FOOD AND CHEMICAL TOXICOLOGY
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2025
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IF 3.5
Yongjun Tang,Zhengning Feng,Chenlu Ma,Nian Jang,Xiaolong Chen,Yingxu He,Francis L. Martin,Hui Liu,Weiyi Pang
Breast cancer has a high global incidence, and benzo[ a ]pyrene (B[ a ]P) is considered a contributing factor that increases carcinogenic risk. This study examined B[ a ]P's oncogenic mechanisms in mammary epithelial cells. Chronic B[ a ]P exposure induced morphological changes and enhanced proliferative/clonogenic capacity in MCF-10A cells. Chronic B[ a ]P exposure altered gene expression in MCF-10A cells, revealing differential levels of circRNAs, lncRNAs, miRNAs, and mRNAs. qRT-PCR validation demonstrated strong alignment with RNA-seq results, ensuring sequencing reliability. Additionally, chronic B[ a ]P exposure upregulated the protein expression of AhR and ARNT, as well as TGF- β , pSmad2/3, and KRT14 , while increasing Vimentin expression and decreasing E-cadherin expression. Notably, treatment with the TGF- β inhibitor SB431542 reversed these protein expression changes in transformed cells. These results show that exposure to Chronic B[ a ]P induces MCF-10A cell transformation. The underlying mechanisms involve significant transcriptional alterations, AhR/ARNT expression regulation, TGF- β signaling pathway activation, KRT14 protein modulation, and EMT. Furthermore, Chronic B[ a ]P exposure may drive transformation through TGF- β modulation. Chronic B[ a ]P exposure promotes breast carcinogenesis, revealing mechanistic insights and potential preventive biomarkers.
研究领域:
肿瘤学
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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
Theranostics
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2025
·Vol. 15
·期 9
·3877
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IF 13.3
Yueyang Li,Yu Zhai,Tianling Wang,Siya Wang,Yu Tian,Zhiqun Bian,Yang Zhang,Chao Zhang,Minghan Liu,Changqing Li
Rationale: Nucleus pulposus (NP) fibrosis is a contributing factor to intervertebral disc degeneration (IVDD), which lacks an effective treatment. This study focuses on elucidating the role and mechanisms of the TGF-β signaling repressor SKI in NP fibrosis and exploring its therapeutic potential. Methods: Single-cell RNA sequencing (scRNA-seq) was used to investigate fibrotic nucleus pulposus cell (NPC) subsets and assess TGF-β signaling activation. Two recombinant plasmids encoding single-chain variable fragments (scFvs) targeting the fibrotic NPC marker FAP and SKI mRNA were co-transfected into HEK-293T cells to yield functionalized exosomes (EX ski+scFv ). The addition of EX ski+scFv to a gelatin/oxidized sodium alginate hydrogel produced a pH-responsive exosome/hydrogel system named Gel@EX ski+scFv . The therapeutic effects and underlying mechanism of Gel@EX ski+scFv were evaluated by RNA sequencing, molecular docking and coimmunoprecipitation. Results: A fibrotic NPC subset was characterized by elevated FAP and diminished SKI expression, along with activation of the TGF-β signaling pathway. SKI overexpression reduced fibrosis in TGF-β-treated NPCs. EX ski+scFv successfully delivered SKI mRNA to FAP-expressing fibrotic NPCs. Gel@EX ski+scFv possessed good mechanical properties, degradability, injectability, and biocompatibility. Gel@EX ski+scFv effectively alleviated NP fibrosis and IVDD in rats. RNA sequencing, molecular docking and coimmunoprecipitation revealed that SKI could interact with FOXO3 to suppress the TGF-β signaling pathway. Conclusion: This study elucidates the mechanism by which SKI -mediated TGF-β signaling inhibition alleviates NP fibrosis. The development of the Gel@EX ski+scFv system for the targeted delivery of SKI mRNA offers a promising therapeutic strategy to alleviate NP fibrosis and IVDD in the future.
研究领域:
生物医学
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分子生物学
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组织工程
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Yu-Qing Li,Xin-Ming Yu,Xue-Mei Shang,Jing-Yi Lin,Rui-Zhi Tan,Jian-Chun Li,Hong-Wei Su,Hong-Ping Shen,Hong-Lian Wang,Li Wang
Background Renal fibrosis is a hallmark of chronic kidney disease (CKD). Smad3 serves as the principal transcription factor mediating the pro-fibrosis effects of TGF-β signaling in renal fibrosis. Biochanin A (BCA), a natural isoflavone, has been shown to attenuate renal fibrosis by inhibiting TGF-β signaling but the detailed mechanisms remain unresolved. This study aimed to elucidate the specific mechanisms by which BCA modulates TGF-β signaling. Methods Renal fibrosis models were established both in vitro , using TGF-β1-stimulated mouse renal tubular TCMK1 cells, and in vivo , employing mice with unilateral ureter obstruction (UUO). RNA-seq was conducted to identify BCA-regulated genes. The AnimalTFDB4.0 database was utilized to predict transcription factors with potential binding to Smad3 promoter. The activities of TGF-β signaling and the cloned mouse Smad3 promoter were assessed using luciferase reporter assays. Plasmid transfection was performed using polyethylenimine in TCMK1 cells or ultrasound microbubbles in UUO kidneys. Gene expression was analyzed by RT-PCR, western blot, and immunohistochemistry assays. Results BCA significantly inhibited TGF-β signaling activity and suppressed TGF-β1-induced fibrotic gene expression in TCMK1 cells. RNA-seq and in silico analyses identified Smad3 as the key gene downregulated by BCA, while leaving Smad2 unaffected. This selective transcriptional suppression of Smad3 by BCA was validated by luciferase reporter assays using the cloned Smad3 promoter. Furthermore, transcription factor binding prediction identified that Klf6, a transcription factor downregulated by BCA, has binding potential to the Smad3 promoter and promotes Smad3 transcription. Klf6 expression was induced in TGF-β1-stimulated TCMK1 cells and UUO kidneys, but this induction was abolished upon BCA treatment. Importantly, Klf6 overexpression restored Smad3 expression and counteracted the anti-fibrosis effects of BCA in both TGF-β1-stimulated TCMK1 cells and UUO kidneys. Conclusion TGF-β-responsive Klf6 transcriptionally transactivates Smad3 expression. BCA exerts anti-renal fibrosis effects by inhibiting the Klf6-Smad3 signaling axis, underscoring its therapeutic potential in the treatment of CKD.
研究领域:
药理学
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分子生物学
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肾病学
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DOI
PubMed
高影响因子
INFLAMMATION
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2023
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IF 5.1
Huang Yina,Zhang Lu,Tan Lingping,Zhang Chi,Li Xiting,Wang Panpan,Gao Li,Zhao Chuanjiang
Periodontitis is a chronic inflammatory disease characterized by the destruction of tooth-supporting tissues. The gingival epithelium is the first barrier of periodontal tissue against oral pathogens and harmful substances. The structure and function of epithelial lining are essential for maintaining the integrity of the epithelial barrier. Abnormal apoptosis can lead to the decrease of functional keratinocytes and break homeostasis in gingival epithelium. Interleukin-22 is a cytokine that plays an important role in epithelial homeostasis in intestinal epithelium, inducing proliferation and inhibiting apoptosis, but its role in gingival epithelium is poorly understood. In this study, we investigated the effect of interleukin-22 on apoptosis of gingival epithelial cells during periodontitis. Interleukin-22 topical injection and Il22 gene knockout were performed in experimental periodontitis mice. Human gingival epithelial cells were co-cultured with Porphyromonas gingivalis with interleukin-22 treatment. We found that interleukin-22 inhibited apoptosis of gingival epithelial cells during periodontitis in vivo and in vitro , decreasing Bax expression and increasing Bcl-xL expression. As for the underlying mechanisms, we found that interleukin-22 reduced the expression of TGF-β receptor type II and inhibited the phosphorylation of Smad2 in gingival epithelial cells during periodontitis. Blockage of TGF-β receptors attenuated apoptosis induced by Porphyromonas gingivalis and increased Bcl-xL expression stimulated by interleukin-22. These results confirmed the inhibitory effect of interleukin-22 on apoptosis of gingival epithelial cells and revealed the involvement of TGF-β signaling pathway in gingival epithelial cell apoptosis during periodontitis.
研究领域:
牙科学
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免疫学
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细胞生物学
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2025
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IF 2.9
Chenyu Xiao,Qianru Li,Meiqi Li,Yongshu Han,Hubin Xu,Haimin Jiang,Suer Zhang,Zhen Jin,Leilei Gao
Iodoacetamide (IAcAm) is a harmful disinfection by-product. Studies have demonstrated that IAcAm can produce toxic effects in various tissues; however, its effect on female reproductive function remains unclear. To explore the effects of IAcAm on ovaries, we constructed a female mouse IAcAm toxicity model of free drinking model. The findings indicated that IAcAm exposure for five weeks did not affect the body growth of mice but increased the ovary/body weight ratio. At the tissue level, the numbers of atretic follicles increased. After the exposure, ovarian and blood samples were collected for analysis. IAcAm exposure caused changes in serum sex hormone levels, with an increase in follicle-stimulating hormone concentration(follicle-stimulating hormone) and a decrease in anti-Müllerian hormone concentration (anti-Müllerian hormone). Subsequent investigations revealed that IAcAm activated the transforming growth factor-β (TGF-β) signaling pathway and promoted ovarian fibrosis in mice. Simultaneously, IAcAm stimulated the granulosa cell apoptosis pathway and promoted granulosa cell apoptosis. Moreover, IAcAm interfered with mitochondrial function and increased reactive oxygen species, leading to a decrease in oocyte developmental potential. In conclusion, IAcAm exposure causes ovarian inflammation and leads to mitochondrial dysfunction in oocytes, affecting follicle maturation and reducing oocyte quality.
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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DOI
PubMed
高影响因子
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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DOI
PubMed
高影响因子
Cell Communication and Signaling
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2023
·Vol. 21
·期 1
·1-18
·
IF 8.4
Liao Zhaohong,Lan Haiqiang,Jian Xiaoting,Huang Jingwen,Wang Han,Hu Jijie,Liao Hua
Background To explore the role of skeletal muscle specific TGF-β signaling on macrophages efferocytosis in inflamed muscle caused by Cardiotoxin (CTX) injection. Methods CTX myoinjury was manipulated in TGF-βr2 flox/flox (control) mice or transgenic mice with TGF-β receptor 2 (TGF-βr2) being specifically deleted in skeletal muscle (SM TGF-βr2 −/− ). Gene levels of TGF-β signal molecules, special inflammatory mediators in damaged muscle or in cultured and differentiated myogenic precursor cells (MPC-myotubes) were monitored by transcriptome microarray or qRT-PCR. TGF-β pathway molecules, myokines and embryonic myosin heavy chain in regenerating myofibers, the phenotype and efferocytosis of macrophages were evaluated by immunofluorescence, immunoblotting, Luminex, or FACS analysis. In vitro apoptotic cells were prepared by UV-irradiation. Results In control mice, TGF-β-Smad2/3 signaling were significantly up-regulated in regenerating centronuclear myofibers after CTX-myoinjury. More severe muscle inflammation was caused by the deficiency of muscle TGF-β signaling, with the increased number of M1, but the decreased number of M2 macrophages. Notably, the deficiency of TGF-β signaling in myofibers dramatically affected on the ability of macrophages to conduct efferocytosis, marked by the decreased number of Annexin-V − F4/80 + Tunel + macrophages in inflamed muscle, and the impaired uptake of macrophages to PKH67 + apoptotic cells transferred into damaged muscle. Further, our study suggested that, the intrinsic TGF-β signaling directed IL-10-Vav1-Rac1 efferocytosis signaling in muscle macrophages. Conclusions Our data demonstrate that muscle inflammation can be suppressed potentially by activating the intrinsic TGF-β signaling in myofibers to promote IL-10 dependent-macrophages efferocytosis.
Video Abstract
研究领域:
免疫学
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肌肉生物学
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细胞信号传导
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炎症
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DOI
PubMed
高影响因子
LIFE SCIENCES
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2019
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IF 3.448
Dai-Yu Sun,Jia-Qi Wu,Zhi-Heng He,Ming-Fang He,Hong-Bin Sun
Aims Prostate cancer (PCa) incidence rates are rising in China currently. Cancer-associated fibroblasts (CAFs), as a major component of tumor microenvironment, are crucial for tumor progression. This study was aimed to explore the promotion effect of patient-derived CAFs on the proliferation and migration of prostate cancer cells. Main methods CAFs were isolated from tumor tissues of PCa patients. The promotion effect of CAFs on the proliferation and migration of PC-3 and LNCaP cells were evaluated in vitro and in vivo . The concentration of TGF-β1 was measured by Luminex assay. The blocking activity of LY2109761 on the promotion effect of CAFs was also evaluated. Key findings CAFs could significantly promote the proliferation and migration of PC-3 and LNCaP cells both in vitro and in vivo . TGF-β1 was identified as a highly increased factor in CAFs-CM compared with the normal culture medium of these two cancer cell lines. TGF-β receptor inhibitor LY2109761 could suppress the CAFs-induced cellular proliferation and migration of PC-3 cells but not LNCaP cells. Significance Our study suggested a crucial role for CAFs and TGF-β signaling in the progression of PCa. Zebrafish xenograft model was an ideal animal model for the study of CAFs and cancer cell interaction.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症生物学
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DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2024
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IF 27.4
Ying Kong,Xu Chen,Feng Liu,Jiageng Tang,Yijing Zhang,Xiangxiang Zhang,Luyao Zhang,Tong Zhang,Yaqi Wang,Mengxiao Su,Qixin Zhang,Hanxiang Chen,Di Zhou,Fan Yi,Hong Liu,Yi Fu
As a central metabolic molecule, nicotinamide adenine dinucleotide (NAD + ) can potentially treat acute kidney injury (AKI) and chronic kidney disease (CKD); however, its bioavailability is poor due to short half-life, instability, the deficiency of targeting, and difficulties in transmembrane transport. Here we designed a physiologically adaptive gallic acid-NAD + nanoparticle, that had ultrasmall size and pH-responsiveness, passed through the glomerular filtration membrane to reach injured renal tubules, and efficiently delivered NAD + into the kidneys. With an effective accumulation in the kidneys, it restored renal function, immune microenvironment homeostasis, and mitochondrial homeostasis of AKI mice via the NAD + -Sirt1 axis, and exerted strong antifibrotic effects on the AKI-to-CKD transition by inhibiting TGF-β signaling. It also exhibited excellent stability, biodegradable, and biocompatible properties, ensuring its long-term safety, practicality, and clinical translational feasibility. The present study shows a potential modality of mitochondrial repair and immunomodulation through nanoagents for the efficient and safe treatment of AKI and CKD. This article is protected by copyright. All rights reserved
研究领域:
肾病学
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药学
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生物医学工程
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR HISTOLOGY
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2025
·Vol. 56
·期 1
·1-14
·
IF 2.2
Ma Jinjie,Yan Jing,Su Nan,Qiu Zhengjun,Hou Huailong,Sun Jingxuan,Sun Xiangyu,Niu Yumei,He Lina
Facial nerve injuries lead to significant functional impairments and psychological distress for affected patients. Effective repair of these injuries remains a challenge. For longer nerve gaps, the regeneration outcomes after nerve grafting remain suboptimal due to limited sources and postoperative immune responses. Tissue engineering techniques are conventional methods for repairing peripheral nerve defects. This study explores the potential of dental pulp cells (DPCs) combined with stem cell factor (SCF) to enhance neurogenic differentiation and improve facial nerve regeneration. DPCs were isolated from rabbit dental pulp, the pluripotency of the cells was identified from three perspectives: osteogenic differentiation, adipogenic differentiation, and neurogenic differentiation. In vivo experiments involved injuring the buccal branch of the facial nerve in New Zealand white rabbits, followed by treatment with PBS, DPCs, SCF, or SCF + DPCs. Functional recovery was assessed over 12 weeks, with SCF + DPCs demonstrating the most significant improvement in whisker movement scores. Histomorphological evaluations revealed enhanced myelinated fiber density and axonal morphology in the SCF + DPCs group. RNA sequencing identified 608 differentially expressed genes, with enrichment in the TGF-β signaling pathway. In in vitro experiments, we demonstrated from multiple angles using Western blot analysis, Real-time quantitative polymerase chain reaction (QPCR) analysis, and immunofluorescence staining that SCF can promote the neurogenic differentiation of DPCs through the TGF-β1 signaling pathway. Our findings indicate that the combination of SCF and DPCs offers a promising strategy for enhancing facial nerve repair.
研究领域:
神经科学
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组织工程
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再生医学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2018
·Vol. 37
·期 1
·1-14
·
IF 6.217
Yao Yuyuan,Guo Qinglong,Cao Yue,Qiu Yangmin,Tan Renxiang,Yu Zhou,Zhou Yuxin,Lu Na
Background Cancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin (ART) is a sesquiterpene lactone extracted from Chinese herb qinghao, and artemether (ARM), artesunate (ARS) and dihydroartemisinin (DHA) were synthesized derivatives of artemisinin, which also have anti-malarial and anti-cancer effects such as artemisinin.Methods In this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism.Results We demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-β signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-β signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo.Conclusion sArtemisinin derivatives are potential therapeutic agents for the treatment of breast cancer.
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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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2023
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IF 6.8
Yin Zhuang,Xiangying Sun,Siting Deng,Ya Wen,Qiujin Xu,Quanquan Guan
Background Bisphenol A (BPA) is known to exhibit endocrine disrupting activities and is associated with adiposity. We examined the obesogenic effect of prenatal BPA exposure in the present study. Methods Pregnant ICR mice were exposed to vehicle or BPA via the drinking water at a dose of 0.5 μg/kg·d throughout the gestation. Obesity-related indexes were investigated in the 12-wk-old offspring. Primary mouse embryonic fibroblasts (MEFs) collected from treated embryos were used to test effects of BPA on adipocyte differentiation. Results Offspring presented a significantly higher rate of weight gain than the control, with impaired insulin sensitivity and increased adipocyte size. Differentiation of MEFs from BPA-treated mice showed a higher propensity for the adipocyte commitment as well as up-regulation of genes enriched in lipid biosynthesis. TGF-β signaling pathway was found to modulate obesogenic effect of BPA in MEF model, but estrogen signaling pathway had no effect. Conclusions The present study provides strong evidence of the association between prenatal exposure to low dose of BPA and a significant increase in body weight in the offspring mice with a critical role played by TGF-β signaling pathway. The potential interactions modulating the binding of BPA and TGF-β that activate its obesogenic effects need to be examined.
研究领域:
毒理学
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内分泌学
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发育生物学
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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）