MOLECULAR BIOLOGY REPORTS
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2024
·Vol. 51
·期 1
·1-15
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IF 2.6
Wumiti Taxi,Wang Lining,Xu Bin,Ma Yong,Zhu Yihua,Zuo Xinchen,Qian Weiqing,Chu Xudong,Sun Haitao
Background Promoting the balance between bone formation and bone resorption is the main therapeutic goal for postmenopausal osteoporosis (PMOP), and bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation plays an important regulatory role in this process. Recently, several long non-coding RNAs (lncRNAs) have been reported to play an important regulatory role in the occurrence and development of OP and participates in a variety of physiological and pathological processes. However, the role of lncRNA tissue inhibitor of metalloproteinases 3 (lncTIMP3) remains to be investigated. Methods The characteristics of BMSCs isolated from the PMOP rat model were verified by flow cytometry assay, alkaline phosphatase (ALP), alizarin red and Oil Red O staining assays. Micro-CT and HE staining assays were performed to examine histological changes of the vertebral trabeculae of the rats. RT-qPCR and western blotting assays were carried out to measure the RNA and protein expression levels. The subcellular location of lncTIMP3 was analyzed by FISH assay. The targeting relationships were verified by luciferase reporter assay and RNA pull-down assay. Results The trabecular spacing was increased in the PMOP rats, while ALP activity and the expression levels of Runx2, Col1a1 and Ocn were all markedly decreased. Among the RNA sequencing results of the clinical samples, lncTIMP3 was the most downregulated differentially expressed lncRNA, also its level was significantly reduced in the OVX rats. Knockdown of lncTIMP3 inhibited osteogenesis of BMSCs, whereas overexpression of lncTIMP3 exhibited the reverse results. Subsequently, lncTIMP3 was confirmed to be located in the cytoplasm of BMSCs, implying its potential as a competing endogenous RNA for miRNAs. Finally, the negative targeting correlations of miR-214 between lncTIMP3 and Smad4 were elucidated in vitro. Conclusion lncTIMP3 may delay the progress of PMOP by promoting the activity of BMSC, the level of osteogenic differentiation marker gene and the formation of calcium nodules by acting on the miR-214/Smad4 axis. This finding may offer valuable insights into the possible management of PMOP.
研究领域:
骨生物学
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干细胞生物学
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分子生物学
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非编码RNA
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骨质疏松症
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PubMed
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BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2016
·Vol. 120
·期 6
·560-570
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IF 3.097
Hongjun Zhang,Baoling Ju,Xiaoli Zhang,Yanfei Zhu,Ying Nie,Yuanhong Xu,Qiuxia Lei
Magnolol is a pharmacological biphenolic compound extracted from Chinese herb Magnolia officinalis , which displays anti-inflammatory and antioxidant effects. This study was aimed at exploring the potential effect of magnolol on immune-related liver fibrosis. Herein, BALB/c mice were injected with concanavalin A (ConA, 8 mg/kg/week) up to 6 weeks to establish hepatic fibrosis, and magnolol (10, 20, 30 mg/kg/day) was given to these mice orally throughout the whole experiment. We found that magnolol preserved liver function and attenuated liver fibrotic injury in vivo . In response to ConA stimulation, the CD4 + T cells preferred to polarizing towards CD4 + T helper 17 (Th17) cells in liver. Magnolol was observed to inhibit Th17 cell differentiation in ConA-treated liver in addition to suppressing interleukin (IL)-17A generation. Hepatic stellate cells were activated in fibrotic liver as demonstrated by increased alpha smooth muscle actin (α-SMA) and desmin. More transforming growth factor (TGF)-β1 and activin A were secreted into the serum. Magnolol suppressed this abnormal HSC activation. Furthermore, the phosphorylation of Smad3 in its linker area (Thr179, Ser 204/208/213) was inhibited by magnolol. In vitro , the recombinant IL-17A plus TGF-β1 or activin A induced activation of human LX2 HSCs and promoted their collagen production. Smad3/Smad4 signalling pathway was activated in LX2 cells exposed to the fibrotic stimuli, as illustrated by the up-regulated phospho-Smad3 and the enhanced interaction between Smad3 and Smad4. These alterations were suppressed by magnolol. Collectively, our study reveals a novel antifibrotic effect of magnolol on Th17 cell-mediated fibrosis.
研究领域:
药理学
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免疫学
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肝病学
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细胞生物学
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PubMed
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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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EXPERIMENTAL AND MOLECULAR PATHOLOGY
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2026
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IF 4.1
Ziqing Zhou,Shaoming Wu,Xiaoran Zhang,Guanbin Chen,Hengyue Ma,Ming Li,Yuchuan Liu,Ting Wang
Resveratrol (RSV), a globally utilized nutraceutical compound, is primarily recognized for its human health benefits, contributing to its widespread and often unregulated use in daily life and clinical settings. However, its influence on cellular stemness remains poorly understood. While numerous reports suggest anti-tumor properties, systematic and robust evidence is lacking. This study employed high-throughput RNA sequencing, RNA interference, RT-qPCR, and whole-mount in situ hybridization, and used the planarian Dugesia japonica as a stem cell model, aiming to investigate the effects of varying RSV concentrations on blastema regeneration following amputation and analyze the associated mechanism. We demonstrated a biphasic effect of RSV on anterior blastema regeneration: low-concentration RSV (5 μM) promoted regeneration, whereas high-concentration RSV (50 μM) caused significant inhibition. RNA-seq identified Smad4 as a key mediator; its inhibition exacerbated the regenerative deficit under low concentration. Intriguingly, PiwiA expression increased in the anterior blastema at both RSV concentrations, most notably at low concentration condition. Conversely, the late stem cell marker Agat1 was significantly suppressed by high-concentration RSV. These findings indicated that RSV promoted stem cell proliferation. Critically, low-concentration RSV enhanced both proliferation and differentiation, while high-concentration RSV inhibited differentiation independently of Smad4 . This study provided the first in vivo evidence at the whole-organism level that RSV concentration dictated divergent stem cell differentiation fates, offering a scientific basis for its rational evaluation and application.
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Molecular Medicine Reports
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2015
·Vol. 12
·期 1
·192-198
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IF 1.554
Jinpeng Li,Hao Liu,Jieping Yu,Honggang Yu
Doxorubicin (Dox) is a commonly used chemotherapeutic drug in human colon cancer. However, it becomes increasingly ineffective with tumor progression, the underlying mechanism of which remains to be elucidated. Emerging evidence has led to the identification of an association between chemoresistance and the acquisition of epithelial‑mesenchymal transition (EMT) in cancer. However, it remains to be elucidated whether this process is involved in the development of resistance to Dox in colon cancer. In HCT116 human colon cancer cells treated with Dox (50 nmol/l), EMT was induced, and transforming growth factor (TGF)β signaling and multi‑drug resistant plasma membrane glycoprotein levels were significantly increased. By contrast, silencing of Smad4, using stable RNA interference, inhibited TGFβ signaling, reversed the process of EMT and markedly increased the sensitivity of HCT116 cells to Dox. The results of the present study suggested that the combination of Dox with the downregulation of TGFβ signaling may be a potential novel therapeutic strategy with which to overcome chemoresistance during colon cancer chemotherapy.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2018
·Vol. 175
·期 15
·3111-3130
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IF 6.81
Siming Yu,Linna Li,Wei Tian,Dan Nie,Wei Mu,Fang Qiu,Yu Liu,Xinghan Liu,Xiaofeng Wang,Zhimin Du,Wen-Feng Chu,Baofeng Yang
Background and Purpose PEP06, a polypeptide modified from endostatin, was investigated for its antitumour effects on colorectal cancer (CRC) and the possible mechanisms of this antitumour activity were examined in in vitro and in vivo models. Experimental Approach After PEP06 treatment, cell proliferation and migration assays were performed in CRC cells. Epithelial–mesenchymal transition (EMT) progression was determined by Western blotting, immunofluorescent staining and immunohistochemistry in vitro and in a residual xenograft model. MiRNAs regulated by PEP06 were identified by miRNA microarray and verified by in situ hybridization and quantitative real-time PCR. The interactions between PEP06 and integrin αvβ3 were determined with Biacore SA biochips. The cellular function of miR-146b-5p was validated by gain-of-function and loss-of-function approaches. A mouse model of lung metastasis was used to determine the effect of PEP06 on metastatic growth. Key Results PEP06 did not affect cell viability but reduced migration and EMT in SW620 and HCT116 cells. PEP06 significantly repressed the expression of miR-146b-5p in these two cell lines through binding to integrin αvβ3. MiR-146b-5p was shown to increase EMT by targeting Smad4, and the miR-146b-5p-Smad4 cascade regulated EMT in CRC. PEP06 also suppressed CRC pulmonary metastasis, increased survival of mice and hampered residual tumour growth by inhibiting EMT through down-regulating miR-146b-5p. Conclusions and Implications PEP06 is a polypeptide that inhibits the growth and metastasis of colon cancer through its RGD motif binding to integrin αvβ3, thereby down-regulating miR-146b-5p to inhibit EMT in vitro and in vivo . It might have potential as a therapeutic for CRC.
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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高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2022
·
IF 14.224
Tianyu Gao,Bingbing Sun,Zhenbiao Xu,Qiaoyun Chen,Meng Yang,Qinli Wan,Linxia Song,Guo Chen,Chunxia Jing,Eddy Y. Zeng,Guang Yang
The potential adverse effects of microplastics (MPs) on ecosystems and human health have received much attention in recent years. However, only limited data are available on the mechanisms for the uptake, distribution, and effects of MPs in freshwater organisms , especially with respect to tissue repair, regeneration and impairment of stem cell functions. To address this knowledge gap, we conducted exposure experiments in which planarians ( Dugesia japonica ) were exposed to polystyrene (PS)-MPs mixed in liver homogenate and examined the tissue growth and regeneration, stem cell functions, and oxidative stress . The body and blastema areas decreased upon exposure to PS-MPs, indicating that the growth and regeneration of planarians were delayed. The proliferation and differentiation processes of stem cells were inhibited, and the proportion of mitotic stem cells decreased, which may be related to the activation of the TGFβ/SMAD4 and Notch signaling pathways. The enhancement of antioxidant enzyme activities and malondialdehyde on the first day of exposure to PS-MPs confirmed the oxidative stress response of planarians to PS-MPs. The present study demonstrated the likelihood of biotoxicity induced by PS-MPs. These results will provide clues for further investigations into the potential risks of PS-MPs to human stem cells.
研究领域:
生态学
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毒理学
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细胞生物学
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Manman Yuan,Jing Ye,Xiangqiao Sun,Zhiwu Tong,Tingting Wang,Renxiang Tan,Xingxin Wu
Acaudiolide ameliorates liver fibrosis in mice • Acaudiolide inhibits TGF-β1/SMAD signaling in HSCs • Acaudiolide inhibits the nuclear translocation of p-SMAD2/3 • Acaudiolide weakens the interaction between SMAD4 and p-SMAD2/3 • SMAD4 is a candidate covalent target of acaudiolide Hepatic stellate cell (HSC) activation is a central driver of fibrosis progression in metabolic dysfunction-associated steatohepatitis (MASH), yet effective antifibrotic pharmacotherapies remain limited. Here, we identify acaudiolide, a sulfur-bridged symmetric dimeric macrodiolide isolated from the fungus Acaulium sp. H-JQSF, as a natural-product lead that suppresses HSC activation and experimental liver fibrosis. In a Western diet (WD)/CCl 4 murine model of MASH, acaudiolide reduced collagen deposition, alpha-smooth muscle actin (α-SMA) expression and fibrogenic gene expression. Transcriptomic profiling of HSCs showed that acaudiolide antagonized transforming growth factor-β1 (TGF-β1)-driven profibrotic programs. Mechanistically, acaudiolide did not measurably alter SMAD2/3 phosphorylation but markedly reduced the nuclear accumulation of phosphorylated SMAD2/3 (p-SMAD2/3). Integration of Connectivity Map (CMap) analysis with isotopic tandem orthogonal proteolysis-activity-based protein profiling (isoTOP-ABPP) chemical proteomics nominated SMAD4 as a candidate covalent target of acaudiolide. Covalent docking suggested Cys363 as a potential engagement site, and co-immunoprecipitation showed that acaudiolide weakened the association of SMAD4 with p-SMAD2/3. These findings support a model in which acaudiolide interferes with SMAD complex assembly, thereby attenuating TGF-β-dependent profibrotic transcription and HSC activation. Collectively, our data nominate acaudiolide as a preclinical antifibrotic lead and SMAD4 as a potentially tractable downstream node for pharmacological modulation of TGF-β signaling in MASH-related fibrosis. Download: Download high-res image (386KB) Download: Download full-size image
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CHEMOSPHERE
·
2020
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IF 5.778
Jing Li,Xiao-jie Quan,Gang Chen,Jia-wei Hong,Qi Wang,Lin-lin Xu,Bing-hua Wang,Ze-hua Yu,Hong-Min Yu
Perfluorooctane sulfonic acid (PFOS), a persistent environmental pollutant, has been associated with decreased birth weight. The dysregulation of long non-coding RNA (lncRNA) H1 9 has been implicated in pregnancy complications such as intra-uterine growth retardation (IUGR), preeclampsia (PE), however, the expression and function of H19 in PFOS-exerted detrimental effects in the placenta remains to be unveiled. Here, we explored the role of H19 in PFOS-induced placental toxicity. Results showed that PFOS caused decreased cell growth in human HTR-8/SVneo cells. Expression of H19 was increased, while miR-19a and miR-19b expression were decreased in mice placenta tissues and in HTR-8/SVneo cells exposed to PFOS. A significant hypomethylation was observed at the H19 promoter in the placentas of mice that were gestational exposed to high dose of PFOS. H19 was confirmed to bind with miR-19a and miR-19b, targeting SMAD4 . Furthermore, H19 appeared to partially improve the cell growth of HTR-8/SVneo cells exposed to PFOS via upregulation of miR-19a and miR-19b. In summary, our findings revealed that H1 9/miR-19a and miR-19b/SMAD4 axis exerted important functions in PFOS-induced placenta cell toxicity.
研究领域:
毒理学
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分子生物学
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生殖健康
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PubMed
高影响因子
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