated SSUH2-mediated enhancement of both mitochondrial function and odontogenic differentiation in SCAPs. Conclusions Our study is the first to reveal that SSUH2 promotes the odontogenic differentiation of SCAPs through the FOXM1/PDK1 axis by regulating mitochondrial function. These findings suggest that SSUH2 could serve as a potential therapeutic target for enhancing the odontogenic differentiation of SCAPs and provide a novel strategic direction for pulp-dentine complex regeneration.
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
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IF 11.3
Juan Zhan,JianHan Zhou,RunQiang Liu,ChaoChen Wu,YiHan Lai,Lin Jiang,Wei Wang,Meng Cheng,YiSen Shao
Objective : Tongue squamous cell carcinoma (TSCC) is characterized by high invasiveness and early lymph node metastasis, leading to a poor prognosis.Current surgical and chemoradiotherapy regimens often cause functional impairment, drug resistance, and other drawbacks. Thus, developing highly effective, low-toxicity treatments is a key research priority. Traditional Chinese medicine (TCM) offers unique advantages via multi-target synergistic effects, enabling innovative therapeutic approaches. Method : In this study, we developed Astragaloside IV-Brucea javanica oil nanoemulsion (AS/BJO-NEs) and characterized its stability, polydispersity, and pharmacokinetic profile. The effects of AS/BJO-NEs on TSCC cells were evaluated through a series of functional assays, including CCK-8 (viability), colony formation (proliferation), and scratch wound healing (migration). Both in vitro and in vivo experiments were performed to investigate whether its mechanism involves regulation of the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis. Results The optimized AS/BJO-NEs exhibited uniform spherical morphology at the nanoscale and demonstrated favorable stability. In both in vitro and in vivo models, AS/BJO-NEs significantly suppressed the malignant phenotype of TSCC cells. Mechanistic investigation further revealed that the anti-tumor effects of AS/BJO-NEs are mediated, at least in part, through targeting the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis, as confirmed by establishing stable MTFR2/HIF-1α knockdown and overexpression cell models. Conclusion : This study demonstrates that AS/BJO-NEs inhibit TSCC progression by targeting the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis. Our findings provide experimental evidence supporting the development of multi-target therapeutic strategies derived from traditional Chinese medicine for the treatment of TSCC.
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高影响因子
CANCER LETTERS
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2016
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IF 5.992
Renyu Lin,Ziheng Zhang,Lingfeng Chen,Yunfang Zhou,Peng Zou,Chen Feng,Li Wang,Guang Liang
Head and neck cancer is the sixth most common cancer worldwide. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, exhibits a wide range of biological roles including a highly efficient and specific anti-tumor activity. Here, we aimed to examine the effect of DHA on head and neck carcinoma cells and elucidate the potential mechanisms. We used five head and neck carcinoma cell lines and two non-tumorigenic normal epithelial cell lines to achieve our goals. Cells were exposed to DHA and subjected to cellular activity assays including viability, cell cycle analysis, cell death, and angiogenic phenotype. Our results show that DHA causes cell cycle arrest which is mediated through Forkhead box protein M1 (FOXM1). We also demonstrate that DHA induces ferroptosis and apoptosis in head and neck carcinoma cells. Lastly, our results show that DHA alters the angiogenic phenotype of cancer cells by reducing the expression of angiogenic factors and the ability of cancer cells to support endothelial cell tubule formation. Our study suggests that DHA specifically causes head and neck cancer cell death through contribution from both ferroptosis and apoptosis. DHA may represent an effective strategy in head and neck cancer treatment.
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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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2024
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IF 2.4
Xingbo Wang,Hong Huang,Wenxiu Xu,Yanling Gong,Songbo Shi,Xu Wan,Li Pengbiao
Introduction Triple negative breast cancer (TNBC) is characterized with higher malignancy and mortality and is prone to distant metastasis, among which bone is the most common site. It’s urgent to explore new strategies for treatment of TNBC and its bone metastases.Methods A tumor environment responsive vector, poly-(dimethylaminoethyl methacrylate)-SS-poly(ethylene glycol)-SS-poly-(dimethylaminoethyl methacrylate) (PDMAEMA-SS-PEG-SS-PDMAEMA), was constructed to co-delivery transforming growth factor-β1 (TGF-β1) siRNA and forkhead box M1 (FOXM1) siRNA in MDA-MB-231 cells. The preparation, characterization, in vitro release, stability, and transfection efficiency of nanoparticles were measured. Cell viability, migration and invasion of MDA-MB-231 cells were determined. Cell chemotactic migration and cell heterogeneity adhesion of MDA-MB-231 cells to the human osteoblast-like cell line MG-63 were determined.Results PDMAEMA-SS-PEG-SS-PDMAEMA self assembled with siRNA at N/P of 15:1 into nanoparticles with particle size of 122 nm. In vitro release exhibited redox and pH sensitivity, and the nanoparticles protected siRNA from degradation by RNase and serum protein, remaining stable at 4 °C with similar transfection efficiency with lipo2000. Nanoparticles co-loaded with TGF-β1 siRNA and FOXM1 siRNA inhibited the cell viability, migration and invasion of MDA-MB-231 cells, as well as chemotactic migration and heterogeneous adhesion of MDA-MB-231 cells to MG-63 cells, showing a synergetic effect. After gene silencing on TGF-β1 and FOXM1, the epithelial to mesenchymal transition (EMT) related molecules vimentin mRNA expression decreased while E-cadherin increased.Conclusion PDMAEMA-SS-PEG-SS-PDMAEMA was suitable for TGF-β1 siRNA and FOXM1 siRNA delivery, exhibiting synergetic inhibition effect on TNBC and its bone metastases, which might be related to its synergetic inhibition on EMT.
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高影响因子
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